Amyotrophic Lateral Sclerosis Modifiers in Reveal the Phospholipase D Pathway As a Potential Therapeutic Target

Overview

Journal Genetics

Publisher Oxford University Press

Specialty Genetics

Date 2020 Apr 30

PMID 32345615

Citations 15

Authors

Mark W Kankel

Anindya Sen

Lei Lu

Marina Theodorou

Douglas N Dimlich

Alexander McCampbell

Christopher E Henderson

Neil A Shneider

Spyros Artavanis-Tsakonas

Affiliations

Soon will be listed here.

Abstract

Amyotrophic lateral sclerosis (ALS), commonly known as Lou Gehrig's disease, is a devastating neurodegenerative disorder lacking effective treatments. ALS pathology is linked to mutations in >20 different genes indicating a complex underlying genetic architecture that is effectively unknown. Here, in an attempt to identify genes and pathways for potential therapeutic intervention and explore the genetic circuitry underlying models of ALS, we carry out two independent genome-wide screens for modifiers of degenerative phenotypes associated with the expression of transgenic constructs carrying familial ALS-causing alleles of FUS (hFUS) and TDP-43 (hTDP-43). We uncover a complex array of genes affecting either or both of the two strains, and investigate their activities in additional ALS models. Our studies indicate the pathway that governs phospholipase D activity as a major modifier of ALS-related phenotypes, a notion supported by data we generated in mice and others collected in humans.

Citing Articles

Complex Genetic Framework in Familial Amyotrophic Lateral Sclerosis With a C9ORF72 Mutation: A Case Report.

Frolov A, Dsa E, Henderson C, Guzman M, Hayat G, Martin 3rd J Cureus. 2025; 16(12):e76027.

PMID: 39835009 PMC: 11743604. DOI: 10.7759/cureus.76027.

TDP43 autoregulation gives rise to dominant negative isoforms that are tightly controlled by transcriptional and post-translational mechanisms.

Dykstra M, Weskamp K, Gomez N, Waksmacki J, Tank E, Glineburg M Cell Rep. 2025; 44(1):115113.

PMID: 39792557 PMC: 11848802. DOI: 10.1016/j.celrep.2024.115113.

TDP43 autoregulation gives rise to shortened isoforms that are tightly controlled by both transcriptional and post-translational mechanisms.

Dykstra M, Weskamp K, Gomez N, Waksmacki J, Tank E, Glineburg M bioRxiv. 2024; .

PMID: 39005384 PMC: 11244999. DOI: 10.1101/2024.07.02.601776.

QnAs with Spyros Artavanis-Tsakonas.

Ravindran S Proc Natl Acad Sci U S A. 2024; 121(29):e2412426121.

PMID: 38985765 PMC: 11260132. DOI: 10.1073/pnas.2412426121.

cAMP/PKA signaling regulates TDP-43 aggregation and mislocalization.

Ho D, Shaban M, Mahmood F, Ganguly P, Todeschini L, Van Vactor D Proc Natl Acad Sci U S A. 2024; 121(24):e2400732121.

PMID: 38838021 PMC: 11181030. DOI: 10.1073/pnas.2400732121.

References

Estes P, Boehringer A, Zwick R, Tang J, Grigsby B, Zarnescu D . Wild-type and A315T mutant TDP-43 exert differential neurotoxicity in a Drosophila model of ALS. Hum Mol Genet. 2011; 20(12):2308-21. PMC: 3098735. DOI: 10.1093/hmg/ddr124. View

Xia R, Liu Y, Yang L, Gal J, Zhu H, Jia J . Motor neuron apoptosis and neuromuscular junction perturbation are prominent features in a Drosophila model of Fus-mediated ALS. Mol Neurodegener. 2012; 7:10. PMC: 3325858. DOI: 10.1186/1750-1326-7-10. View

Hautbergue G, Castelli L, Ferraiuolo L, Sanchez-Martinez A, Cooper-Knock J, Higginbottom A . SRSF1-dependent nuclear export inhibition of C9ORF72 repeat transcripts prevents neurodegeneration and associated motor deficits. Nat Commun. 2017; 8:16063. PMC: 5504286. DOI: 10.1038/ncomms16063. View

Cai D, Zhong M, Wang R, Netzer W, Shields D, Zheng H . Phospholipase D1 corrects impaired betaAPP trafficking and neurite outgrowth in familial Alzheimer's disease-linked presenilin-1 mutant neurons. Proc Natl Acad Sci U S A. 2006; 103(6):1936-40. PMC: 1413666. DOI: 10.1073/pnas.0510710103. View

Ritson G, Custer S, Freibaum B, Guinto J, Geffel D, Moore J . TDP-43 mediates degeneration in a novel Drosophila model of disease caused by mutations in VCP/p97. J Neurosci. 2010; 30(22):7729-39. PMC: 2890254. DOI: 10.1523/JNEUROSCI.5894-09.2010. View

Hardiman O, van den Berg L . Edaravone: a new treatment for ALS on the horizon?. Lancet Neurol. 2017; 16(7):490-491. DOI: 10.1016/S1474-4422(17)30163-1. View

Wegorzewska I, Bell S, Cairns N, Miller T, Baloh R . TDP-43 mutant transgenic mice develop features of ALS and frontotemporal lobar degeneration. Proc Natl Acad Sci U S A. 2009; 106(44):18809-14. PMC: 2762420. DOI: 10.1073/pnas.0908767106. View

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

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

10.

Henriques A, Pitzer C, Schneider A . Characterization of a novel SOD-1(G93A) transgenic mouse line with very decelerated disease development. PLoS One. 2010; 5(11):e15445. PMC: 2978730. DOI: 10.1371/journal.pone.0015445. View

11.

Zhang Z, Krainer A . Involvement of SR proteins in mRNA surveillance. Mol Cell. 2004; 16(4):597-607. DOI: 10.1016/j.molcel.2004.10.031. 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.

Lin M, Cheng C, Shen C . Neuronal function and dysfunction of Drosophila dTDP. PLoS One. 2011; 6(6):e20371. PMC: 3105987. DOI: 10.1371/journal.pone.0020371. View

14.

Coyne A, Siddegowda B, Estes P, Johannesmeyer J, Kovalik T, Daniel S . Futsch/MAP1B mRNA is a translational target of TDP-43 and is neuroprotective in a Drosophila model of amyotrophic lateral sclerosis. J Neurosci. 2014; 34(48):15962-74. PMC: 4244467. DOI: 10.1523/JNEUROSCI.2526-14.2014. View

15.

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

16.

Nagy M, Fenton W, Li D, Furtak K, Horwich A . Extended survival of misfolded G85R SOD1-linked ALS mice by transgenic expression of chaperone Hsp110. Proc Natl Acad Sci U S A. 2016; 113(19):5424-8. PMC: 4868459. DOI: 10.1073/pnas.1604885113. View

17.

LARKIN M, Blackshields G, Brown N, Chenna R, McGettigan P, McWilliam H . Clustal W and Clustal X version 2.0. Bioinformatics. 2007; 23(21):2947-8. DOI: 10.1093/bioinformatics/btm404. View

18.

Wang J, Brent J, Tomlinson A, Shneider N, McCabe B . The ALS-associated proteins FUS and TDP-43 function together to affect Drosophila locomotion and life span. J Clin Invest. 2011; 121(10):4118-26. PMC: 3195475. DOI: 10.1172/JCI57883. View

19.

Bunton-Stasyshyn R, Saccon R, Fratta P, Fisher E . SOD1 Function and Its Implications for Amyotrophic Lateral Sclerosis Pathology: New and Renascent Themes. Neuroscientist. 2014; 21(5):519-29. DOI: 10.1177/1073858414561795. View

20.

Vance C, Rogelj B, Hortobagyi T, De Vos K, Nishimura A, Sreedharan J . Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science. 2009; 323(5918):1208-1211. PMC: 4516382. DOI: 10.1126/science.1165942. View