Explore the vast range of titles available.

Amyotrophic lateral sclerosis (ALS) is a genetically heterogeneous neurodegenerative disease in which 97% of patients exhibit cytoplasmic aggregates containing the RNA binding protein TDP-43. Using tagged ribosome affinity purifications in Drosophila models of TDP-43 proteinopathy, we identified TDP-43 dependent translational alterations in motor neurons impacting the spliceosome, pentose phosphate and oxidative phosphorylation pathways. A subset of the mRNAs with altered ribosome association are also enriched in TDP-43 complexes suggesting that they may be direct targets. Among these, dlp mRNA, which encodes the glypican Dally like protein (Dlp)/GPC6, a wingless (Wg/Wnt) signaling regulator is insolubilized both in flies and patient tissues with TDP-43 pathology. While Dlp/GPC6 forms puncta in the Drosophila neuropil and ALS spinal cords, it is reduced at the neuromuscular synapse in flies suggesting compartment specific effects of TDP-43 proteinopathy. These findings together with genetic interaction data show that Dlp/GPC6 is a novel, physiologically relevant target of TDP-43 proteinopathy.

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease affecting both upper and lower motor neuron and marked by progressive muscle weakness. However, the pathogenic mechanisms underlying motor neuron death remain unclear. Currently there is no cure for ALS. Therapies fully capable of mitigating complex disease processes are not well developed and greatly needed. So far, three drugs Riluzole, Radicava and recently Terasemtiv, have been approved for ALS, but none of them are very effective. Recently, a small molecule modulator of vesicle trafficking (Apilimod) has been reported to rescue patients motor neuron survival and improve the degree of degeneration in mouse model of ALS based on C9ORF72 mutations. Here, I used a Drosophila model of ALS to test the therapeutic potential of Apilimod and its target, PIKFYVE, in TDP-43 proteinopathy. My results show that PIKFYVE knock down (PIKFYVE RNAi) in motor neurons rescue locomotor dysfunction caused by TDP-43. Consistent with the PIKFYVE knockdown results, Apilimod also rescues TDP-43-dependent locomotor dysfunction. PIKFYVE knockdown was also able to slightly improve lifespan in TDP-43 mutants. These findings confirm that PIKFYVE may provide a useful, albeit limited therapeutic target for TDP-43 proteinopathy.

Abstract Amyotrophic lateral sclerosis (ALS) is a genetically heterogeneous neurodegenerative disease in which 97% of patients exhibit cytoplasmic aggregates containing the RNA binding protein TDP-43. Using tagged ribosome affinity purifications in Drosophila models of TDP-43 proteinopathy, we identified TDP-43 dependent translational alterations in motor neurons impacting the spliceosome, pentose phosphate and oxidative phosphorylation pathways. A subset of the mRNAs with altered ribosome association are also enriched in TDP-43 complexes suggesting that they may be direct targets. Among these, dlp mRNA, which encodes the glypican Dally like protein (Dlp)/GPC6, a wingless (Wg/Wnt) signaling regulator is insolubilized both in flies and patient tissues with TDP-43 pathology. While Dlp/GPC6 forms puncta in the Drosophila neuropil and ALS spinal cords, it is reduced at the neuromuscular synapse in flies suggesting compartment specific effects of TDP-43 proteinopathy. These findings together with genetic interaction data show that Dlp/GPC6 is a novel, physiologically relevant target of TDP-43 proteinopathy. Competing Interest Statement The authors have declared no competing interest. Footnotes * The manuscript was originally submitted in Summer 2020, the manuscript was pulled back to enhance our bio-informatic analyses and assay toxic loss of function versus gain of function in our model of TDP-43 proteinopathy. * https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE156222