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Mutations in the ubiquitin (Ub) chaperone Ubiquilin 2 (UBQLN2) cause X-linked forms of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) through unknown mechanisms. Here, we show that aggregation-prone, ALS-associated mutants of UBQLN2 (UBQLN2ALS) trigger heat stress-dependent neurodegeneration in Drosophila. A genetic modifier screen implicated endolysosomal and axon guidance genes, including the netrin receptor, Unc-5, as key modulators of UBQLN2 toxicity. Reduced gene dosage of Unc-5 or its coreceptor Dcc/frazzled diminished neurodegenerative phenotypes, including motor dysfunction, neuromuscular junction defects, and shortened lifespan, in flies expressing UBQLN2ALS alleles. Induced pluripotent stem cells (iPSCs) harboring UBQLN2ALS knockin mutations exhibited lysosomal defects while inducible motor neurons (iMNs) expressing UBQLN2ALS alleles exhibited cytosolic UBQLN2 inclusions, reduced neurite complexity, and growth cone defects that were partially reversed by silencing of UNC5B and DCC. The combined findings suggest that altered growth cone dynamics are a conserved pathomechanism in UBQLN2-associated ALS/FTD.
Pubmed ID: 37039476 RIS Download
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Software performing alignment of high-throughput RNA-seq data. Aligns RNA-seq reads to reference genome using uncompressed suffix arrays.
View all literature mentionsDatabase of Drosophila genetic and genomic information with information about stock collections and fly genetic tools. Gene Ontology (GO) terms are used to describe three attributes of wild-type gene products: their molecular function, the biological processes in which they play a role, and their subcellular location. Additionally, FlyBase accepts data submissions. FlyBase can be searched for genes, alleles, aberrations and other genetic objects, phenotypes, sequences, stocks, images and movies, controlled terms, and Drosophila researchers using the tools available from the "Tools" drop-down menu in the Navigation bar.
View all literature mentionsCommercial vendor and service provider of laboratory reagents and antibodies. Supplier of scientific instrumentation, reagents and consumables, and software services.
View all literature mentionsA read summarization program, which counts mapped reads for the genomic features such as genes and exons.
View all literature mentionsAn antibody supplier which banks and distributes hybridomas and monoclonal antibodies for use in research. The bank includes antibodies against targets such as GFP, transcription factors, stem cells, and human.
View all literature mentionsSoftware package for differential gene expression analysis based on the negative binomial distribution. Used for analyzing RNA-seq data for differential analysis of count data, using shrinkage estimation for dispersions and fold changes to improve stability and interpretability of estimates.
View all literature mentionsWeb service to analyze gene or protein lists. Provides automated meta analysis tools to understand pathways within a group of orthogonal target-discovery studies.
View all literature mentionsDrosophila melanogaster with name lilli[A17-2] cn[1] bw[1]/CyO from BDSC.
View all literature mentionsDrosophila melanogaster with name sc[1] pn[3] g[2rv] Bx[2] from BDSC.
View all literature mentionsDrosophila melanogaster with name w[1118]; Df(2L)ED4651/SM6a from BDSC.
View all literature mentionsDrosophila melanogaster with name Df(2L)BSC37, dpp[EP2232]/CyO from BDSC.
View all literature mentionsDrosophila melanogaster with name w[1118]; Df(2L)BSC180/CyO from BDSC.
View all literature mentionsDrosophila melanogaster with name y[1] sc[*] v[1] sev[21]; P{y[+t7.7] v[+t1.8]=TRiP.HMS01147}attP2 from BDSC.
View all literature mentionsDrosophila melanogaster with name y[1] v[1]; P{y[+t7.7] v[+t1.8]=TRiP.JF01457}attP2 from BDSC.
View all literature mentionsDrosophila melanogaster with name y[1] v[1]; P{y[+t7.7] v[+t1.8]=TRiP.JF01231}attP2 from BDSC.
View all literature mentionsDrosophila melanogaster with name y[1] sc[*] v[1] sev[21]; P{y[+t7.7] v[+t1.8]=UAS-mCherry.VALIUM10}attP2 from BDSC.
View all literature mentionsDrosophila melanogaster with name w[1118]; Df(2R)BSC346/CyO from BDSC.
View all literature mentionsDrosophila melanogaster with name w[1118]; P{w[+mC]=UAS-EGFP}34/TM3, Sb[1] from BDSC.
View all literature mentionsDrosophila melanogaster with name y[1] sc[*] v[1] sev[21]; P{y[+t7.7] v[+t1.8]=TRiP.HMS01099}attP2 from BDSC.
View all literature mentionsDrosophila melanogaster with name w[*]; P{w[+mC]=UAS-GFP-Rab5}3 from BDSC.
View all literature mentionsDrosophila melanogaster with name w[1118]; PBac{w[+mC]=WH}beat-Ib[f04746] from BDSC.
View all literature mentionsDrosophila melanogaster with name y[1] v[1]; P{y[+t7.7] v[+t1.8]=TRiP.JF03335}attP2 from BDSC.
View all literature mentionsDrosophila melanogaster with name y[1] v[1]; P{y[+t7.7] v[+t1.8]=TRiP.JF01355}attP2 from BDSC.
View all literature mentionsDrosophila melanogaster with name y[1] sc[*] v[1] sev[21]; P{y[+t7.7] v[+t1.8]=TRiP.HMS00147}attP2 from BDSC.
View all literature mentionsDrosophila melanogaster with name y[1] sc[*] v[1] sev[21]; P{y[+t7.7] v[+t1.8]=TRiP.HMC04226}attP40 from BDSC.
View all literature mentionsDrosophila melanogaster with name y[1] sc[*] v[1] sev[21]; P{y[+t7.7] v[+t1.8]=TRiP.HMC05547}attP40 from BDSC.
View all literature mentionsDrosophila melanogaster with name w[1118]; Df(2L)Exel6038, P{w[+mC]=XP-U}Exel6038/CyO from BDSC.
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