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Wen, X., An, P., Li, H., Zhou, Z., Sun, Y., Wang, J., Ma, L., Lu, B. (2020). Tau Accumulation via Reduced Autophagy Mediates GGGGCC Repeat Expansion-Induced Neurodegeneration in Drosophila Model of ALS.  Neurosci. Bull. 36(12): 1414--1428.
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Research paper

Expansions of trinucleotide or hexanucleotide repeats lead to several neurodegenerative disorders, including Huntington disease <up>caused by expanded CAG repeats (CAGr) in the HTT gene</up>, and amyotrophic lateral sclerosis <up>ALS, possibly caused by expanded GGGGCC repeats (G4C2r) in the C9ORF72 gene</up>, of which the molecular mechanisms remain unclear. Here, we demonstrated that lowering the Drosophila homologue of tau protein (dtau) significantly rescued in vivo neurodegeneration, motor performance impairments, and the shortened life-span in Drosophila expressing expanded CAGr or expanded G4C2r. Expression of human tau (htau4R) restored the disease-related phenotypes that had been mitigated by the loss of dtau, suggesting an evolutionarily-conserved role of tau in neurodegeneration. We further revealed that G4C2r expression increased tau accumulation by inhibiting autophagosome-lysosome fusion, possibly due to lowering the level of BAG3, a regulator of autophagy and tau. Taken together, our results reveal a novel mechanism by which expanded G4C2r causes neurodegeneration via an evolutionarily-conserved mechanism. Our findings provide novel autophagy-related mechanistic insights into C9ORF72-ALS and possible entry points to disease treatment.

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PubMed Central ID
PMC7719145 (PMC) (EuropePMC)
Related Publication(s)

Tau Accumulation and Defective Autophagy: A Common Pathological Mechanism Underlying Repeat-Expansion-Induced Neurodegenerative Diseases?
Song and Zhang, 2020, Neurosci. Bull. 36(12): 1411--1413 [FBrf0248635]

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    Publication Type
    Neurosci. Bull.
    Neuroscience bulletin
    1673-7067 1995-8218
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