Linking RNA Dysfunction and Neurodegeneration in Amyotrophic Lateral Sclerosis

Overview

Journal Neurotherapeutics

Specialty Neurology

Date 2015 Feb 19

PMID 25689976

Citations 21

Authors

Sami J Barmada

Affiliations

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Abstract

The degeneration of motor neurons in amyotrophic lateral sclerosis (ALS) inevitably causes paralysis and death within a matter of years. Mounting genetic and functional evidence suggest that abnormalities in RNA processing and metabolism underlie motor neuron loss in sporadic and familial ALS. Abnormal localization and aggregation of essential RNA-binding proteins are fundamental pathological features of sporadic ALS, and mutations in genes encoding RNA processing enzymes cause familial disease. Also, expansion mutations occurring in the noncoding region of C9orf72-the most common cause of inherited ALS-result in nuclear RNA foci, underscoring the link between abnormal RNA metabolism and neurodegeneration in ALS. This review summarizes the current understanding of RNA dysfunction in ALS, and builds upon this knowledge base to identify converging mechanisms of neurodegeneration in ALS. Potential targets for therapy development are highlighted, with particular emphasis on early and conserved pathways that lead to motor neuron loss in ALS.

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References

Bose J, Huang C, Shen C . Regulation of autophagy by neuropathological protein TDP-43. J Biol Chem. 2011; 286(52):44441-8. PMC: 3247982. DOI: 10.1074/jbc.M111.237115. View

Liu-Yesucevitz L, Lin A, Ebata A, Boon J, Reid W, Xu Y . ALS-linked mutations enlarge TDP-43-enriched neuronal RNA granules in the dendritic arbor. J Neurosci. 2014; 34(12):4167-74. PMC: 3960463. DOI: 10.1523/JNEUROSCI.2350-13.2014. View

Ward M, Taubes A, Chen R, Miller B, Sephton C, Gelfand J . Early retinal neurodegeneration and impaired Ran-mediated nuclear import of TDP-43 in progranulin-deficient FTLD. J Exp Med. 2014; 211(10):1937-45. PMC: 4172214. DOI: 10.1084/jem.20140214. View

Couthouis J, Hart M, Shorter J, DeJesus-Hernandez M, Erion R, Oristano R . A yeast functional screen predicts new candidate ALS disease genes. Proc Natl Acad Sci U S A. 2011; 108(52):20881-90. PMC: 3248518. DOI: 10.1073/pnas.1109434108. View

Barmada S, Skibinski G, Korb E, Rao E, Wu J, Finkbeiner S . Cytoplasmic mislocalization of TDP-43 is toxic to neurons and enhanced by a mutation associated with familial amyotrophic lateral sclerosis. J Neurosci. 2010; 30(2):639-49. PMC: 2821110. DOI: 10.1523/JNEUROSCI.4988-09.2010. View

Renton A, Majounie E, Waite A, Simon-Sanchez J, Rollinson S, Gibbs J . A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron. 2011; 72(2):257-68. PMC: 3200438. DOI: 10.1016/j.neuron.2011.09.010. View

Deng H, Chen W, Hong S, Boycott K, Gorrie G, Siddique N . Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia. Nature. 2011; 477(7363):211-5. PMC: 3169705. DOI: 10.1038/nature10353. View

Furukawa Y, Kaneko K, Watanabe S, Yamanaka K, Nukina N . A seeding reaction recapitulates intracellular formation of Sarkosyl-insoluble transactivation response element (TAR) DNA-binding protein-43 inclusions. J Biol Chem. 2011; 286(21):18664-72. PMC: 3099683. DOI: 10.1074/jbc.M111.231209. View

Igaz L, Kwong L, Xu Y, Truax A, Uryu K, Neumann M . Enrichment of C-terminal fragments in TAR DNA-binding protein-43 cytoplasmic inclusions in brain but not in spinal cord of frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Am J Pathol. 2008; 173(1):182-94. PMC: 2438296. DOI: 10.2353/ajpath.2008.080003. View

10.

Pulst S, Nechiporuk A, Nechiporuk T, Gispert S, Chen X, Lopes-Cendes I . Moderate expansion of a normally biallelic trinucleotide repeat in spinocerebellar ataxia type 2. Nat Genet. 1996; 14(3):269-76. DOI: 10.1038/ng1196-269. View

11.

Lattante S, Millecamps S, Stevanin G, Rivaud-Pechoux S, Moigneu C, Camuzat A . Contribution of ATXN2 intermediary polyQ expansions in a spectrum of neurodegenerative disorders. Neurology. 2014; 83(11):990-5. PMC: 4162303. DOI: 10.1212/WNL.0000000000000778. View

12.

King O, Gitler A, Shorter J . The tip of the iceberg: RNA-binding proteins with prion-like domains in neurodegenerative disease. Brain Res. 2012; 1462:61-80. PMC: 3372647. DOI: 10.1016/j.brainres.2012.01.016. View

13.

Ravits J, Appel S, Baloh R, Barohn R, Brooks B, Elman L . Deciphering amyotrophic lateral sclerosis: what phenotype, neuropathology and genetics are telling us about pathogenesis. Amyotroph Lateral Scler Frontotemporal Degener. 2013; 14 Suppl 1:5-18. PMC: 3779649. DOI: 10.3109/21678421.2013.778548. View

14.

Gitler A, Shorter J . RNA-binding proteins with prion-like domains in ALS and FTLD-U. Prion. 2011; 5(3):179-87. PMC: 3226045. DOI: 10.4161/pri.5.3.17230. View

15.

Schwartz J, Ebmeier C, Podell E, Heimiller J, Taatjes D, Cech T . FUS binds the CTD of RNA polymerase II and regulates its phosphorylation at Ser2. Genes Dev. 2012; 26(24):2690-5. PMC: 3533074. DOI: 10.1101/gad.204602.112. View

16.

Figley M, Bieri G, Kolaitis R, Taylor J, Gitler A . Profilin 1 associates with stress granules and ALS-linked mutations alter stress granule dynamics. J Neurosci. 2014; 34(24):8083-97. PMC: 4051967. DOI: 10.1523/JNEUROSCI.0543-14.2014. View

17.

Li Y, King O, Shorter J, Gitler A . Stress granules as crucibles of ALS pathogenesis. J Cell Biol. 2013; 201(3):361-72. PMC: 3639398. DOI: 10.1083/jcb.201302044. View

18.

Bosco D, Morfini G, Karabacak N, Song Y, Gros-Louis F, Pasinelli P . Wild-type and mutant SOD1 share an aberrant conformation and a common pathogenic pathway in ALS. Nat Neurosci. 2010; 13(11):1396-403. PMC: 2967729. DOI: 10.1038/nn.2660. View

19.

Sareen D, ORourke J, Meera P, Muhammad A, Grant S, Simpkinson M . Targeting RNA foci in iPSC-derived motor neurons from ALS patients with a C9ORF72 repeat expansion. Sci Transl Med. 2013; 5(208):208ra149. PMC: 4090945. DOI: 10.1126/scitranslmed.3007529. View

20.

Wen X, Tan W, Westergard T, Krishnamurthy K, Markandaiah S, Shi Y . Antisense proline-arginine RAN dipeptides linked to C9ORF72-ALS/FTD form toxic nuclear aggregates that initiate in vitro and in vivo neuronal death. Neuron. 2014; 84(6):1213-25. PMC: 4632245. DOI: 10.1016/j.neuron.2014.12.010. View