The Development of C9orf72-Related Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Disorders

Overview

Journal Front Genet

Date 2020 Sep 28

PMID 32983232

Citations 18

Authors

Qijie Yang

Bin Jiao

Lu Shen

Affiliations

Soon will be listed here.

Abstract

The expanded GGGGCC hexanucleotide repeat in the non-coding region of the gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). There are three main disease mechanisms: loss of function of C9ORF72 protein, gain of function from the accumulation of sense and antisense (GGGGCC)n in RNA, and from the production of toxic dipeptides repeat proteins (DPRs) by non-AUG initiated translation. While many of the downstream mechanisms have been identified, the specific pathogenic pathway is still unclear. In this article, we provide an overview on the currently available literature and propose several hypotheses: (1) The pathogenesis of -associated ALS/FTD, which cannot be explained by a single mechanism, involves a dual mechanism of both loss and gain of function. (2) The loss of function and gain of function can cause TDP-43 aggregation and damage nucleocytoplasmic transport. (3) Neurodegeneration can be caused by an accumulation of toxic substances in neurons themselves. In addition, we suggest that microglia may cause neurodegeneration by releasing inflammatory factors to neurons. Finally, we summarize several of the most promising treatment strategies.

Citing Articles

Understanding Amyotrophic Lateral Sclerosis: Pathophysiology, Diagnosis, and Therapeutic Advances.

Rizea R, Corlatescu A, Costin H, Dumitru A, Ciurea A Int J Mol Sci. 2024; 25(18).

PMID: 39337454 PMC: 11432652. DOI: 10.3390/ijms25189966.

C9orf72-Associated Dipeptide Repeat Expansions Perturb ER-Golgi Vesicular Trafficking, Inducing Golgi Fragmentation and ER Stress, in ALS/FTD.

Sultana J, Ragagnin A, Parakh S, Saravanabavan S, Soo K, Vidal M Mol Neurobiol. 2024; 61(12):10318-10338.

PMID: 38722513 PMC: 11584443. DOI: 10.1007/s12035-024-04187-4.

Loss of TDP-43 function contributes to genomic instability in amyotrophic lateral sclerosis.

Fang M, Deibler S, Nana A, Vatsavayai S, Banday S, Zhou Y Front Neurosci. 2023; 17:1251228.

PMID: 37849894 PMC: 10577185. DOI: 10.3389/fnins.2023.1251228.

Insight into Tetramolecular DNA G-Quadruplexes Associated with ALS and FTLD: Cation Interactions and Formation of Higher-Ordered Structure.

Zalar M, Wang B, Plavec J, Sket P Int J Mol Sci. 2023; 24(17).

PMID: 37686239 PMC: 10487854. DOI: 10.3390/ijms241713437.

RNA-binding proteins as a common ground for neurodegeneration and inflammation in amyotrophic lateral sclerosis and multiple sclerosis.

Acosta-Galeana I, Hernandez-Martinez R, Reyes-Cruz T, Chiquete E, Aceves-Buendia J Front Mol Neurosci. 2023; 16:1193636.

PMID: 37475885 PMC: 10355071. DOI: 10.3389/fnmol.2023.1193636.

References

Stepto A, Gallo J, Shaw C, Hirth F . Modelling C9ORF72 hexanucleotide repeat expansion in amyotrophic lateral sclerosis and frontotemporal dementia. Acta Neuropathol. 2013; 127(3):377-89. DOI: 10.1007/s00401-013-1235-1. View

Peters O, Cabrera G, Tran H, Gendron T, McKeon J, Metterville J . Human C9ORF72 Hexanucleotide Expansion Reproduces RNA Foci and Dipeptide Repeat Proteins but Not Neurodegeneration in BAC Transgenic Mice. Neuron. 2015; 88(5):902-909. PMC: 4828340. DOI: 10.1016/j.neuron.2015.11.018. View

Lomen-Hoerth C, Murphy J, Langmore S, Kramer J, Olney R, Miller B . Are amyotrophic lateral sclerosis patients cognitively normal?. Neurology. 2003; 60(7):1094-7. DOI: 10.1212/01.wnl.0000055861.95202.8d. View

Xu Z, Poidevin M, Li X, Li Y, Shu L, Nelson D . Expanded GGGGCC repeat RNA associated with amyotrophic lateral sclerosis and frontotemporal dementia causes neurodegeneration. Proc Natl Acad Sci U S A. 2013; 110(19):7778-83. PMC: 3651485. DOI: 10.1073/pnas.1219643110. View

Schludi M, Edbauer D . Targeting RNA G-quadruplexes as new treatment strategy for ALS/FTD. EMBO Mol Med. 2017; 10(1):4-6. PMC: 5760851. DOI: 10.15252/emmm.201708572. View

Mizielinska S, Gronke S, Niccoli T, Ridler C, Clayton E, Devoy A . C9orf72 repeat expansions cause neurodegeneration in Drosophila through arginine-rich proteins. Science. 2014; 345(6201):1192-1194. PMC: 4944841. DOI: 10.1126/science.1256800. View

Xu W, Bao P, Jiang X, Wang H, Qin M, Wang R . Reactivation of nonsense-mediated mRNA decay protects against C9orf72 dipeptide-repeat neurotoxicity. Brain. 2019; 142(5):1349-1364. PMC: 6487333. DOI: 10.1093/brain/awz070. View

ORourke J, Bogdanik L, Yanez A, Lall D, Wolf A, Muhammad A . C9orf72 is required for proper macrophage and microglial function in mice. Science. 2016; 351(6279):1324-9. PMC: 5120541. DOI: 10.1126/science.aaf1064. View

Kim H, Taylor J . Lost in Transportation: Nucleocytoplasmic Transport Defects in ALS and Other Neurodegenerative Diseases. Neuron. 2017; 96(2):285-297. PMC: 5678982. DOI: 10.1016/j.neuron.2017.07.029. View

10.

Ciura S, Lattante S, Le Ber I, Latouche M, Tostivint H, Brice A . Loss of function of C9orf72 causes motor deficits in a zebrafish model of amyotrophic lateral sclerosis. Ann Neurol. 2013; 74(2):180-7. DOI: 10.1002/ana.23946. View

11.

Freibaum B, Lu Y, Lopez-Gonzalez R, Kim N, Almeida S, Lee K . GGGGCC repeat expansion in C9orf72 compromises nucleocytoplasmic transport. Nature. 2015; 525(7567):129-33. PMC: 4631399. DOI: 10.1038/nature14974. View

12.

Dirren E, Aebischer J, Rochat C, Towne C, Schneider B, Aebischer P . SOD1 silencing in motoneurons or glia rescues neuromuscular function in ALS mice. Ann Clin Transl Neurol. 2015; 2(2):167-84. PMC: 4338957. DOI: 10.1002/acn3.162. View

13.

Mizielinska S, Ridler C, Balendra R, Thoeng A, Woodling N, Grasser F . Bidirectional nucleolar dysfunction in C9orf72 frontotemporal lobar degeneration. Acta Neuropathol Commun. 2017; 5(1):29. PMC: 5395972. DOI: 10.1186/s40478-017-0432-x. View

14.

Zhang Y, Gendron T, Ebbert M, ORaw A, Yue M, Jansen-West K . Poly(GR) impairs protein translation and stress granule dynamics in C9orf72-associated frontotemporal dementia and amyotrophic lateral sclerosis. Nat Med. 2018; 24(8):1136-1142. PMC: 6520050. DOI: 10.1038/s41591-018-0071-1. View

15.

Xiao S, MacNair L, McGoldrick P, McKeever P, McLean J, Zhang M . Isoform-specific antibodies reveal distinct subcellular localizations of C9orf72 in amyotrophic lateral sclerosis. Ann Neurol. 2015; 78(4):568-83. DOI: 10.1002/ana.24469. View

16.

Boxer A, Mackenzie I, Boeve B, Baker M, Seeley W, Crook R . Clinical, neuroimaging and neuropathological features of a new chromosome 9p-linked FTD-ALS family. J Neurol Neurosurg Psychiatry. 2010; 82(2):196-203. PMC: 3017222. DOI: 10.1136/jnnp.2009.204081. View

17.

Swinnen B, Bento-Abreu A, Gendron T, Boeynaems S, Bogaert E, Nuyts R . A zebrafish model for C9orf72 ALS reveals RNA toxicity as a pathogenic mechanism. Acta Neuropathol. 2018; 135(3):427-443. DOI: 10.1007/s00401-017-1796-5. View

18.

Mackenzie I, Frick P, Grasser F, Gendron T, Petrucelli L, Cashman N . Quantitative analysis and clinico-pathological correlations of different dipeptide repeat protein pathologies in C9ORF72 mutation carriers. Acta Neuropathol. 2015; 130(6):845-61. DOI: 10.1007/s00401-015-1476-2. View

19.

Vatsavayai S, Yoon S, Gardner R, Gendron T, Vargas J, Trujillo A . Timing and significance of pathological features in C9orf72 expansion-associated frontotemporal dementia. Brain. 2016; 139(Pt 12):3202-3216. PMC: 5790143. DOI: 10.1093/brain/aww250. View

20.

Cooper-Knock J, Walsh M, Higginbottom A, Highley J, Dickman M, Edbauer D . Sequestration of multiple RNA recognition motif-containing proteins by C9orf72 repeat expansions. Brain. 2014; 137(Pt 7):2040-51. PMC: 4065024. DOI: 10.1093/brain/awu120. View