ALS Research Journal News - November 2012

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

Quick Summary:

Feature News Story

• SOD1 in CSF May be a Marker for Response to SOD1-lowering Therapy

Cellular, Molecular, and Genetic Research

• Somatic Brain Transgenic Mice Expressing FUS as a Model for ALS and FTLD
• Reduction of Contact Between FUS and Transportin Correlates with Disease Duration
• FUS is Methylated by PRMT1
• TDP-43 May Play a Role at the Synapse
• TDP-43, FUS Promote Polyglutamine Toxicity
• Increasing Ataxin-2 Decreases Nuclear Localization of mutant FUS and TDP-43
• Blocking Apoptosis Promoter c-abl Prolongs SOD1 Mouse Lifespan
• ALS-related Angiogenin Mutations Alter Catalytic Activity
• A Second Ribonuclease Associated with ALS
• Micro RNAs and Guamanian ALS
• SOD1 and BMAA
• Disruption of Proteasomes, but not Autophagy, Replicates ALS
• Autophagy Activated by TDP-43 Overexpression
• TDP-43 and Inositol Triphosphate Receptor
• Deletion of Galectin-3, a Carbohydrate-binding Lectin, Worsens Mouse Disease Progression
• Senataxin Has a Role in Replication
• Oculomotor Neuron Transcriptional Profiling
• Hox5 Genes Required for Phrenic Motor Neuron Development and Survival

Also of Interest

• Second ER Lipid Gene Implicated in Motor Neuron Disease
• New Profilin 1 Mutation
• Population Study of ALS Genes in Italy
• Ubiquilin-2 Mutations in 2% of Familial ALS
• PMA and ALS Gene Overlap
• No Evidence of C9ORF72 mutations in Parkinson's Disease
• Multiple Sclerosis and C9ORF72 ALS
• C9ORF72 in Alzheimer’s Disease

Clinical Research and Drug Development

• Blockade of Overexpressed Calcium Channels is Therapeutic in ALS Mice
• Spasticity in ALS Linked to Serotonergic Neurodegeneration
• Immune Markers Correlate with Progression and Survival in Patients
• C9ORF72 Prognosis

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Reviews  

Feature News Story

SOD1 in CSF May be a Marker for Response to SOD1-lowering Therapy

Antisense therapy to lower levels of SOD1 in the brain and spinal cord has emerged as a promising therapeutic strategy for ALS. Antibody-based anti-SOD1 strategies are also in development. An important challenge for any therapy targeting SOD1 is to be able to measure decline in the protein over time, and to distinguish that decline from natural variation in SOD1 levels within the central nervous system.

Because cerebrospinal fluid is accessible and relatively safe to obtain compared to brain or spinal cord tissue, researchers sought to determine if CSF SOD1 could serve as a marker for response to antisense therapy against SOD1. The study was led by Timothy Miller, MD, PhD, of Washington University in Saint Louis, who was funded in part by The ALS Association.

To address that challenge, researchers first established that antisense therapy reliably lowered CSF SOD1 in SOD1-transgenic rats in parallel with reductions in CNS tissue. They found that brain protein declined by 48%, CSF protein declined by 42%, results that “strongly suggest that measurements from human CSF samples may be a viable surrogate for knockdown in the human brain and spinal cord.”

They next explored whether, in humans, how natural levels of SOD1 varied over time in ALS patients, other neurologic controls, and healthy controls. They found that SOD1 levels were elevated in both ALS and other neurologic diseases, and that in ALS, they did not correlate with either severity or rate of progression.

“Although there was substantial variability among individuals’ absolute levels of CSF SOD1, there was surprisingly little variability within individuals over time (mean [SD] variation, 7.1% [5.7%]),” over approximately 2 years, they wrote. “The maximum variation between any 2 points for a given participant was 21%. Among the 55 total time points, there were 4 instances of variability greater than 15%. Given that within the same individual, SOD1 varies little over time, CSF SOD1 measurements are likely to accurately reflect the effects of an SOD1-lowering therapy rather than the natural variability of SOD1 metabolism or of the measurement itself.”
http://www.ncbi.nlm.nih.gov/pubmed/23147550
Winer L, Srinivasan D, Chun S, Lacomis D, Jaffa M, Fagan A, Holtzman DM, Wancewicz E, Bennett CF, Bowser R, Cudkowicz M, Miller TM. SOD1 in Cerebral Spinal Fluid as a Pharmacodynamic Marker for Antisense Oligonucleotide Therapy. Arch Neurol. 2012 Nov 12:1-7. doi: 10.1001/jamaneurol.2013.593. [Epub ahead of print]  

Cellular, Molecular, and Genetic Research

Somatic Brain Transgenic Mice Expressing FUS as a Model for ALS and FTLD
Mice expressing mutant FUS, delivered through recombinant adeno-associated virus (rAAV) somatic gene transfer,” recapitulated many aspects of FUS proteinopathies, including insoluble FUS, basophilic and eosiniphilic NCIs, and other pathologic markers,” according to the authors, suggesting these mice “will provide a valuable platform for dissecting the pathogenic mechanism of FUS mutations”.
http://www.ncbi.nlm.nih.gov/pubmed/23046583
Verbeeck C, Deng Q, Dejesus-Hernandez M, Taylor G, Ceballos-Diaz C, Kocerha J, Golde TE, Das P, Rademakers R, Dickson DW, Kukar T. Expression of Fused in sarcoma mutations in mice recapitulates the neuropathology of FUS proteinopathies and provides insight into disease pathogenesis. Mol Neurodegener. 2012 Oct 10;7(1):53. [Epub ahead of print]

Reduction of Contact Between FUS and Transportin Correlates with Disease Duration
Crystallography and binding affinity measurements of FUS and its nuclear-import binding partner transportin indicate that ALS-associated mutations “caused a decreased affinity and the range of this reduction varied widely from 1.4-fold over 700-fold. The affinity of the mutants correlated with the extent of impaired nuclear localization, and more importantly, with the duration of disease progression in ALS patients.”
http://www.ncbi.nlm.nih.gov/pubmed/23056579
Niu C, Zhang J, Gao F, Yang L, Jia M, Zhu H, Gong W. FUS-NLS/Transportin 1 Complex Structure Provides Insights into the Nuclear Targeting Mechanism of FUS and the Implications in ALS. PLoS One. 2012;7(10):e47056. doi: 10.1371/journal.pone.0047056. Epub 2012 Oct 8.

FUS is Methylated by PRMT1
A yeast two-hybrid screen found that protein arginine methyltransferase 1 (PRMT1) is a binding partner for FUS, primarily in the nucleus, and FUS is methylated by PRMT1. Altering the expression or activity of PRMT1 altered slightly the nucleus-cytoplasmic ratio of FUS/TLS, and mutant FUS partially co-localized in the cytoplasm with PRMT1.
http://www.ncbi.nlm.nih.gov/pubmed/23152885
Yamaguchi A, Kitajo K. The Effect of PRMT1-Mediated Arginine Methylation on the Subcellular Localization, Stress Granules, and Detergent-Insoluble Aggregates of FUS/TLS. PLoS One. 2012;7(11):e49267. doi: 10.1371/journal.pone.0049267. Epub 2012 Nov 13.

TDP-43 May Play a Role at the Synapse
Identification of RNA bound to TDP-43 protein from mouse brain led to identification of RNAs from multiple functional groupings, including synaptic function, a finding confirmed by immunohistochemistry of TDP-43 protein at the presynaptic membrane of axon terminals in the neuromuscular junction in mice.
http://www.ncbi.nlm.nih.gov/pubmed/23134510
Narayanan RK, Mangelsdorf M, Panwar A, Butler TJ, Noakes PG, Wallace RH. Identification of RNA bound to the TDP-43 ribonucleoprotein complex in the adult mouse brain. Amyotroph Lateral Scler. 2012 Oct 24. [Epub ahead of print]

TDP-43, FUS Promote Polyglutamine Toxicity
“Genetic loss of function mutations for nematode orthologues of TDP-43 or FUS reduced behavioural defects and neurodegeneration caused by huntingtin exon-1 with expanded polyglutamines. siRNA against TDP-43 or FUS reduced cell death caused by mutant huntingtin. Moreover, we found that TDP-43 and the survival factor progranulin genetically interact to regulate polyglutamine toxicity in C. elegans and mammalian cells. Altogether our data point towards a conserved function for TDP-43 and FUS in promoting polyglutamine toxicity and that delivery of progranulin may have therapeutic benefits.”
http://www.ncbi.nlm.nih.gov/pubmed/23172908
Tauffenberger A, Chitramuthu BP, Bateman A, Bennett HP, Parker JA. Reduction of polyglutamine toxicity by TDP-43, FUS and Progranulin in Huntington's Disease models. Hum Mol Genet. 2012 Nov 19. [Epub ahead of print]

Increasing Ataxin-2 Decreases Nuclear Localization of mutant FUS and TDP-43
“These data indicate that increased ataxin-2 impairs the assembly of TDP-43 and FUS into mRNP granules, leading to an aberrant distribution of RNA-binding proteins. Consequently, these sequences may exacerbate the impairment of the RNA-quality control system mediated by ALS/FTLD-associated RNA-binding proteins, which forms the core of the degenerative cascade.”
http://www.ncbi.nlm.nih.gov/pubmed/23048034
Nihei Y, Ito D, Suzuki N. Roles of ataxin-2 in pathological cascades mediated by TAR DNA-binding Protein 43 (TDP-43) and Fused in Sarcoma (FUS). J Biol Chem. 2012 Oct 9. [Epub ahead of print]

Blocking Apoptosis Promoter c-abl Prolongs SOD1 Mouse Lifespan
The apoptosis-related gene c-Abl is upregulated in sporadic ALS motor neurons. The authors found that in mice, mutant SOD1 upregulated c-Abl and decreased cell viability, and that the c-Abl inhibitor dasatinib inhibited cytotoxicity. “The present results suggest that c-Abl is a potential therapeutic target for ALS and that the c-Abl inhibitor dasatinib has neuroprotective properties in vitro and in vivo.”
http://www.ncbi.nlm.nih.gov/pubmed/23049975
Katsumata R, Ishigaki S, Katsuno M, Kawai K, Sone J, Huang Z, Adachi H, Tanaka F, Urano F, Sobue G. c-Abl Inhibition Delays Motor Neuron Degeneration in the G93A Mouse, an Animal Model of Amyotrophic Lateral Sclerosis. PLoS One. 2012;7(9):e46185. doi: 10.1371/journal.pone.0046185. Epub 2012 Sep 25.

ALS-related Angiogenin Mutations Alter Catalytic Activity
Detailed structure-function studies of angiogenin mutants associated with ALS indicate that disease-causing mutations either increase or decrease catalytic activity, both of which impair neuronal survival, possibly through reducing the neuron’s ability to form stress granules.
http://www.ncbi.nlm.nih.gov/pubmed/23047679
Thiyagarajan N, Ferguson R, Subramanian V, Acharya KR.
Structural and molecular insights into the mechanism of action of human angiogenin-ALS variants in neurons. Nat Commun. 2012 Oct 9;3:1121. doi: 10.1038/ncomms2126.

A Second Ribonuclease Associated with ALS
Sequencing of RNASE4, in the same family as the ALS gene angiogenin, revealed an ALS-associated SNP within the gene’s coding region. Systemic treatment with non-ALS-associated RNASE4 protein slowed weight loss and enhanced neuromuscular function of SOD1 ( G93A ) mice.
http://www.ncbi.nlm.nih.gov/pubmed/23143660
Li S, Sheng J, Hu JK, Yu W, Kishikawa H, Hu MG, Shima K, Wu D, Xu Z, Xin W, Sims KB, Landers JE, Brown RH Jr, Hu GF. Ribonuclease 4 protects neuron degeneration by promoting angiogenesis, neurogenesis, and neuronal survival under stress. Angiogenesis. 2012 Nov 10. [Epub ahead of print]

Micro RNAs and Guamanian ALS
Bioinformatic analysis of micro RNAs whose expression is changed by exposure to cycad toxins. The authors identify a set of miRNAs that may be implicated in Guamanian ALS, as well as several cancers.
http://www.ncbi.nlm.nih.gov/pubmed/23060898
Spencer P, Fry RC, Kisby GE.Unraveling 50-Year-Old Clues Linking Neurodegeneration and Cancer to Cycad Toxins: Are microRNAs Common Mediators? Front Genet. 2012;3:192. doi: 10.3389/fgene.2012.00192. Epub 2012 Sep 28.

SOD1 and BMAA
“We show that BMAA shows a dramatic cell-type specific effect with mutant SOD1. Flies with expression of mutant hSOD1 in MNs survived longer on BMAA compared to control flies. In contrast, BMAA significantly shortened the lifespan of flies expressing mutant hSOD1 in glia. Consistent with a neuronal protection role, flies expressing these mutant hSOD1s in both MNs and glia also lived longer. Hence, our studies reveal a synergistic effect of mutant SOD1 with H2O2 and novel roles for mutant hSOD1s in neurons to reduce BMAA toxicity and in glia to enhance the toxicity of BMAA in flies.”
http://f1000research.com/articles/als-linked-sod1-in-glial-cells-enhances-s-n-methylamino-l-alanine-bmaa-induced-toxicity-in-drosophila/
Rafique Islam, Emily L Kumimoto, Hong Bao, Bing Zhang. ALS-linked SOD1 in glial cells enhances ß-N-Methylamino L-Alanine (BMAA)-induced toxicity in Drosophila [v1; ref status: Indexed, http://f1000r.es/S4BZRP]

Disruption of Proteasomes, but not Autophagy, Replicates ALS
Motor neuron-specific conditional knockout of a proteasome subunit in mice induced an ALS phenotype accompanied by cellular hallmarks of disease. Knockout of an autophagy pathway component did not produce similar effects, suggesting that “proteasomes, but not autophagy, fundamentally govern the development of ALS in which TDP-43 and FUS proteinopathy may play a crucial role.”
http://www.ncbi.nlm.nih.gov/pubmed/23095749
Tashiro Y, Urushitani M, Inoue H, Koike M, Uchiyama Y, Komatsu M, Tanaka K, Yamazaki M, Abe M, Misawa H, Sakimura K, Ito H, Takahashi R. Motor Neuron-specific Disruption of Proteasomes, but not Autophagy, Replicates Amyotrophic Lateral Sclerosis. J Biol Chem. 2012 Oct 24. [Epub ahead of print]

Autophagy Activated by TDP-43 Overexpression
“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.”
http://www.ncbi.nlm.nih.gov/pubmed/23063673
Hong K, Li Y, Duan W, Guo Y, Jiang H, Li W, Li C. Full-length TDP-43 and its C-terminal fragments activate mitophagy in NSC34 cell line. Neurosci Lett. 2012 Nov 21;530(2):144-9. doi: 10.1016/j.neulet.2012.10.003. Epub 2012 Oct 9.

TDP-43 and Inositol Triphosphate Receptor
A genome-wide RNAi screen identified approximately 60 genes whose silencing increased the cytosolic localization of TDP-43. The type 1 inositol-1,4,5-trisphosphate (IP3) receptor (ITPR1)  emerged as a strong modulator of TDP-43 nucleocytoplasmic shuttling, and evidence suggested that diminished ITPR1 function leads to autophagosomal clearance of TDP-43.   
http://www.ncbi.nlm.nih.gov/pubmed/22872699
Kim SH, Zhan L, Hanson KA, Tibbetts RS. High-content RNAi screening identifies the Type 1 inositol triphosphate receptor as a modifier of TDP-43 localization and neurotoxicity. Hum Mol Genet. 2012 Nov 15;21(22):4845-56. doi: 10.1093/hmg/dds321. Epub 2012 Aug 7.   

Deletion of Galectin-3, a Carbohydrate-binding Lectin, Worsens Mouse Disease Progression
Genetic deletion of galectin-3 in SOD1(G93A) mice had no effect on disease onset, but led to more rapid progression, and increased expression of inflammation and injury markers on microglia.
http://www.ncbi.nlm.nih.gov/pubmed/23139902
Lerman BJ, Hoffman EP, Sutherland ML, Bouri K, Hsu DK, Liu FT, Rothstein JD, Knoblach SM. Deletion of galectin-3 exacerbates microglial activation and accelerates disease progression and demise in a SOD1(G93A) mouse model of amyotrophic lateral sclerosis. Brain Behav. 2012 Sep;2(5):563-75. doi: 10.1002/brb3.75. Epub 2012 Jul 23.

Senataxin Has a Role in Replication
The ALS gene senataxin associates with replication forks, according to  this study, promoting their progression across RNA polymerase II-transcribed genes.
http://www.ncbi.nlm.nih.gov/pubmed/23141540
Alzu A, Bermejo R, Begnis M, Lucca C, Piccini D, Carotenuto W, Saponaro M, Brambati A, Cocito A, Foiani M, Liberi G. Senataxin Associates with Replication Forks to Protect Fork Integrity across RNA-Polymerase-II-Transcribed Genes. Cell. 2012 Nov 9;151(4):835-46. doi: 10.1016/j.cell.2012.09.041.

Oculomotor Neuron Transcriptional Profiling
Oculomotor neurons, which are spared in ALS, have a  transcriptional profile distinct from spinal motor neurons, with significant differential expression of 1,757 named genes, as well as a reduced AMPA-mediated inward calcium current, and a higher GABA-mediated chloride current, than spinal motor neurons.
http://www.ncbi.nlm.nih.gov/pubmed/23143228
Brockington A, Ning K, Heath PR, Wood E, Kirby J, Fusi N, Lawrence N, Wharton SB, Ince PG, Shaw PJ. Unravelling the enigma of selective vulnerability in neurodegeneration: motor neurons resistant to degeneration in ALS show distinct gene expression characteristics and decreased susceptibility to excitotoxicity. Acta Neuropathol. 2012 Nov 13. [Epub ahead of print]

Hox5 Genes Required for Phrenic Motor Neuron Development and Survival
“Two Hox genes, Hoxa5 and Hoxc5, control diverse aspects of phrenic motor column development including their clustering, intramuscular branching, and survival,” and are required continuously for survival of these motor neurons.
http://www.ncbi.nlm.nih.gov/pubmed/23103965
Philippidou P, Walsh CM, Aubin J, Jeannotte L, Dasen JS. Sustained Hox5 gene activity is required for respiratory motor neuron development. Nat Neurosci. 2012 Nov;15(12):1636-44. doi: 10.1038/nn.3242. Epub 2012 Oct 28.  

Also of Interest:

http://www.ncbi.nlm.nih.gov/pubmed/23118353
Jaronen M, Vehviläinen P, Malm T, Keksa-Goldsteine V, Pollari E, Valonen P, Koistinaho J, Goldsteins G. Protein disulfide isomerase in ALS mouse glia links protein misfolding with NADPH oxidase-catalyzed superoxide production. Hum Mol Genet. 2012 Nov 15. [Epub ahead of print]

Second ER Lipid Gene Implicated in Motor Neuron Disease
Mutations in ERLIN2 are responsible for some cases of primary lateral sclerosis, according to new research. The erlin-2 protein is a component of endoplasmic reticulum lipid rafts. The same authors recently showed that SIGMAR1, the gene for another component, is linked to juvenile amyotrophic lateral sclerosis.
http://www.ncbi.nlm.nih.gov/pubmed/23109145
Al-Saif A, Bohlega S, Al-Mohanna F. Loss of ERLIN2 function leads to juvenile primary lateral sclerosis. Ann Neurol. 2012 Oct;72(4):510-6. doi: 10.1002/ana.23641.

New Profilin 1 Mutation
A screen of Northern European and US families revealed a new heterozygous PFN1 mutation p.Thr109Met, which was absent in controls. This novel mutation abrogates a phosphorylation site in profilin 1. “The novel p.Thr109Met mutation provides additional proof-of-principle that mutant proteins involved in the regulation of cytoskeletal dynamics can cause motor neuron degeneration. Moreover, this new mutation suggests that fine-tuning of actin polymerization by phosphorylation of profilin 1 might be necessary for motor neuron survival.”
http://www.ncbi.nlm.nih.gov/pubmed/23141414
Ingre C, Landers JE, Rizik N, Volk AE, Akimoto C, Birve A, Hübers A, Keagle PJ, Piotrowska K, Press R, Andersen PM, Ludolph AC, Weishaupt JH. A novel phosphorylation site mutation in profilin 1 revealed in a large screen of US, Nordic, and German amyotrophic lateral sclerosis/frontotemporal dementia cohorts. Neurobiol Aging. 2012 Nov 8. pii: S0197-4580(12)00520-9. doi: 10.1016/j.neurobiolaging.2012.10.009. [Epub ahead of print]

Population Study of ALS Genes in Italy
A study of all 475 ALS cases diagnosed in Piemonte, Italy, from January 2007 to June 2011, indicated that 51 (10.7%) carried a mutation of an ALS-related gene (C9ORF72, 32; SOD1, 10; TARDBP, 7; FUS, 1; OPTN, 1; ANG, none). A positive family history for ALS or frontotemporal dementia (FTD) was found in 46 (9.7%) patients. Comorbid FTD or a young age at onset were strong indicators of a possible genetic origin of the disease.
http://www.ncbi.nlm.nih.gov/pubmed/23100398
Chiò A, Calvo A, Mazzini L, Cantello R, Mora G, Moglia C, Corrado L, D'Alfonso S, Majounie E, Renton A, Pisano F, Ossola I, Brunetti M, Traynor BJ, Restagno G; On behalf of PARALS. Extensive genetics of ALS: A population-based study in Italy. Neurology. 2012 Nov 6;79(19):1983-1989. Epub 2012 Oct 24.

Ubiquilin-2 Mutations in 2% of Familial ALS
In a study of 819 sporadic ALS cases, 226 familial ALS cases, 53 ALS-FTD patients, and 63 patients with a clinical record of FTD, researchers found mutations in the UBQLN2 gene in 5 unrelated FALS patients, including two new variants.
http://www.ncbi.nlm.nih.gov/pubmed/23138764
Gellera C, Tiloca C, Del Bo R, Corrado L, Pensato V, Agostini J, Cereda C, Ratti A, Castellotti B, Corti S, Bagarotti A, Cagnin A, Milani P, Gabelli C, Riboldi G, Mazzini L, Sorarù G, D'Alfonso S, Taroni F, Comi GP, Ticozzi N, Silani V; The SLAGEN Consortium. Ubiquilin 2 mutations in Italian patients with amyotrophic lateral sclerosis and frontotemporal dementia. J Neurol Neurosurg Psychiatry. 2012 Nov 8. [Epub ahead of print]

PMA and ALS Gene Overlap
Comparison of mutation frequencies in known ALS genes (not including C9ORF72) between patients with apparently sporadic progressive muscular atrophy and sporadic ALS indicated similar overall mutation frequencies (2.7% vs. 2%), with PMA patients carrying mutations in SOD1, ANG, FUS/TLS, TARDBP, and CHMP2B.
http://www.ncbi.nlm.nih.gov/pubmed/23155438
van Blitterswijk M, Vlam L, van Es MA, van der Pol WL, Hennekam EA, Dooijes D, Schelhaas HJ, van der Kooi AJ, de Visser M, Veldink JH, van den Berg LH. Genetic Overlap between Apparently Sporadic Motor Neuron Diseases. PLoS One. 2012;7(11):e48983. doi: 10.1371/journal.pone.0048983. Epub 2012 Nov 14.

No Evidence of C9ORF72 mutations in Parkinson's Disease
Although parkinsonism is a recognized feature in some cases of C9ORF72 ALS, a study of 478 PD patients revealed no gene expansions, suggesting that C9ORF72 expansions are not a common cause of PD.
http://www.ncbi.nlm.nih.gov/pubmed/23116878
Harms MB, Neumann D, Benitez BA, Cooper B, Carrell D, Racette BA, Perlmutter JS, Goate A, Cruchaga C. Parkinson disease is not associated with C9ORF72 repeat expansions. Neurobiol Aging. 2012 Oct 29. pii: S0197-4580(12)00491-5. doi: 10.1016/j.neurobiolaging.2012.10.001.

Multiple Sclerosis and C9ORF72 ALS
From approximately 650 ALS patients from the North of England, 7 were identified who initially presented with MS. DNA from 5 of them revealed the C9ORF72 expansion in 4 patients, but not in any of 215 patients with MS alone. In the presence of preceding MS, C9ORF72-ALS was more rapidly progressive. “We propose that MS-associated neuroinflammation may affect penetrance and progression of the C9ORF72 expansion,” the authors state.
http://www.ncbi.nlm.nih.gov/pubmed/23085936
Ismail A, Cooper-Knock J, Highley JR, Milano A, Kirby J, Goodall E, Lowe J, Scott I, Constantinescu CS, Walters SJ, Price S, McDermott CJ, Sawcer S, Compston DA, Sharrack B, Shaw PJ. Concurrence of multiple sclerosis and amyotrophic lateral sclerosis in patients with hexanucleotide repeat expansions of C9ORF72. J Neurol Neurosurg Psychiatry. 2012 Oct 20. [Epub ahead of print]

C9ORF72 in Alzheimer’s Disease
C9ORF72 expansions were found in 0.76% of over 1000 Alzheimer’s disease cases versus none in control subjects.
http://www.ncbi.nlm.nih.gov/pubmed/23107433
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. Repeat expansions in the C9ORF72 gene contribute to Alzheimer's disease in Caucasians. Neurobiol Aging. 2012 Oct 27. doi:pii: S0197-4580(12)00493-9. 10.1016/j.neurobiolaging.2012.10.003. [Epub ahead of print]  

Clinical Research and Drug Development

Blockade of Overexpressed Calcium Channels is Therapeutic in ALS Mice
N-type Ca(2+) channels are over expressed in motor cortex of G93A mice, and blockade  of these channels in vitro improves neuronal survival.
http://www.ncbi.nlm.nih.gov/pubmed/23142186
Pieri M, Caioli S, Canu N, Mercuri NB, Guatteo E, Zona C. Over-expression of N-type calcium channels in cortical neurons from a mouse model of Amyotrophic Lateral Sclerosis. Exp Neurol. 2012 Nov 8. pii: S0014-4886(12)00419-0. doi: 10.1016/j.expneurol.2012.11.002. [Epub ahead of print]

Spasticity in ALS Linked to Serotonergic Neurodegeneration
Pathologic examination in 7 ALS patients revealed degeneration of central serotonergic neurons, as well as of distal serotonergic projections to spinal cord motor neurons and hippocampus  Similar features were observed in SOD1 mice, and the role of the serotonin system was strengthened by the finding that tail muscle spastic-like contractions in response to mechanical stimulation were abolished by 5-hydroxytryptamine-2b/c receptors inverse agonists.
http://www.ncbi.nlm.nih.gov/pubmed/23114367
Dentel C, Palamiuc L, Henriques A, Lannes B, Spreux-Varoquaux O, Gutknecht L, René F, Echaniz-Laguna A, Gonzalez de Aguilar JL, Lesch KP, Meininger V, Loeffler JP, Dupuis L. Degeneration of serotonergic neurons in amyotrophic lateral sclerosis: a link to spasticity. Brain. 2012 Oct 31. [Epub ahead of print]

Immune Markers Correlate with Progression and Survival in Patients
Regulatory T-lymphocytes (Tregs) and FoxP3, a transcription factor required for Treg function, were reduced in rapidly progressing ALS patients and inversely correlated with progression rates, and in a larger cohort, early reduced FoxP3 levels “were indicative of progression rates at collection and predictive of future rapid progression and attenuated survival.”
http://www.ncbi.nlm.nih.gov/pubmed/23143995
Henkel JS, Beers DR, Wen S, Rivera AL, Toennis KM, Appel JE, Zhao W, Moore DH, Powell SZ, Appel SH. Regulatory T-lymphocytes mediate amyotrophic lateral sclerosis progression and survival. EMBO Mol Med. 2012 Nov 9. doi: 10.1002/emmm.201201544. [Epub ahead of print]

C9ORF72 Prognosis
In a retrospective case-control study of ALS patients with and without C9ORF72 expansions, and FTD patients with and without expansions, researchers found that patients with expanded repeats had an earlier age of onset, more rapid progression, and an earlier age of death  than those without repeats.
http://www.ncbi.nlm.nih.gov/pubmed/23117491
Irwin DJ, McMillan CT, Brettschneider J, Libon DJ, Powers J, Rascovsky K, Toledo JB, Boller A, Bekisz J, Chandrasekaran K, Wood EM, Shaw LM, Woo JH, Cook PA, Wolk DA, Arnold SE, Van Deerlin VM, McCluskey LF, Elman L, Lee VM, Trojanowski JQ, Grossman M. Cognitive decline and reduced survival in C9orf72 expansion frontotemporal degeneration and amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry. 2012 Nov 14. [Epub ahead of print]  

Reviews

http://www.ncbi.nlm.nih.gov/pubmed/23026741
Southwell AL, Skotte NH, Bennett CF, Hayden MR. Antisense oligonucleotide therapeutics for inherited neurodegenerative diseases. Trends Mol Med. 2012 Nov;18(11):634-43. doi: 10.1016/j.molmed.2012.09.001. Epub 2012 Sep 28.

http://www.ncbi.nlm.nih.gov/pubmed/22827270
Song CY, Guo JF, Liu Y, Tang BS. Autophagy and Its Comprehensive Impact on ALS. Int J Neurosci. 2012 Dec;122(12):695-703. doi: 10.3109/00207454.2012.714430. Epub 2012 Sep 3.