News from the 2013 Society for Neuroscience Annual Meeting

November 11, 2013

The Annual Meeting of the Society for Neuroscience is the largest gathering of neuroscientists in the world, with more than 29,000 scientists attending this year's meeting in San Diego, November 9-13. Below are some of the highlights of research on ALS presented at the meeting. Abstracts may be viewed online using the links provided.

Identification of potential ALS therapeutics using stem cell derived motor neurons
Gupta and colleagues screened for potential disease pathways and therapeutics in motor neurons derived from mouse embryonic stem cells carrying a SOD1 mutation. They tested the ability of various compounds to prolong cell life after withdrawing neurotrophic factors. From a screen of 500 compounds, they found a significant effect with an inhibitor of aurora kinase, a regulator of cell proliferation. The details of the involvement of this pathway in ALS are unknown.
S. GUPTA, G. GULATI, Y. YANG, L. RUBIN;
http://www.abstractsonline.com/Plan/ViewAbstract.aspx?mID=3236&cKey=4ad69054-09df-414f-8965-c8fdae293ebd&sKey=216c2239-973e-4a2f-ad4d-90d55fee7ea6

iPSCs-derived neural stem cells transplantation as therapeutic strategy for amyotrophic lateral sclerosis
Rizzo and colleagues are exploring the therapeutic potential of induced pluripotent stem cells (iPS cells) derived from human skin cells. They developed iPS cells from healthy human donors and injected them into mice carrying the G93A mutation in SOD1. Injections were performed either intravenously or into the intrathecal space surrounding the spinal cord. Treatment prolonged lifespan, slowed functional decline, and preserved neuromuscular junctions.
F. RIZZO, M. NIZZARDO, C. SIMONE, M. RUGGIERI, S. SALANI, I. FARAVELLI, C. ZANETTA, N. BRESOLIN, G. COMI, S. CORTI;
http://www.abstractsonline.com/Plan/ViewAbstract.aspx?mID=3236&cKey=10b9974c-591c-4a58-9d17-c61f07cc8745&sKey=216c2239-973e-4a2f-ad4d-90d55fee7ea6

Induced pluripotent stem cell-derived astrocytes engraft in the SOD1G93A rat model of ALS
Staggenborg and colleagues have generated astrocytes from iPS cells, grown them up as spherical cells in culture fluid (not attached to a plate), and transplanted them into a rat model of ALS. Early results indicate the cells are viable after transplantation but have not yet increased survival of motor neurons in the rats.
K. J. STAGGENBORG, D. SAREEN, G. GOWING, A. SAHABIAN, R. PARADIS, P. AVALOS, J. LATTER, M. CHEN, C. SVENDSEN;
http://www.abstractsonline.com/Plan/ViewAbstract.aspx?mID=3236&cKey=5b5a3b19-0584-4eff-bea1-3fd7aca257a0&sKey=216c2239-973e-4a2f-ad4d-90d55fee7ea6

Guanabenz treatment ameliorates ALS disease by enhancing the unfolded protein response (UPR)
Wang and colleagues show the potential importance of the unfolded protein response in ALS, by demonstrating that an FDA-approved promoter of one part of the UPR is therapeutic in G93A SOD1 mice. They showed that guanabenz treatment delayed disease onset by about 10 percent and increased lifespan by about 15 percent. Guanabenz is an α-2 adrenergic receptor agonist approved for the treatment of hypertension, which inhibits GADD34. GADD34 inactivates a kinase central to a fast-acting branch of the UPR. Guanabenz's ability to prevent this inactivation point to this pathway as a potentially important target for therapeutic development.
L.-J. WANG, B. POPKO, R. P. ROOS;
http://www.abstractsonline.com/Plan/ViewAbstract.aspx?mID=3236&cKey=ba005c58-8e38-4f61-bb82-95720c327396&sKey=216c2239-973e-4a2f-ad4d-90d55fee7ea6

Nanobody against SOD1 reduces in vitro aggregation, rescues SOD1 induced axonopathy and extends survival in ALS models
Nanobodies are single-domain antibodies that are much smaller and less immunogenic than full-size antibodies. Hernandez and colleagues generated nanobodies to mutant SOD1 and showed their ability to prevent SOD1 fibril formation and aggregation in vitro. In vivo, injection of nanobodies reduced axonopathy in zebrafish and delayed onset and increased survival in mice.
S. HERNANDEZ1, W. ROBBERECHT2, *P. DUPONT2;
http://www.abstractsonline.com/Plan/ViewAbstract.aspx?mID=3236&cKey=05968821-ff03-4916-a2e9-108cddb2fc6d&sKey=216c2239-973e-4a2f-ad4d-90d55fee7ea6

C9orf72 frontotemporal lobar degeneration is characterised by frequent neuronal sense and antisense RNA foci
Mizielinska and colleagues show that both sense and antisense RNA foci accumulate in the brains of patients with frontotemporal dementia due to C9ORF72 mutation, similar to the foci seen in ALS. Foci were present in hippocampus, cerebellum, and especially frontal cortex, where more than half of all neurons contained foci. Antisense foci were found in fewer cells than sense foci, but were similarly distributed and were more abundant per cell. Age at onset was inversely correlated with sense foci burden, but only marginally with antisense foci. Both sense and antisense foci were found in astrocytes, microglia, and oligodendrocytes, at lower concentrations. The full text of their publication is available online.
Sarah Mizielinska, Tammaryn Lashley, Frances E. Norona, Emma L. Clayton, Charlotte E. Ridler, Pietro Fratta, Adrian M. Isaacs
http://link.springer.com/article/10.1007/s00401-013-1200-z

Expression pattern of the C9ORF72 mouse ortholog corresponds with the selectivity of neural degeneration in ALS / FTD
Suzuki and colleagues used gene-targeted disruption to show that the C9ORF72 gene was most highly expressed in orticospinal motor neurons, callosal projection neurons, and anterior horn motor neuron cells, and at lower rates in astrocytes and microglia. “Thus, our studies provide a potential mechanistic explanation for the cell type specificity of degeneration caused by these mutations,” they conclude.
N. SUZUKI, A. MAROOF, K. KOSZKA, A. INTOH, E. KISKINIS, K. EGGAN;
http://www.abstractsonline.com/Plan/ViewAbstract.aspx?mID=3236&cKey=d3f2d97f-adff-4a10-9515-71174b5fbeb0&sKey=079033c2-a31f-4395-b7ec-1502e3debfd7

Indications of motor neuron toxicity triggered by Schwann cells in the In vitro mouse model of Amyotrophic Lateral Sclerosis
Alves and colleagues show that, analogous to the toxic effect of SOD-mutant glia, Schwann cells carrying the G93A SOD1 mutation are toxic to motor neurons in culture. Toxicity was conferred by both cells themselves, and conditioned media.
C. J. ALVES1, A. B. GUIMARÃES2, D. G. ISHIBARU2, P. C. MARTHO2, J. R. MAXIMINO2, G. CHADI2;
http://www.abstractsonline.com/Plan/ViewAbstract.aspx?mID=3236&cKey=08f18b58-2a39-4dc6-8a3b-0df1de731f8f&sKey=079033c2-a31f-4395-b7ec-1502e3debfd7

The role of RBM45 in antioxidant responses in ALS
Bakkar and Bowser showed that the RNA binding protein RBM45, which is increased in ALS cerebrospinal  fluid, plays a role in regulation of the oxidative stress response. The protein binds to KEAP, an inhibitor of the antioxidant response transcription factor NRF2, reducing the ability of cells in culture to mount an antioxidant response, suggesting RBM45 elevation may be linked to a reduction in this protective response in ALS.
N. BAKKAR, R. BOWSER;
http://www.abstractsonline.com/Plan/ViewAbstract.aspx?mID=3236&cKey=419924a9-99d5-4e80-b5f2-6945e2db7109&sKey=7b165dfe-2c88-48d0-bab2-8bb64e429eb6

Astrocytes carrying an Amyotrophic Lateral Sclerosis-linked mutation in Fused in Sarcoma (FUS) trigger degeneration of wild-type motor neurons
Kia and colleagues expressed mutant FUS in astrocytes, and grew them together with wild-type motor neurons. Motor neurons died in response, an effect that could be partially replicated with media conditioned by exposure to the astrocytes.”Thus, like for SOD1-ALS but not for TDP-43-ALS (Serio et al., PNAS 2012), our data highlight a non-cell autonomous glial effect in disease and provide a viable in vitro system to further understand how mutations in different genes differentially affect glia-neurons interactions,” they conclude.
A. T. KIA, K. KRISHNAMURTHY, A. BOGUSH, D. TROTTI, P. PASINELLI;
http://www.abstractsonline.com/Plan/ViewAbstract.aspx?mID=3236&cKey=12702194-df04-40a4-bb66-24eaebecb450&sKey=8d62c808-847b-4d11-8f72-8a60fdb37776

Neuronal toxicity of the ALS-linked intronic GGGGCC repeat expansions of the C9ORF72 gene
Tan and colleagues showed that GGGGCC repeats were toxic in primary cortical and motor neuron culture, and that higher repeat number accelerated neuronal death over time, while C9ORF72 protein knockdown did not. RAN dipeptide proteins were also toxic, in particular proline-arginine.
W. TAN, X. WEN, D. TROTTI, P. PASINELLI;
http://www.abstractsonline.com/Plan/ViewAbstract.aspx?mID=3236&cKey=1cbf0a57-47c6-43b9-811a-3a97f1a27562&sKey=8d62c808-847b-4d11-8f72-8a60fdb37776

PGC-1α is a sex-dependent disease modifier of human and experimental amyotrophic lateral sclerosis in part via Vegf-A
Weydt and colleagues show that among two large groups of European ALS patients, variants in the gene for the transcriptional co-activator PGC-1-alpha were correlated with age at onset (in one population) or disease duration (in the other)  in males, but not in females. Reducing  PGC-1-alpha in ALS mice led to earlier disease in male mice, but not female mice, coincident with a reduction in the growth factor VEGF-A in males, but not females.
P. WEYDT1, J. ESCHBACH1, B. SCHWALENSTÖCKER1, S. SOYAL2, T. MEYER3, H. BAYER1, D. WIESNER1, C. AKIMOTO4, A.-C. NILSSON4, A. BIRVE4, L. DUPUIS5, K. DANZER1, P. M. ANDERSEN4, A. C. LUDOLPH1, W. PATSCH2, A. WITTING1;
http://www.abstractsonline.com/Plan/ViewAbstract.aspx?mID=3236&cKey=4a19b704-fd25-4372-a0c5-e7c065e4eb1f&sKey=8d62c808-847b-4d11-8f72-8a60fdb37776

Generation and characterization of a zebrafish C9ORF72 ALS model
Boeynaems and colleagues examined the effect of injecting GGGGCC hexanucleotide repeat RNA into zebrafish embryo. Transient activity of the repeat led to axonopathy in the late embryo stage. In addition, RAN peptide expression in the fish embryo was toxic.
S. BOEYNAEMS1,2, A. BENTO-ABREU1,2, M. TIMMERS1,2, P. VAN DAMME1,2,3, *L. M. VAN DEN BOSCH4,2,1, W. ROBBERECHT1,2,3;
http://www.abstractsonline.com/Plan/ViewAbstract.aspx?mID=3236&cKey=d8f33746-623a-40e8-97de-c9a1793cadb1&sKey=8d62c808-847b-4d11-8f72-8a60fdb37776

Motor neuron-derived osteopontin is an aggravation factor in the disease onset of ALS mice
Niikura and colleagues showed that in two different SOD1 mutant models, osteopontin was secreted from motor neurons and accumulated as granules near disease onset, and increased in number and distribution as the disease progressed. In SOD mutant mice deficient in osteopontin, disease onset was delayed and progression slowed. “We propose that OPN is one of the α-motor neuron-derived factors that modulate neuron-glia interaction during chronic inflammation in the ALS mice,” the authors state.
M. NIIKURA1, S. TANABE1, Y. MORIWAKI1, K. YAMANAKA2,3, *H. MISAWA1;
http://www.abstractsonline.com/Plan/ViewAbstract.aspx?mID=3236&cKey=107070ca-624b-4b4a-8af7-85eb7f42ae68&sKey=0986c93e-9c68-4ec1-8296-18342ea85571

Ablation of neuronal TDP-43 develops FTLD/ALS phenotypes in mice
Takeuchi  and colleagues have developed a conditional knockout model of TDP-43. Loss of TDP-43 caused rapid paralysis, cognitive dysfunction, neuronal loss, and death. “We propose that TDP-43 neurotoxicity is caused by a loss of its normal function,” they state.
H. TAKEUCHI1,3, H. HORIUCHI1, H. MIZOGUCHI2, A. SUZUMURA1, L. KWONG3, J. TROJANOWSKI3, V. LEE3;
http://www.abstractsonline.com/Plan/ViewAbstract.aspx?mID=3236&cKey=0b6c43a4-0ee8-44e8-bb7b-7d84458e8d6d&sKey=0986c93e-9c68-4ec1-8296-18342ea85571

ALS astrocytes adopt natural killer properties to induce motor neuron death
Song and colleagues show that astrocytes derived from neural progenitors of human sporadic and familial ALS patients, and from SOD1 mutant mice, adopt a natural killer phenotype that is toxic to wild-type motor neurons in culture. Expression of NK-specific cytolytic genes was also detected in astrocytes derived from patient spinal cord.
S. SONG1,3, C. J. MIRANDA1, L. BRAUN1, K. MEYER1, A. K. BEVAN1,4, A. FRAKES1,4, L. FERRAIUOLO1, S. LIKHITE1,3, K. D. FOUST1,5, K. J. CAMPBELL2, M. J. MCCONNELL7,8, C. M. WALKER2,6, B. K. KASPAR1,3,4,5,6;
http://www.abstractsonline.com/Plan/ViewAbstract.aspx?mID=3236&cKey=bf7270f5-a90a-43e0-84e8-96821ca87313&sKey=cdd956a6-889a-4518-9ff6-6c3bbcb9ac4e

Development and characterization of single-copy insertion C. elegans ALS models
Yersak and colleagues have developed a worm model of SOD1 ALS based on deleting both copies of the wild-type worm gene and inserting two copies of a slow-progressing mutant. Mutant worms display a phenotype of increased pharyngeal pumping and increased sensitivity to a cholinergic inhibitor.
J. YERSAK1, P. O'HERN1, H. L. BENNETT2, A. C. HART1;
http://www.abstractsonline.com/Plan/ViewAbstract.aspx?mID=3236&sKey=0986c93e-9c68-4ec1-8296-18342ea85571&cKey=5d254530-0604-45d7-a056-4c5fd2a7be64&mKey=8d2a5bec-4825-4cd6-9439-b42bb151d1cf

Biomarker-based predictive models for prognosis in amyotrophic lateral sclerosis
Su and colleagues show that a combination of plasma and CSF biomarkers, taken at a single time point approximately 12 months after onset, is highly predictive of disease duration. The most predictive biomarkers included inflammatory cytokines in both plasma and CSF and a plasma iron storage protein. The model combining these markers achieved a very high predictive value of R-squared=0.962.
The full article is available to subscribers at http://archneur.jamanetwork.com/article.aspx?articleid=1757020.
*X. W. SU1, Z. SIMMONS2, R. M. MITCHELL1, H. E. STEPHENS2, J. R. CONNOR1;
http://www.abstractsonline.com/Plan/ViewAbstract.aspx?mID=3236&cKey=e4a0d6ca-8c43-4ef5-90f2-3566332df328&sKey=385c3709-bc90-4e4a-948b-edac86cbd32c

Microglia induce motor neuron death via the classical NF-κB pathway in amyotrophic lateral sclerosis
Frakes and colleagues show that selective inhibition of NF-kappaB in ALS microglia protect motor neurons in culture from microglia-induced death and extend survival in ALS mice by 47 percent.  Constitutive activity of NF-kappaB in microglia of wild-type mice recapitulated the proinflammatory state seen in ALS mice, and in vitro, mimicked the toxic effect of genetic ALS.
*A. FRAKES1, L. FERRAIUOLO2, L. SCHMELZER2, L. BRAUN2, C. MIRANDA2, B. KASPAR2;
http://www.abstractsonline.com/Plan/ViewAbstract.aspx?mID=3236&cKey=4f54cee2-4d02-450c-84e9-0cf502e2784c&sKey=f5595fa0-7f16-46ee-adc4-74c26724cc83

Skin derived astrocytes from C9orf72 and sporadic ALS patients are toxic to motor neurons
Astrocytes derived from fibroblasts of ALS patients are toxic to motor neurons, whether those fibroblasts originate from known genetic or sporadic forms of the disease. The authors employed a novel protocol for deriving the astrocytes, avoiding transformation into pluripotent stem cells, and instead proceeding directly from fibroblasts to neural progenitor cells, a process requiring less than one month.
*K. C. MEYER1, L. FERRAIUOLO1, C. MIRANDA1, S. LIKHITE1, S. MCELROY1, C. LARGIER-TOURENNE2, J. RAVITS3, P. SHAW4, D. CLEVELAND2, S. KOLB5, B. KASPAR1;
http://www.abstractsonline.com/Plan/ViewAbstract.aspx?mID=3236&cKey=5af1b3c9-c280-42e1-9e0a-60a6e7a42c4c&sKey=f5595fa0-7f16-46ee-adc4-74c26724cc83

Mutant TDP-43 in astrocytes causes non-cell-autonomous motor neuron death in transgenic rats
Mutant TDP-43 restricted to astrocytes in rats led to progressive paralysis, loss of motor neurons, and denervation atrophy, accompanied by global astrocyte and microglia activation. Further work will be needed to determine if the toxic effect is due to the mutation itself or to overexpression of TDP-43. In addition, the authors showed that mutant TDP-43 in motor neurons induces production of the neurotoxin Lcn2 in astrocytes.
B. HUANG, C. HUANG, X. LIU, *H. ZHOU;
http://www.abstractsonline.com/Plan/ViewAbstract.aspx?mID=3236&cKey=b24b05d3-8928-4e92-8811-9c974873fc6a&sKey=f5595fa0-7f16-46ee-adc4-74c26724cc83

Oligodendrocytes from the ALS mouse model and ALS patients are toxic to motor neurons in vitro
ALS patient fibroblasts differentiated into oligodendrocytes are toxic to motor neurons in culture.
*L. FERRAIUOLO, K. MEYER, C. MIRANDA, L. BRAUN, B. KASPAR;
http://www.abstractsonline.com/Plan/ViewAbstract.aspx?mID=3236&cKey=b2df4f6b-bcc7-4130-9860-abe281bbae97&sKey=f5595fa0-7f16-46ee-adc4-74c26724cc83

Oligodendroglia significantly contribute to neuronal injury in ALS
Mice carrying the SOD1 mutant G37R had delayed disease onset and slower progression when the mutant gene was selectively excised from oligodendrocytes. Harmful activated microglial and astroglial responses were also delayed.
*Y. LI1, D. BERGLES2, J. D. ROTHSTEIN3;
http://www.abstractsonline.com/Plan/ViewAbstract.aspx?mID=3236&cKey=13f3cd9f-66ff-40bb-a767-577f1ee6f11c&sKey=b16c7bc3-c6d0-4685-ad4d-2f9cedd1681e

Pharmacological inhibition of Rho kinase improves motor function and survival in the SOD1(G93A) mouse model of ALS
In the G93A mouse, treatment with the Rho kinase inhibitor fasudil beginning at day 60 extended survival for 10 days. The authors showed that therapy increased microglia activity, while shifting the pattern of cytokine expression to a more protective pattern.
L. TÖNGES1, R. GÜNTHER1, M. SUHR1, J. JANSEN1, A. BALCK1, K.-A. SAAL1, E. BARSKI1, T. NIENTIEDT4, A. GÖTZ2, J. C. KOCH1, J. H. WEISHAUPT5, M. W. SEREDA4, U.-K. HANISCH2, M. BÄHR1, *P. LINGOR3;
http://www.abstractsonline.com/Plan/ViewAbstract.aspx?mID=3236&cKey=18027afb-b284-446b-8357-327cc032776b&sKey=2975647c-302e-4f2e-b1d8-f821a17a8b62

AAV9-mediated SOD1 downregulation improves survival in mouse models of amyotrophic lateral sclerosis
shRNA directed against SOD1 and delivered via adeno-associated virus led to a 30-day increase in survival in the G93A mouse when injected peripherally at day 85. Even larger increases were obtained with injection at earlier time points. In the slower-progressing G37R mouse, injection at onset increased survival by 87 days. Transduction occurred primarily in astrocytes, rather than motor neurons. In wild-type mice, no safety concerns were seen for up to 6 months after a day-21 injection. Intrathecal injection into Cynomolgus monkeys led to significant reduction in SOD1 protein. 
*S. B. LIKHITE1,2, K. D. FOUST3, D. L. SALAZAR4, L. FERRAIUOLO1, D. DITSWORTH4, L. SCHMELZER1, L. BRAUN1, D. W. CLEVELAND4, B. K. KASPAR1,2;
http://www.abstractsonline.com/Plan/ViewAbstract.aspx?mID=3236&cKey=8de2d81a-b9fd-4c42-b345-8587f3ebc132&sKey=2975647c-302e-4f2e-b1d8-f821a17a8b62

Impairment of microtubule-dependent transport of TDP-43 triggers its aggregation, leading to neurodegeneration in Drosophila models of TDP-43 proteinopathies
TDP-43 is transported by dynactin. and loss of dynactin or other transport proteins promotes TDP-43 aggregation, according to Fujikake and colleagues, working in a fly model.
N. FUJIKAKE1, N. KIMURA2, Y. SAITOH1, *M. SUZUKI1, A. YOKOSEKI3, O. ONODERA3, K. WADA1, Y. NAGAI1;
http://www.abstractsonline.com/Plan/ViewAbstract.aspx?mID=3236&cKey=b9df8d4d-1169-4993-987e-1e1d56590d18&sKey=f5595fa0-7f16-46ee-adc4-74c26724cc83


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