期刊
ACTA NEUROPATHOLOGICA COMMUNICATIONS
卷 9, 期 1, 页码 -出版社
BMC
DOI: 10.1186/s40478-021-01148-z
关键词
ALS; TDP-43; Translation; Motor neuron; Neuromuscular junction; Glypican; Wnt signaling; Drosophila
资金
- National Institutes of Health NIH [NS091299, NS115514]
- ARCS foundation
- NIH [T32-GM008659]
- Undergraduate Biology Research Program
- Beckman Scholars Program
- UArizona Graduate College Award
- Muscular Dystrophy Association B2I award
- Target ALS Foundation
- Sandra Harsha Estate
ALS is a genetically heterogeneous neurodegenerative disease characterized by cytoplasmic aggregates containing TDP-43. Using Drosophila models, it was found that TDP-43 proteinopathy affects translational alterations in motor neurons, particularly impacting spliceosome, pentose phosphate, and oxidative phosphorylation pathways. The study also identified Dlp/GPC6 as a novel target of TDP-43 proteinopathy.
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.
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