C9orf72-mediated ALS and FTD: Multiple Pathways to Disease

Overview

Journal Nat Rev Neurol

Specialty Neurology

Date 2018 Aug 19

PMID 30120348

Citations 347

Authors

Rubika Balendra

Adrian M Isaacs

Affiliations

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Abstract

The discovery that repeat expansions in the C9orf72 gene are a frequent cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) has revolutionized our understanding of these diseases. Substantial headway has been made in characterizing C9orf72-mediated disease and unravelling its underlying aetiopathogenesis. Three main disease mechanisms have been proposed: loss of function of the C9orf72 protein and toxic gain of function from C9orf72 repeat RNA or from dipeptide repeat proteins produced by repeat-associated non-ATG translation. Several downstream processes across a range of cellular functions have also been implicated. In this article, we review the pathological and mechanistic features of C9orf72-associated FTD and ALS (collectively termed C9FTD/ALS), the model systems used to study these conditions, and the probable initiators of downstream disease mechanisms. We suggest that a combination of upstream mechanisms involving both loss and gain of function and downstream cellular pathways involving both cell-autonomous and non-cell-autonomous effects contributes to disease progression.

Citing Articles

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References

Gallia G, Johnson E, Khalili K . Puralpha: a multifunctional single-stranded DNA- and RNA-binding protein. Nucleic Acids Res. 2000; 28(17):3197-205. PMC: 110688. DOI: 10.1093/nar/28.17.3197. View

Ohashi S, Kobayashi S, Omori A, OHara S, Omae A, Muramatsu T . The single-stranded DNA- and RNA-binding proteins pur alpha and pur beta link BC1 RNA to microtubules through binding to the dendrite-targeting RNA motifs. J Neurochem. 2000; 75(5):1781-90. DOI: 10.1046/j.1471-4159.2000.0751781.x. View

Kanai Y, Dohmae N, Hirokawa N . Kinesin transports RNA: isolation and characterization of an RNA-transporting granule. Neuron. 2004; 43(4):513-25. DOI: 10.1016/j.neuron.2004.07.022. View

Masliah E, Rockenstein E, Adame A, Alford M, Crews L, Hashimoto M . Effects of alpha-synuclein immunization in a mouse model of Parkinson's disease. Neuron. 2005; 46(6):857-68. DOI: 10.1016/j.neuron.2005.05.010. View

Hara T, Nakamura K, Matsui M, Yamamoto A, Nakahara Y, Suzuki-Migishima R . Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature. 2006; 441(7095):885-9. DOI: 10.1038/nature04724. View

Komatsu M, Waguri S, Chiba T, Murata S, Iwata J, Tanida I . Loss of autophagy in the central nervous system causes neurodegeneration in mice. Nature. 2006; 441(7095):880-4. DOI: 10.1038/nature04723. View

Neumann M, Sampathu D, Kwong L, Truax A, Micsenyi M, Chou T . Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science. 2006; 314(5796):130-3. DOI: 10.1126/science.1134108. View

Arai T, Hasegawa M, Akiyama H, Ikeda K, Nonaka T, Mori H . TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Biochem Biophys Res Commun. 2006; 351(3):602-11. DOI: 10.1016/j.bbrc.2006.10.093. View

Asuni A, Boutajangout A, Quartermain D, Sigurdsson E . Immunotherapy targeting pathological tau conformers in a tangle mouse model reduces brain pathology with associated functional improvements. J Neurosci. 2007; 27(34):9115-29. PMC: 6672191. DOI: 10.1523/JNEUROSCI.2361-07.2007. View

10.

Lagier-Tourenne C, Polymenidou M, Cleveland D . TDP-43 and FUS/TLS: emerging roles in RNA processing and neurodegeneration. Hum Mol Genet. 2010; 19(R1):R46-64. PMC: 3167692. DOI: 10.1093/hmg/ddq137. View

11.

Elden A, Kim H, Hart M, Chen-Plotkin A, Johnson B, Fang X . Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS. Nature. 2010; 466(7310):1069-75. PMC: 2965417. DOI: 10.1038/nature09320. View

12.

Masliah E, Rockenstein E, Mante M, Crews L, Spencer B, Adame A . Passive immunization reduces behavioral and neuropathological deficits in an alpha-synuclein transgenic model of Lewy body disease. PLoS One. 2011; 6(4):e19338. PMC: 3084838. DOI: 10.1371/journal.pone.0019338. View

13.

Barry A, Klyubin I, Mc Donald J, Mably A, Farrell M, Scott M . Alzheimer's disease brain-derived amyloid-β-mediated inhibition of LTP in vivo is prevented by immunotargeting cellular prion protein. J Neurosci. 2011; 31(20):7259-63. PMC: 6622598. DOI: 10.1523/JNEUROSCI.6500-10.2011. View

14.

Boutajangout A, Ingadottir J, Davies P, Sigurdsson E . Passive immunization targeting pathological phospho-tau protein in a mouse model reduces functional decline and clears tau aggregates from the brain. J Neurochem. 2011; 118(4):658-67. PMC: 3366469. DOI: 10.1111/j.1471-4159.2011.07337.x. View

15.

DeJesus-Hernandez M, Mackenzie I, Boeve B, Boxer A, Baker M, Rutherford N . Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron. 2011; 72(2):245-56. PMC: 3202986. DOI: 10.1016/j.neuron.2011.09.011. View

16.

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

17.

Murray M, DeJesus-Hernandez M, Rutherford N, Baker M, Duara R, Graff-Radford N . Clinical and neuropathologic heterogeneity of c9FTD/ALS associated with hexanucleotide repeat expansion in C9ORF72. Acta Neuropathol. 2011; 122(6):673-90. PMC: 3277860. DOI: 10.1007/s00401-011-0907-y. View

18.

Gijselinck I, Van Langenhove T, van der Zee J, Sleegers K, Philtjens S, Kleinberger G . A C9orf72 promoter repeat expansion in a Flanders-Belgian cohort with disorders of the frontotemporal lobar degeneration-amyotrophic lateral sclerosis spectrum: a gene identification study. Lancet Neurol. 2011; 11(1):54-65. DOI: 10.1016/S1474-4422(11)70261-7. View

19.

Simon-Sanchez J, Dopper E, Cohn-Hokke P, Hukema R, Nicolaou N, Seelaar H . The clinical and pathological phenotype of C9ORF72 hexanucleotide repeat expansions. Brain. 2012; 135(Pt 3):723-35. DOI: 10.1093/brain/awr353. View

20.

Hsiung G, DeJesus-Hernandez M, Feldman H, Sengdy P, Bouchard-Kerr P, Dwosh E . Clinical and pathological features of familial frontotemporal dementia caused by C9ORF72 mutation on chromosome 9p. Brain. 2012; 135(Pt 3):709-22. PMC: 3286328. DOI: 10.1093/brain/awr354. View