ALS Research Journal News - January 2013

This summary includes some of the most recent advances in ALS research. If you would like particular news items featured, or have questions, please contact researchgrants@alsa-national.org

Quick Summary:

This month brings a wealth of clinical/genetic news, including that lower C9ORF72 repeat numbers than previously thought can lead to frontotemporal neurodegeneration, and that the gene was not found in this one sample of Parkinson’s disease patients, but does occur in rare cases of Alzheimer’s disease. Elsewhere, copper chelators mitigated the effect of SOD1 mutations, and most SOD1 mutations expose a binding site on the protein for derlin-1, a component of the endoplasmic reticulum homeostatic system.

Feature News Story

• SOD1 Mutations Expose ER Protein Binding Site

Cellular, Molecular, and Genetic Research

SOD1 and Results from SOD1 Models

• Dysregulation of intracellular copper homeostasis is common to transgenic mice expressing human mutant superoxide dismutase-1s regardless of their copper-binding abilities.
• Early interneuron dysfunction in ALS: Insights from a mutant SOD1 zebrafish model.
• Effect of Sex on Lifespan, Disease Progression, and the Response to Methionine Sulfoximine in the SOD1 G93A Mouse Model for ALS.
• Extracellular aggregated Cu/Zn superoxide dismutase activates microglia to give a cytotoxic phenotype.
• A novel monoclonal antibody reveals a conformational alteration shared by amyotrophic lateral sclerosis-linked SOD1 mutants.
• RNA-Seq Profiling of Spinal Cord Motor Neurons from a Presymptomatic SOD1 ALS Mouse.
• Widespread aggregation of mutant VAPB associated with ALS does not cause motor neuron degeneration or modulate mutant SOD1 aggregation and toxicity in mice.
• Also of Interest

C9ORF72 and Results from C9ORF72 Models

• The product of C9orf72, a gene strongly implicated in neurodegeneration, is structurally related to DENN Rab-GEFs.
• Also of Interest

TDP-43 and Results from TDP-43 Models

• Reduced expression of BTBD10 in anterior horn cells with Golgi fragmentation and pTDP-43-positive inclusions in patients with sporadic amyotrophic lateral sclerosis.
• Loss and gain of Drosophila TDP-43 impairs synaptic efficacy and motor control leading to age-related neurodegeneration by loss-of-function phenotypes.
• Full-length TDP-43 and its C-terminal fragments activate mitophagy in NSC34 cell line.
• High-content RNAi screening identifies the Type 1 inositol triphosphate receptor as a modifier of TDP-43 localization and neurotoxicity.
• Calcium Channel Agonists Protect against Neuromuscular Dysfunction in a Genetic Model of TDP-43 Mutation in ALS.
• Also of Interest

FUS and Results from FUS Models

• RNA-binding ability of FUS regulates neurodegeneration, cytoplasmic mislocalization and incorporation into stress granules associated with FUS carrying ALS-linked mutations.
• FUS stimulates microRNA biogenesis by facilitating co-transcriptional Drosha recruitment.
• Also of Interest

Stem Cells and Stem Cell Models

• Direct lineage reprogramming of post-mitotic callosal neurons into corticofugal neurons in vivo. Rouaux C, Arlotta P.
• Multimodal Actions of Neural Stem Cells in a Mouse Model of ALS: A Meta-Analysis.
• Accelerated High-Yield Generation of Limb-Innervating Motor Neurons from Human Stem Cells.
• Amyotrophic lateral sclerosis model derived from human embryonic stem cells overexpressing mutant superoxide dismutase 1.

Other Cellular, Molecular, and Genetic Results

• Loss of ERLIN2 function leads to juvenile primary lateral sclerosis.
• Identification of epigenetically altered genes in sporadic amyotrophic lateral sclerosis.
• Meta-analysis of gene expression profiling in amyotrophic lateral sclerosis: A comparison between transgenic mouse models and human patients.
• Spliceosome Integrity is Defective in the Motor Neuron Diseases ALS and SMA.
• Altered localization, abnormal modification and loss of function of Sigma receptor-1 in amyotrophic lateral sclerosis.
• Neurodegenerative diseases: Quantitative predictions of protein-RNA interactions.
• NeuroDNet - an open source platform for constructing and analyzing neurodegenerative disease networks.
• Also of Interest

Clinical Research and Drug Development

Epidemiology

• Severe head injury and amyotrophic lateral sclerosis.
• Association between extremely low-frequency electromagnetic fields occupations and amyotrophic lateral sclerosis: a meta-analysis.
• Is exposure to cyanobacteria an environmental risk factor for amyotrophic lateral sclerosis and other neurodegenerative diseases?
• Intakes of vitamin C and carotenoids and risk of amyotrophic lateral sclerosis: Pooled results from 5 cohort studies

Neuroimaging

• Upper motor neuron involvement in amyotrophic lateral sclerosis evaluated by triple stimulation technique and diffusion tensor MRI.
• Molecular imaging of microglial activation in amyotrophic lateral sclerosis.
• Diffusion tensor imaging patterns differ in bulbar and limb onset amyotrophic lateral sclerosis.

Clinical Genetics and Genetic Testing

• C9ORF72 Repeat Expansions in the Frontotemporal Dementias Spectrum of Diseases: A Flowchart for Genetic Testing
• Truncating mutations in FUS/TLS give rise to a more aggressive ALS-phenotype than missense mutations: a clinico-genetic study in Germany.
• C9ORF72 hexanucleotide expansions of 20-22 repeats are associated with frontotemporal deterioration.
• Investigation of C9orf72 repeat expansions in Parkinson's disease.
• Repeat expansions in the C9ORF72 gene contribute to Alzheimer's disease in Caucasians.
• TARDBP mutations in Parkinson's disease.
• Ataxin-1 and ataxin-2 intermediate-length PolyQ expansions in amyotrophic lateral sclerosis.
• ZNF512B gene is a prognostic factor in patients with amyotrophic lateral sclerosis.

Clinical Trials and Treatment

• Overview, hurdles, and future work in adaptive designs: perspectives from a National Institutes of Health-funded workshop.
• Expressive disclosure to improve well-being in patients with amyotrophic lateral sclerosis: A randomized, controlled trial.

Preclinical Therapy Development

• CDP-choline is not protective in the SOD1-G93A mouse model of ALS.
• Therapeutic Potential of N-Acetyl-Glucagon-Like Peptide-1 in Primary Motor Neuron Cultures Derived From Non-Transgenic and SOD1-G93A ALS Mice.
• Bone marrow transplantation in hind limb muscles of motoneuron degenerative mice reduces neuronal death and improves motor function.
• Also of Interest  

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Feature News Story

SOD1 Mutations Expose ER Protein Binding Site

Most SOD1 mutations expose a site on the protein that binds to an endoplasmic reticulum protein, derlin-1, according to new research, and mutant toxicity is correlated with derlin-1 binding.

The authors had previously shown that three ALS-causing SOD1 mutants (A4V, G85R, and G93A) bind to the cytosolic carboxyterminal region of derlin-1. Here, they extended that work by showing the same phenomenon in 124 of 132 known SOD1 mutants. “Derlin-1 is a component of the ER-associated degradation (ERAD machinery, and is required for retrotranslocation of unfolded proteins from the ER lumen to the cytosol,” they explain. Those SOD1 mutants that bound derlin-1 caused ER stress and increased motor neuron death, while mutants that did not bind derlin-1 did not.

Mapping of the derlin-1 binding site indicated it was located in the first 14 residues of the C-terminal end of SOD1. The authors created a monoclonal antibody to the site, termed MS785, and used it to further explore binding site exposure. The antibody recognized all derlin-binding mutants except those with point mutations in the epitope region. It did not recognize 5 of the 8 non-derlin-binding mutants. The antibody also precipitated SOD1 from 14 ALS patients with SOD1 mutations, but not 3 healthy controls.

Finally, they showed that serum starvation of cells in culture induced a mutant-like conformation of wild-type SOD1 protein.

“Our findings suggest that ALS-linked pathogenic SOD1 mutations induce a common conformational change in SOD1 that eventually leads to motor neuron toxicity,” they conclude.

A novel monoclonal antibody reveals a conformational alteration shared by amyotrophic lateral sclerosis-linked SOD1 mutants.
Fujisawa T, Homma K, Yamaguchi N, Kadowaki H, Tsuburaya N, Naguro I, Matsuzawa A, Takeda K, Takahashi Y, Goto J, Tsuji S, Nishitoh H, Ichijo H.
Ann Neurol. 2012 Nov;72(5):739-49. doi: 10.1002/ana.23668.  

Cellular, Molecular, and Genetic Research 

SOD1 and Results from SOD1 Models

Dysregulation of intracellular copper homeostasis is common to transgenic mice expressing human mutant superoxide dismutase-1s regardless of their copper-binding abilities.
Tokuda E, Okawa E, Watanabe S, Ono SI, Marklund SL.
Neurobiol Dis. 2013 Jan 12. doi:pii: S0969-9961(13)00013-2. 10.1016/j.nbd.2013.01.001. [Epub ahead of print]
Loss of copper regulation may contribute to ALS due to SOD1 mutation, and reducing copper may be therapeutic, according to this study. “We show that copper dyshomeostasis is common to SOD1 mutants. The SOD1 mutants shifted the copper trafficking systems toward copper accumulation in spinal cords of the mice...Ammonium tetrathiomolybdate (TTM), a copper chelating agent, prolonged survival and slowed the disease progression of SOD1(G93A) mice, even when the treatment was started after the disease onset. TTM markedly attenuated pathology, including the loss of motor neurons and axons, and atrophy of skeletal muscles. Additionally, TTM decreased amounts of SOD1 aggregates.”

Early interneuron dysfunction in ALS: Insights from a mutant sod1 zebrafish model.
McGown A, McDearmid JR, Panagiotaki N, Tong H, Al Mashhadi S, Redhead N, Lyon AN, Beattie CE, Shaw PJ, Ramesh TM.
Ann Neurol. 2012 Oct 1. doi: 10.1002/ana.23780. [Epub ahead of print]
Interneurons are affected early, and riluzole mitigates damage to them, according to this report. “We show that mutant SOD1 fish first exhibited the heat shock response in glycinergic interneurons at 24 hours postfertilization (hpf). By 96 hpf, we observed a significant reduction in spontaneous glycinergic currents induced in spinal motor neurons. … Riluzole, the only approved ALS drug and apomorphine, an NRF2 activator, reduced the observed early neuronal stress response.”

Effect of Sex on Lifespan, Disease Progression, and the Response to Methionine Sulfoximine in the SOD1 G93A Mouse Model for ALS.
Bame M, Pentiak PA, Needleman R, Brusilow WS.
Gend Med. 2012 Dec;9(6):524-35. doi: 10.1016/j.genm.2012.10.014.
Reduced levels of male sex hormones is protective in ALS mice, according to this report. “Methionine sulfoximine (MSO) treatment improves the survival of both male and female mice, but the effects are significantly greater on female mice. Saline-treated (control) female mice have delayed neuromuscular degeneration compared with saline-treated male mice, and MSO further delays disease progression in females, to a greater extent than in males. Ovariectomization or castration completely eliminates the effect of the drug on either survival or neuromuscular deterioration.”

Extracellular aggregated Cu/Zn superoxide dismutase activates microglia to give a cytotoxic phenotype.
Roberts K, Zeineddine R, Corcoran L, Li W, Campbell IL, Yerbury JJ.
Glia. 2012 Dec 22. doi: 10.1002/glia.22444. [Epub ahead of print]
SOD1 aggregates stimulate microglia to become cytotoxic, according to this study. Microglia are believed to contribute to ALS pathogenesis. “We found that aggregated SOD1 was able to much more efficiently activate microglia in culture when compared with the unaggregated form of mutant SOD1.”

RNA-Seq Profiling of Spinal Cord Motor Neurons from a Presymptomatic SOD1 ALS Mouse.
Bandyopadhyay U, Cotney J, Nagy M, Oh S, Leng J, Mahajan M, Mane S, Fenton WA, Noonan JP, Horwich AL.
PLoS One. 2013;8(1):e53575. doi: 10.1371/journal.pone.0053575. Epub 2013 Jan 3.
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Wild-type and SOD1 mice have similar messenger RNA profiles, according to this study, indicating that the explanation for SOD1’s pathogenic effect lies elsewhere.  “We observed only a small number of transcripts with altered expression levels or splicing in the G85R transgenic compared to age-matched animals of a wild-type SOD1 transgenic strain. Our results indicate that a major disturbance of polyadenylated RNA metabolism does not occur in motor neurons of mutant SOD1 mice, suggesting that the toxicity of the mutant protein lies at the level of translational or post-translational effects.”

Widespread aggregation of mutant VAPB associated with ALS does not cause motor neuron degeneration or modulate mutant SOD1 aggregation and toxicity in mice.
Qiu L, Qiao T, Beers M, Tan W, Wang H, Yang B, Xu Z.
Mol Neurodegener. 2013 Jan 3;8(1):1. doi: 10.1186/1750-1326-8-1.
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Rare ALS-causing mutations in VAPB do not cause disease through either protein accumulation or by exacerbating SOD1 toxicity, according to this study. “Overexpression of VAPBP56S mutant to approximately two-fold of the endogenous VAPB in mouse spinal cord produced abundant VAPB aggregates but was not sufficient to cause motor dysfunction or motor neuron degeneration. Furthermore, overexpression of either muVAPB or wtVAPB does not modulate the course of ALS in SOD1G93A mice. These results suggest that changes in wild type VAPB do not play a significant role in ALS cases that are not caused by VAPB mutations. Furthermore, these results suggest that muVAPB aggregates are innocuous and do not cause motor neuron degeneration by a gain-of-toxicity, and therefore, a loss of function may be the underlying mechanism.”

Also of Interest:

Gene expression profile of SOD1-G93A mouse spinal cord, blood and muscle.
Saris CG, Groen EJ, Van Vught PW, van Es MA, Blauw HM, Veldink JH, van den Berg LH.
Amyotroph Lateral Scler Frontotemporal Degener. 2013 Jan 8. [Epub ahead of print]

Altered astrocytic response to activation in SOD1(G93A) mice and its implications on amyotrophic lateral sclerosis pathogenesis.
Benkler C, Ben-Zur T, Barhum Y, Offen D.
Glia. 2012 Dec 22. doi: 10.1002/glia.22428. [Epub ahead of print]

Disulfide scrambling describes the oligomer formation of SOD1 proteins in the familial form of ALS.
Toichi K, Yamanaka K, Furukawa Y.
J Biol Chem. 2012 Dec 21. [Epub ahead of print]
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C9ORF72 and Results from C9ORF72 Models

The product of C9orf72, a gene strongly implicated in neurodegeneration, is structurally related to DENN Rab-GEFs
Levine TP, Daniels RD, Gatta AT, Wong LH, Hayes MJ.
Bioinformatics. 2013 Jan 16. [Epub ahead of print]
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The function of the protein product of the C9ORF72 gene is unknown. The authors report that it is related to a protein that regulates membrane traffic. “Sensitive homology searches showed that C9ORF72 is a full-length distant homologue of proteins related to Differentially Expressed in Normal and Neoplasia (DENN), which is a GDP/GTP exchange factor (GEF) that activates Rab-GTPases. Our results suggest that C9ORF72 is likely to regulate membrane traffic in conjunction with Rab-GTPase switches, and we propose to name the gene and its product DENN-like 72 (DENNL72).”

Also of Interest:

C9orf72 hexanucleotide repeat associated with amyotrophic lateral sclerosis and frontotemporal dementia forms RNA G-quadruplexes.
Fratta P, Mizielinska S, Nicoll AJ, Zloh M, Fisher EM, Parkinson G, Isaacs AM.
Sci Rep. 2012;2:1016. doi: 10.1038/srep01016. Epub 2012 Dec 21.
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TDP43 and Results from TDP43 Models

Reduced expression of BTBD10 in anterior horn cells with Golgi fragmentation and pTDP-43-positive inclusions in patients with sporadic amyotrophic lateral sclerosis.
Furuta N, Makioka K, Fujita Y, Ikeda M, Takatama M, Matsuoka M, Okamoto K.
Neuropathology. 2013 Jan 16. doi: 10.1111/neup.12010. [Epub ahead of print]
Previous work has shown that suppressing the protein BTB10 increases motor neuron death, and overexpressing it reduces motor neuron loss in animal models. Here, the authors examine levels in ALS patients. “Spinal cords from 13 patients with sporadic ALS and 10 with non-ALS disorders were immunostained using a polyclonal anti-BTBD10 antibody. Reduced BTBD10 expression in the anterior horn cells was more frequent in spinal cords from ALS patients…[In ALS patient spinal cords,] whereas 89.7-96.5% of the neurons with normal BTBD10 immunoreactivity showed normal Golgi apparatus morphology and no pTDP-43 cytoplasmic aggregates, 86.2-94.3% of the neurons with reduced BTBD10 expression showed GA fragmentation and abnormal pTDP-43 aggregates. These findings suggest that reduced BTBD10 expression is closely linked to the pathogenesis of sporadic ALS.”

Loss and gain of Drosophila TDP-43 impair synaptic efficacy and motor control leading to age-related neurodegeneration by loss-of-function phenotypes.
Diaper DC, Adachi Y, Sutcliffe B, Humphrey DM, Elliott CJ, Stepto A, Ludlow ZN, Broeck LV, Callaerts P, Dermaut B, Al-Chalabi A, Shaw CE, Robinson IM, Hirth F.
Hum Mol Genet. 2013 Jan 10. [Epub ahead of print]
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“Both loss and gain of TBPH [the fly form of TDP-43] severely affect development and result in premature lethality….Prolonged loss and gain of TBPH in adults resulted in synaptic defects and age-related, progressive degeneration of neurons involved in motor control.”

Full-length TDP-43 and its C-terminal fragments activate mitophagy in NSC34 cell line.
Hong K, Li Y, Duan W, Guo Y, Jiang H, Li W, Li C.
Neurosci Lett. 2012 Nov 21;530(2):144-9. doi: 10.1016/j.neulet.2012.10.003. Epub 2012 Oct 9.
“Overexpression of TDP-43 and its C-terminal fragments resulted in mitochondrial damage. In addition, full-length TDP-43 and truncated TDP-43 were localized in the mitochondria, where autophagy was activated…. These studies suggest that human TDP-43 and its C-terminal fragments may cause mitochondrial dysfunction and enhance mitophagy.”

High-content RNAi screening identifies the Type 1 inositol triphosphate receptor as a modifier of TDP-43 localization and neurotoxicity.
Kim SH, Zhan L, Hanson KA, Tibbetts RS.
Hum Mol Genet. 2012 Nov 15;21(22):4845-56. doi: 10.1093/hmg/dds321. Epub 2012 Aug 7.
The authors identify a cell-surface receptor as a potential therapeutic target, based on results showing that reducing its action helps clear TDP-43. “Knockdown or chemical inhibition of the type 1 inositol-1,4,5-trisphosphate (IP3) receptor (ITPR1) induced TDP-43 nuclear export in immortalized cells and primary neurons and strongly potentiated the recruitment of TDP-43 to Ubiquilin-positive autophagosomes, suggesting that diminished ITPR1 function leads to autophagosomal clearance of TDP-43. The functional significance of the TDP-43-ITPR1 genetic interaction was tested in Drosophila, where mutant alleles of ITPR1 were found to significantly extended lifespan and mobility of flies expressing TDP-43 under a motor neuron driver. These combined findings implicate IP3-gated Ca(2+) as a key regulator of TDP-43 nucleoplasmic shuttling and proteostasis and suggest pharmacologic inhibition of ITPR1 as a strategy to combat TDP-43-induced neurodegeneration in vivo.”

Calcium Channel Agonists Protect against Neuromuscular Dysfunction in a Genetic Model of TDP-43 Mutation in ALS.
Armstrong GA, Drapeau P.
J Neurosci. 2013 Jan 23;33(4):1741-52. doi: 10.1523/JNEUROSCI.4003-12.2013.
Drugs that stimulate calcium channels may be therapeutic in ALS, according to this study. “Here we expressed the wild-type human gene (wtTARDBP) or the ALS mutation G348C (mutTARDBP) in zebrafish larvae and characterized their motor (swimming) activity and the structure and function of their neuromuscular junctions (NMJs). Of these groups only mutTARDBP larvae showed impaired swimming and increased motoneuron vulnerability with reduced synaptic fidelity, reduced quantal transmission, and more orphaned presynaptic and postsynaptic structures at the NMJ. Remarkably, all behavioral and cellular features were stabilized by chronic treatment with either of the L-type calcium channel agonists FPL 64176 or Bay K 8644. These results indicate that expression of mutTARDBP results in defective NMJs and that calcium channel agonists could be novel therapeutics for ALS.”

Also of Interest:

Glucocorticoids Exacerbate Cognitive Deficits in TDP-25 Transgenic Mice via a Glutathione-Mediated Mechanism: Implications for Aging, Stress and TDP-43 Proteinopathies.
Caccamo A, Medina DX, Oddo S.
J Neurosci. 2013 Jan 16;33(3):906-13. doi: 10.1523/JNEUROSCI.3314-12.2013.

Premature death of TDP-43 (A315T) transgenic mice due to gastrointestinal complications prior to development of full neurological symptoms of amyotrophic lateral sclerosis.
Esmaeili MA, Panahi M, Yadav S, Hennings L, Kiaei M.
Int J Exp Pathol. 2013 Feb;94(1):56-64. doi: 10.1111/iep.12006.

A role for calpain-dependent cleavage of TDP-43 in amyotrophic lateral sclerosis pathology.
Yamashita T, Hideyama T, Hachiga K, Teramoto S, Takano J, Iwata N, Saido TC, Kwak S.
Nat Commun. 2012 Dec 18;3:1307. doi: 10.1038/ncomms2303.

Abnormal Regenerative Responses and Impaired Axonal Outgrowth after Nerve Crush in TDP-43 Transgenic Mouse Models of Amyotrophic Lateral Sclerosis.
Swarup V, Audet JN, Phaneuf D, Kriz J, Julien JP.
J Neurosci. 2012 Dec 12;32(50):18186-95. doi: 10.1523/JNEUROSCI.2267-12.2012.

 

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FUS and Results from FUS Models

RNA-binding ability of FUS regulates neurodegeneration, cytoplasmic mislocalization and incorporation into stress granules associated with FUS carrying ALS-linked mutations.
Daigle JG, Lanson NA Jr, Smith RB, Casci I, Maltare A, Monaghan J, Nichols CD, Kryndushkin D, Shewmaker F, Pandey UB.
Hum Mol Genet. 2013 Jan 11. [Epub ahead of print]
Loss of RNA binding precents toxicity of otherwise pathogenic FUS mutations, this study reports. “[We] generated RNA-binding-incompetent FUS mutants with and without ALS-causing mutations (R518K or R521C). …We observed that these RNA-binding mutations block neurodegenerative phenotypes seen in the fly brains, eyes and motor neurons compared with the expression of RNA-binding-competent FUS carrying ALS-causing mutations.…Incorporation of mutant FUS into the stress granule compartment is dependent on the RNA-binding ability of FUS.”

Truncating mutations in FUS/TLS give rise to a more aggressive ALS-phenotype than missense mutations: a clinico-genetic study in Germany.
Waibel S, Neumann M, Rosenbohm A, Birve A, Volk AE, Weishaupt JH, Meyer T, Müller U, Andersen PM, Ludolph AC.
Eur J Neurol. 2012 Dec 6. doi: 10.1111/ene.12031. [Epub ahead of print]
“Mutations in FUS/TLS account for 8.7% (16 of 184) of FALS in Germany. This is a higher prevalence than reported from other countries. Truncating FUS/TLS mutations result in a more severe phenotype than most missense mutations. The wide phenotypic differences have implications for genetic counseling.

FUS stimulates microRNA biogenesis by facilitating co-transcriptional Drosha recruitment.
Morlando M, Dini Modigliani S, Torrelli G, Rosa A, Di Carlo V, Caffarelli E, Bozzoni I.
EMBO J. 2012 Dec 12;31(24):4502-10. doi: 10.1038/emboj.2012.319.
“We show that the FUS protein…contributes to the biogenesis of a specific subset of microRNAs. Among them, species with roles in neuronal function, differentiation and synaptogenesis were identified.”

Also of Interest:
FUS binds the CTD of RNA polymerase II and regulates its phosphorylation at Ser2.
Schwartz JC, Ebmeier CC, Podell ER, Heimiller J, Taatjes DJ, Cech TR.
Genes Dev. 2012 Dec 15;26(24):2690-5. doi: 10.1101/gad.204602.112.

 

Stem Cells and Stem Cell Models

Direct lineage reprogramming of post-mitotic callosal neurons into corticofugal neurons in vivo.
Rouaux C, Arlotta P.
Nat Cell Biol. 2013 Jan 20. doi: 10.1038/ncb2660. [Epub ahead of print]
Neurons of one type can be transformed into another type even after birth, according to this study. The results may have significance for ALS, since the final neuronal type in this study is a predecessor of motor neurons. “We show that embryonic and early postnatal callosal projection neurons of layer II/III can be post-mitotically lineage reprogrammed into layer-V/VI corticofugal projection neurons following expression of the transcription factor encoded by Fezf2. Reprogrammed callosal neurons acquire molecular properties of corticofugal projection neurons and change their axonal connectivity from interhemispheric, intracortical projections to corticofugal projections directed below the cortex.”

Multimodal Actions of Neural Stem Cells in a Mouse Model of ALS: A Meta-Analysis.
Teng YD, Benn SC, Kalkanis SN, Shefner JM, Onario RC, Cheng B, Lachyankar MB, Marconi M, Li J, Yu D, Han I, Maragakis NJ, Lládo J, Erkmen K, Redmond DE Jr, Sidman RL, Przedborski S, Rothstein JD, Brown RH Jr, Snyder EY.
Sci Transl Med. 2012 Dec 19;4(165):165ra164. doi: 10.1126/scitranslmed.3004579.
Stem cell therapy may offer real benefits in ALS, according to this analysis of published studies. “On the basis of a meta-analysis of 11 independent studies performed by a consortium of ALS investigators, we propose that transplanted [undifferentiated multipotent migratory] neural stem cells (both mouse and human) can slow both the onset and the progression of clinical signs and prolong survival in ALS mice, particularly if regions sustaining vital functions such as respiration are rendered chimeric. The beneficial effects of transplanted NSCs seem to be mediated by a number of actions including their ability to produce trophic factors, preserve neuromuscular function, and reduce astrogliosis and inflammation. We conclude that the widespread, pleiotropic, modulatory actions exerted by transplanted NSCs may represent an accessible therapeutic application of stem cells for treating ALS and other untreatable degenerative diseases."

Accelerated High-Yield Generation of Limb-Innervating Motor Neurons from Human Stem Cells.
Amoroso MW, Croft GF, Williams DJ, O'Keeffe S, Carrasco MA, Davis AR, Roybon L, Oakley DH, Maniatis T, Henderson CE, Wichterle H.
J Neurosci. 2013 Jan 9;33(2):574-586.
“We report a combination of small molecules that within 3 weeks induce motor neurons [from human pluripotent stem cells] at up to 50% abundance and with defined subtype identities of relevance to neurodegenerative disease [which] exhibited spontaneous and induced activity, and projected axons toward muscles when grafted into developing chick spinal cord. Strikingly, this novel protocol preferentially generates motor neurons expressing markers of limb-innervating lateral motor column motor neurons.”

Amyotrophic lateral sclerosis model derived from human embryonic stem cells overexpressing mutant superoxide dismutase 1.
Wada T, Goparaju SK, Tooi N, Inoue H, Takahashi R, Nakatsuji N, Aiba K.
Stem Cells Transl Med. 2012 May;1(5):396-402. doi: 10.5966/sctm.2011-0061. Epub 2012 May 8.
“We report the establishment of an in vitro FALS model from human embryonic stem cells overexpressing either a wild-type (WT) or a mutant SOD1 (G93A) gene [exhibiting] (a) selective degeneration of spinal motor neurons expressing the G93A SOD1 but not those expressing the WT gene; (b) susceptibility of G93A SOD1-derived sMNs to form ubiquitinated inclusions; (c) astrocyte-derived factor(s) in the selective degeneration of G93A SOD1 sMNs; and (d) cell-autonomous, as well as non-cell-autonomous, dependent sMN degeneration.”  

Other Cellular, Molecular, and Genetic Results

Loss of ERLIN2 function leads to juvenile primary lateral sclerosis.
Al-Saif A, Bohlega S, Al-Mohanna F.
Ann Neurol. 2012 Oct;72(4):510-6. doi: 10.1002/ana.23641.
“In this study, we identify mutation of the ERLIN2 gene in juvenile PLS patients and describe an in vitro model for loss of ERLIN2 function….The identification of mutation in another component of the ER lipid rafts in juvenile PLS patients emphasizes their role in motor neuron function.”

Identification of epigenetically altered genes in sporadic amyotrophic lateral sclerosis.
Figueroa-Romero C, Hur J, Bender DE, Delaney CE, Cataldo MD, Smith AL, Yung R, Ruden DM, Callaghan BC, Feldman EL.
PLoS One. 2012;7(12):e52672. doi: 10.1371/journal.pone.0052672. Epub 2012 Dec 26.
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Spinal cord tissue of sporadic ALS patients displays changes in gene methylation and transcription, according to this study. Methylation is a gene regulatory change that reduces transcription, and the results suggest that sALS tissue undergoes a predictable change in gene expression during the disease.  “Integration of methylomics and transcriptomics data successfully revealed methylation changes in sALS spinal cord. This study represents an initial identification of epigenetic regulatory mechanisms in sALS which may improve our understanding of sALS pathogenesis for the identification of biomarkers and new therapeutic targets.”

Meta-analysis of gene expression profiling in amyotrophic lateral sclerosis: A comparison between transgenic mouse models and human patients.
Saris CG, Groen EJ, Koekkoek JA, Veldink JH, Van Den Berg LH.
Amyotroph Lateral Scler Frontotemporal Degener. 2013 Jan 4. [Epub ahead of print]
“We provide a meta-analysis of the reported significant gene lists of gene expression studies in ALS, and compare results between mouse models and human post mortem tissue….Evidence was found for shared dysfunction in protein turnover in the ubiquitin-proteasome system. Differential expression of Cathepsin B and D, GFAP and SERPINA3 was repeatedly found to be significant in both the mouse model and ALS patients.”

Spliceosome Integrity is Defective in the Motor Neuron Diseases ALS and SMA.
Tsuiji H, Iguchi Y, Furuya A, Kataoka A, Hatsuta H, Atsuta N, Tanaka F, Hashizume Y, Akatsu H, Murayama S, Sobue G, Yamanaka K.
EMBO Mol Med. 2012 Dec 19. doi: 10.1002/emmm.201202303. [Epub ahead of print]
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Two proteins linked to ALS bind to the spinal muscular atrophy protein SMN to maintain the spliceosome, according to this study. The spliceosome is the site of RNA editing. “Here, we show that TDP-43 and FUS/TLS localize in nuclear Gems through an association with SMN, and that all three proteins function in spliceosome maintenance. We also show that in ALS, Gems are lost, U snRNA levels are up-regulated and spliceosomal U snRNPs abnormally and extensively accumulate in motor neuron nuclei, but not in the temporal lobe of FTLD with TDP-43 pathology. This aberrant accumulation of U snRNAs in ALS motor neurons is in direct contrast to SMA motor neurons, which show reduced amounts of U snRNAs, while both have defects in the spliceosome.”

Altered localization, abnormal modification and loss of function of Sigma receptor-1 in amyotrophic lateral sclerosis.
Prause J, Goswami A, Katona I, Roos A, Schnizler M, Bushuven E, Dreier A, Buchkremer S, Johann S, Beyer C, Deschauer M, Troost D, Weis J.
Hum Mol Genet. 2013 Jan 11. [Epub ahead of print]
The sigma 1 receptor is a chaperone protein found on the endoplasmic reticulum that regulates calcium signaling. This study finds loss of SigR1 signaling in ALS. “Levels of the sigma receptor 1 protein were reduced in lumbar ALS patient spinal cord. SigR1 was abnormally accumulated in enlarged C-terminals and endoplasmic reticulum (ER) structures of alpha motor neurons....shRNA knockdown of SigR1 lead to deranged calcium signaling and caused abnormalities in ER and Golgi structures in cultured NSC-34 cells. Finally, pharmacological activation of SigR1 induced the clearance of mutant protein aggregates in these cells.”

Neurodegenerative diseases: Quantitative predictions of protein-RNA interactions.
Cirillo D, Agostini F, Klus P, Marchese D, Rodriguez S, Bolognesi B, Tartaglia GG.
RNA. 2013 Feb;19(2):129-40. doi: 10.1261/rna.034777.112. Epub 2012 Dec 21.
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“We recently introduced a theoretical framework, catRAPID, to predict the binding ability of protein and RNA molecules. Here, we use catRAPID to investigate ribonucleoprotein interactions linked to inherited intellectual disability, amyotrophic lateral sclerosis, Creutzfeuld-Jakob, Alzheimer's, and Parkinson's diseases.”

NeuroDNet - an open source platform for constructing and analyzing neurodegenerative disease networks.
Vasaikar SV, Padhi AK, Jayaram B, Gomes J.
BMC Neurosci. 2013 Jan 3;14(1):3. [Epub ahead of print]
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“NeuroDNet is a database with interactive tools that enables the creation of interaction networks for twelve neurodegenerative diseases under one portal for interrogation and analyses. It is the first of its kind, which enables the construction and analysis of neurodegenerative diseases through protein interaction networks, regulatory networks and Boolean networks….NeuroDNet is accessible at http://bioschool.iitd.ac.in/NeuroDNet/ “

Also of Interest:

Immunoexpression of gemins 2 and 4 in the rat spinal cord. Is the SMN complex a new target in investigations of sporadic amyotrophic lateral sclerosis pathogenesis?
Rafałowska J, Sulejczak D, Gadamski R, Dziewulska D.
Folia Neuropathol. 2012;50(4):390-6.

Acidotoxicity and acid-sensing ion channels contribute to motoneuron degeneration.
Behan AT, Breen B, Hogg M, Woods I, Coughlan K, Mitchem M, Prehn JH.
Cell Death Differ. 2013 Jan 11. doi: 10.1038/cdd.2012.158. [Epub ahead of print]

Protein SUMOylation, an emerging pathway in Amyotrophic Lateral Sclerosis.
Dangoumau A, Veyrat-Durebex C, Blasco H, Praline J, Corcia P, Andres CR, Vourc'h P.
Int J Neurosci. 2013 Jan 4. [Epub ahead of print]

Detection of a novel frameshift mutation and regions with homozygosis within ARHGEF28 gene in familial amyotrophic lateral sclerosis.
Droppelmann CA, Wang J, Campos-Melo D, Keller B, Volkening K, Hegele RA, Strong MJ.
Amyotroph Lateral Scler Frontotemporal Degener. 2013 Jan 4. [Epub ahead of print]

mTOR dysfunction contributes to vacuolar pathology and weakness in valosin-containing protein associated inclusion body myopathy.
Ching JK, Elizabeth SV, Ju JS, Lusk C, Pittman SK, Weihl CC.
Hum Mol Genet. 2013 Jan 10. [Epub ahead of print]

Keap1 is localized in neuronal and glial cytoplasmic inclusions in various neurodegenerative diseases.
Tanji K, Maruyama A, Odagiri S, Mori F, Itoh K, Kakita A, Takahashi H, Wakabayashi K.
J Neuropathol Exp Neurol. 2013 Jan;72(1):18-28. doi: 10.1097/NEN.0b013e31827b5713.  

Clinical Research and Drug Development   

Epidemiology

Severe head injury and amyotrophic lateral sclerosis.
Peters TL, Fang F, Weibull CE, Sandler DP, Kamel F, Ye W.
Amyotroph Lateral Scler Frontotemporal Degener. 2013 Jan 4. [Epub ahead of print]
Severe head injury may increase risk of ALS, but only in the short term, according to this study. “The study included 4004 ALS patients identified from the Swedish Patient Register during follow-up and 20,020 randomly selected controls matched by gender and birth year…There was an association of ALS risk with severe head injury ≤ 1 year before diagnosis (OR: 3.9, 95% CI 2.6-6.1). No association was observed for severe head injury > 3 years before ALS diagnosis, nor was ALS associated with subtypes of head injury or repeated injuries occurring > 3 years before diagnosis.”

Association between extremely low-frequency electromagnetic fields occupations and amyotrophic lateral sclerosis: a meta-analysis.
Zhou H, Chen G, Chen C, Yu Y, Xu Z.
PLoS One. 2012;7(11):e48354. doi: 10.1371/journal.pone.0048354. Epub 2012 Nov 26.
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Long-term exposure to certain types of electrical fields may raise the risk of ALS, according to this report, although this is not seen in all study types. “Occupational exposure to extremely low-frequency electromagnetic fields was significantly associated with increased risk of ALS in pooled studies (RR = 1.29, 95%CI = 1.02-1.62), and case-control studies (OR = 1.39, 95%CI = 1.05-1.84), but not cohort studies (RR = 1.16, 95% CI = 0.80-1.69).” Workers exposed to such fields include electricians, telephone installers and repairers, “and persons operating electrical equipment such as welders, carpenters, and machinists.”

Is exposure to cyanobacteria an environmental risk factor for amyotrophic lateral sclerosis and other neurodegenerative diseases?
Bradley WG, Borenstein AR, Nelson LM, Codd GA, Rosen BH, Stommel EW, Cox PA.
Amyotroph Lateral Scler Frontotemporal Degener. 2013 Jan 4. [Epub ahead of print]
“Recent evidence has strengthened the theory that chronic environmental exposure to the neurotoxic amino acid β-N-methylamino-L-alanine (BMAA) produced by cyanobacteria may be an environmental risk factor for ALS. Here we describe methods that may be used to assess exposure to cyanobacteria, and hence potentially to BMAA, namely an epidemiologic questionnaire and direct and indirect methods for estimating the cyanobacterial load in ecosystems.”

Intakes of vitamin C and carotenoids and risk of amyotrophic lateral sclerosis: Pooled results from 5 cohort studies
Fitzgerald KC, O'Reilly EJ, Fondell E, Falcone GJ, McCullough ML, Park Y, Kolonel LN, Ascherio A
Ann Neurol Article first published online: 29 JAN 2013 | DOI: 10.1002/ana.23820
Consumption of foods high in carotenoids may help prevent or delay onset of ALS, according to a new study. Carotenoids are antioxidant and antiinflammatory compounds found in orange-colored vegetables such as carrots and sweet potatoes, as well as dark green vegetables such as spinach. Among pooled studies of over one million individuals, a total of 1,153 ALS deaths occurred. “A greater total major carotenoids intake was associated with a reduced risk of ALS (pooled, multivariate-adjusted RR for the highest to the lowest quintile = 0.75, 95% confidence interval [CI] = 0.61–0.91, p for trend = 0.004). Individually, higher dietary intakes of β-carotene and lutein were inversely associated with ALS risk. The pooled multivariate RRs comparing the highest to the lowest quintile for β-carotene and lutein were 0.85 (95% CI = 0.64–1.13, p for trend = 0.03) and 0.79 (95% CI = 0.64–0.96, p for trend = 0.01), respectively. Lycopene, β-cryptoxanthin, and vitamin C were not associated with reduced risk of ALS.”

 

Neuroimaging

Upper motor neuron involvement in amyotrophic lateral sclerosis evaluated by triple stimulation technique and diffusion tensor MRI.
Furtula J, Johnsen B, Frandsen J, Rodell A, Christensen PB, Pugdahl K, Fuglsang-Frederiksen A.
J Neurol. 2013 Jan 9. [Epub ahead of print]
An imaging technique may be useful as a biomarker for ALS, according to this study. “Triple stimulation technique amplitude and area ratio were used as an estimate of the degree of central motor conduction failure. DTI fractional anisotropy was used as a quantitative measure of the structural integrity of the corticospinal tract and the posterior limb of the internal capsule. Mean TST amplitude and area ratio were lower in patients than controls, while there were no differences in mean fractional anisotropy of the corticospinal tract or the posterior limb of the internal capsule. …Our findings indicate that TST has a significant diagnostic value as an early objective marker of UMN degeneration in ALS, while the value of DTI analysis seems limited.”

Molecular imaging of microglial activation in amyotrophic lateral sclerosis.
Corcia P, Tauber C, Vercoullie J, Arlicot N, Prunier C, Praline J, Nicolas G, Venel Y, Hommet C, Baulieu JL, Cottier JP, Roussel C, Kassiou M, Guilloteau D, Ribeiro MJ.
PLoS One. 2012;7(12):e52941. doi: 10.1371/journal.pone.0052941. Epub 2012 Dec 31.
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Activation of microglia can be imaged in ALS, and occurs early, according to this study. “We evaluated neuroinflammation in ALS patients using a radioligand of [18 kDa translocator protein] TSPO, (18)F-DPA-714. … microglial activation was found in the ALS sample in primary motor, supplementary motor and temporal cortex (p = 0.009, p = 0.001 and p = 0.004, respectively). These results suggested that the cortical uptake of (18)F-DPA-714 was increased in ALS patients during the "time of diagnosis" phase of the disease.”

Diffusion tensor imaging patterns differ in bulbar and limb onset amyotrophic lateral sclerosis.
Prell T, Peschel T, Hartung V, Kaufmann J, Klauschies R, Bodammer N, Kollewe K, Dengler R, Grosskreutz J.
Clin Neurol Neurosurg. 2012 Dec 21. doi:pii: S0303-8467(12)00609-9. 10.1016/j.clineuro.2012.11.031. [Epub ahead of print]
“In ALS patients, an increased diffusivity in the white matter was found below the precentral gyrus and along the corticospinal tract (CST) right into the internal capsule. The fractional anisotropy was decreased in the posterior limb of internal capsule and in the subcortical white matter in the precentral gyrus. In bulbar onset increased diffusivity was found in the CST, whilst in limb onset, frontal subcortical areas displayed an increased diffusivity.”

 

Clinical Genetics and Genetic Testing

C9ORF72 hexanucleotide expansions of 20-22 repeats are associated with frontotemporal deterioration.
Gómez-Tortosa E, Gallego J, Guerrero-López R, Marcos A, Gil-Neciga E, Sainz MJ, Díaz A, Franco-Macías E, Trujillo-Tiebas MJ, Ayuso C, Pérez-Pérez J.
Neurology. 2013 Jan 2. [Epub ahead of print]
Frontotemporal dementia from C9ORF72 expansion occurs at lower repeat numbers than previously thought, according to this study. “A screening of our cohort of cases with FTD (n = 109) revealed 4 mutation carriers (>30 repetitions) but also 5 probands with 20-22 confirmed repetitions….No different patterns were found in the clinical phenotype or aggressiveness of the disease when comparing cases with long or short expansions….None of 216 controls had alleles with more than 14 repetitions.”

C9ORF72 Repeat Expansions in the Frontotemporal Dementias Spectrum of Diseases: A Flowchart for Genetic Testing.
Le Ber I, Camuzat A, Guillot-Noel L, Hannequin D, Lacomblez L, Golfier V, Puel M, Martinaud O, Deramecourt V, Rivaud-Pechoux S, Millecamps S, Vercelletto M, Couratier P, Sellal F, Pasquier F, Salachas F, Thomas-Antérion C, Didic M, Pariente J, Seilhean D, Ruberg M, Wargon I, Blanc F, Camu W, Michel BF, Berger E, Sauvée M, Thauvin-Robinet C, Mondon K, Tournier-Lasserve E, Goizet C, Fleury M, Viennet G, Verpillat P, Meininger V, Duyckaerts C, Dubois B, Brice A.
J Alzheimers Dis. 2012 Dec 19. [Epub ahead of print]
One in eight patients with non-familial FTD-ALS may carry repeat expansions in the C9ORF72 gene, arguing for more widespread genetic testing, according to this study. “C9ORF72 was analyzed in 833 bvFTD, FTD-ALS, PPA, and PSP/CBDS probands; 202 patients from 151 families carried an expansion…. The frequency of carriers in non-familial FTD-ALS (12.7%) indicates that C9ORF72 should be analyzed even when family history is negative…. A flowchart for genetic testing is thus proposed.”

Investigation of C9orf72 repeat expansions in Parkinson's disease.
Daoud H, Noreau A, Rochefort D, Paquin-Lanthier G, Gauthier MT, Provencher P, Pourcher E, Dupré N, Chouinard S, Jodoin N, Soland V, Fon EA, Dion PA, Rouleau GA.
Neurobiol Aging. 2012 Dec 27. doi:pii: S0197-4580(12)00613-6. 10.1016/j.neurobiolaging.2012.11.025. [Epub ahead of print]
Despite reports that parkinsonian symptoms are associated with ALS-FTD from C9ORF72 mutation, “No pathologic expansion was found in our cohort of [Parkinson’s disease] patients suggesting that C9orf72 repeat expansions do not play a major role in the pathogenesis of Parkinson's disease.”

Repeat expansions in the C9ORF72 gene contribute to Alzheimer's disease in Caucasians.
Kohli MA, John-Williams K, Rajbhandary R, Naj A, Whitehead P, Hamilton K, Carney RM, Wright C, Crocco E, Gwirtzman HE, Lang R, Beecham G, Martin ER, Gilbert J, Benatar M, Small GW, Mash D, Byrd G, Haines JL, Pericak-Vance MA, Züchner S.
Neurobiol Aging. 2012 Oct 27. doi:pii: S0197-4580(12)00493-9. 10.1016/j.neurobiolaging.2012.10.003. [Epub ahead of print]
“We found C9ORF72 expansions in the pathogenic range of FTD/ALS (>30 repeats) at a proportion of 0.76% in AD cases versus 0 in control subjects (p = 3.3E-03; 1182 cases, 1039 controls)…. In the range of normal variation of C9ORF72 expansions (0-23 repeat copies), we detected significant differences in distribution and mean repeat counts between Caucasians and African Americans.”

TARDBP mutations in Parkinson's disease.
Rayaprolu S, Fujioka S, Traynor S, Soto-Ortolaza AI, Petrucelli L, Dickson DW, Rademakers R, Boylan KB, Graff-Radford NR, Uitti RJ, Wszolek ZK, Ross OA.
Parkinsonism Relat Disord. 2012 Dec 8. doi:pii: S1353-8020(12)00436-1. 10.1016/j.parkreldis.2012.11.003. [Epub ahead of print]
“Herein we report the presence of a TDP-43 mutation in a patient with a clinical diagnosis of Parkinson's disease.”

Ataxin-1 and ataxin-2 intermediate-length PolyQ expansions in amyotrophic lateral sclerosis.
Conforti FL, Spataro R, Sproviero W, Mazzei R, Cavalcanti F, Condino F, Simone IL, Logroscino G, Patitucci A, Magariello A, Muglia M, Rodolico C, Valentino P, Bono F, Colletti T, Monsurrò MR, Gambardella A, La Bella V.
Neurology. 2012 Dec 11;79(24):2315-2320. Epub 2012 Nov 28.
The ataxin genes cause a variety of ataxia disorders when expanded beyond 35 repeat units (“polyQ” expansions). Here, the authors assess the effect of shorter expansions on the risk for ALS. “We assessed the PolyQ lengths of ATXN-1 and ATXN-2 in 405 patients with sALS, 13 patients with fALS, and 296 unrelated controls without history of neurodegenerative disorders. We found significantly higher intermediate PolyQ expansions ≥32 for ATXN-1 alleles and ≥28 for ATXN-2 alleles in the sALS cohort (ATXN-1: ALS, 7.07% vs controls, 2.38%; p = 0.0001; ATXN-2: ALS, 2.72% vs controls, 0.5%; p = 0.001).”

ZNF512B gene is a prognostic factor in patients with amyotrophic lateral sclerosis.
Tetsuka S, Morita M, Iida A, Uehara R, Ikegawa S, Nakano I.
J Neurol Sci. 2013 Jan 15;324(1-2):163-6. doi: 10.1016/j.jns.2012.10.029. Epub 2012 Nov 17.
“ZNF512B…is a transcription factor promoting the expression of a downstream gene in the signal transduction pathway of the transforming growth factor-β (TGF-β), which is essential for the protection and survival of neurons…We conducted a retrospective analysis of the ZNF512B gene in 176 patients diagnosed as having ALS at our hospital. Evaluation of the prognosis after the onset using Kaplan-Meier survival curves in patients with versus without the risk allele (C allele: CC and CT genotypes) revealed a significantly lower survival probability in those with the risk allele (log-rank test, P

 

Clinical Trials and Treatment

Overview, hurdles, and future work in adaptive designs: perspectives from a National Institutes of Health-funded workshop.
Coffey CS, Levin B, Clark C, Timmerman C, Wittes J, Gilbert P, Harris S.
Clin Trials. 2012;9(6):671-80. doi: 10.1177/1740774512461859.
“Adaptive clinical trial designs, … provide the flexibility to adjust trial characteristics on the basis of data reviewed at interim stages….We organized the Scientific Advances in Adaptive Clinical Trial Designs Workshop to begin a conversation about using ADs in publicly funded research….[We] provide a brief overview of ADs, describe the rationale behind conducting the workshop, and summarize the main recommendations that were produced as a result of this workshop.”

Expressive disclosure to improve well-being in patients with amyotrophic lateral sclerosis: A randomised, controlled trial.
Averill AJ, Kasarskis EJ, Segerstrom SC.
Psychol Health. 2013 Jan 7. [Epub ahead of print]
Expressive disclosure involves either writing or speaking about stressful or traumatic events over a period of three or four days. “Expressive disclosure may help people with ALS, particularly those who are emotionally or socially inhibited, meet psychological challenges associated with the disease. …Results of multi-level models indicated that the group that disclosed thoughts and feelings about ALS had higher well-being than the control group at three months post-intervention, but not six months.”

 

Preclinical Therapy Development

CDP-choline is not protective in the SOD1-G93A mouse model of ALS.
Knippenberg S, Skripuletz T, Rath KJ, Thau N, Gudi V, Pul R, Körner S, Dengler R, Stangel M, Petri S.
Amyotroph Lateral Scler Frontotemporal Degener. 2013 Jan 4. [Epub ahead of print]
“Cytidine 5-diphosphocholine (CDP-choline) has recently been reported to have neuroprotective effects in animal models for neurodegenerative diseases… In this study we administered either CDP-choline or vehicle to transgenic SOD1-G93A mice….None of the behavioural motor function tests revealed differences between groups and no differences in motor neuron survival, astrocytosis or myelination were detected by histological analyses.”

Therapeutic Potential of N-Acetyl-Glucagon-Like Peptide-1 in Primary Motor Neuron Cultures Derived From Non-Transgenic and SOD1-G93A ALS Mice.
Sun H, Knippenberg S, Thau N, Ragancokova D, Körner S, Huang D, Dengler R, Döhler K, Petri S.
Cell Mol Neurobiol. 2012 Dec 28. [Epub ahead of print]
PMID:23271639 [PubMed - as supplied by publisher]
“GLP-1 has initially been studied as a treatment for type II diabetes based on its function as insulin secretagogue. We detected neuroprotective effects of N-ac-GLP-1 in our in vitro system, which could be attributed to an attenuation of intracellular calcium transients.”

Bone marrow transplantation in hindlimb muscles of motoneuron degenerative mice reduces neuronal death and improves motor function.
Pastor D, Viso-León M, Botella-Lopez A, Jaramillo-Merchán J, Moraleda JM, Jones J, Martinez S.
Stem Cells Dev. 2013 Jan 2. [Epub ahead of print]“We transplanted bone marrow cells into a mouse model of motoneuron degeneration, with the particularity of placing the cells in the hind limb muscles rather than in the spinal cord where neuronal degeneration occurs…the mice significantly improved their motor functions. This coincided with an increased number of motoneurons innervating the treated muscle compared to the neurons innervating the non-treated contralateral symmetric muscle. Also, we detected an increase in GDNF in the spinal cord.”

Also of Interest:

Identification of pharmacological targets in amyotrophic lateral sclerosis through genomic analysis of deregulated genes and pathways.
Paratore S, Pezzino S, Cavallaro S.
Curr Genomics. 2012 Jun;13(4):321-33. doi: 10.2174/138920212800793366.
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Mutations in the gene encoding p62 in Japanese patients with amyotrophic lateral sclerosis.
Hirano M, Nakamura Y, Saigoh K, Sakamoto H, Ueno S, Isono C, Miyamoto K, Akamatsu M, Mitsui Y, Kusunoki S.
Neurology. 2013 Jan 9. [Epub ahead of print]