Pathogenic tauR406W induced neurodegeneration and memory deficits rescued by HDAC6 null mutation in Drosophila melanogaster

神经退行性变 黑腹果蝇 HDAC6型 生物 细胞生物学 神经科学 基因 遗传学 病理 医学 疾病 组蛋白 组蛋白脱乙酰基酶
作者
Arkajyoti Sarkar,Sahabudeen Sheik Mohideen
出处
期刊:Alzheimers & Dementia [Wiley]
卷期号:17 (S2) 被引量:1
标识
DOI:10.1002/alz.058020
摘要

Genetic screening was performed by Drosophila melanogaster to observe how different variants of HDAC6 regulate tauR406W mediated neurodegeneration.The versatile Gal4-UAS gene expression system was used to express variants of HDAC6 and tauR406W with the help of pan-eye specific GMR-Gal4, and pan-neuronal elav-Gal4 in the flies. The extent of neurodegeneration was quantified by automated analysis of degenerated tissues, the number of aggregates, immunofluorescence, and also with the help of various behavioral and memory assays. Live imaging was performed on the wing with GCamP6f to study the role of HDAC6 on axonal transport.On expressing the HDAC6 mutants (H237A, H664A) the levels of total tau were increased followed by a decrease in acetylated α-tubulin levels. We have also noticed a reduction in mRNA levels of Atg1, Atg8, and Atg12. On analyzing the various regions of the eye, there was a significant surface degeneration as well as an increase in the number of aggregates. The wings of flies expressing a GCamp6f and eb1-eGFP displayed a defective axonal transport as well as damaged neuronal morphology. Upon expressing HDAC6[KO], there was amelioration in memory deficits, neurodegeneration and the flies regained a better retinal surface morphology.HDAC6 can interact with tau mutations outside the microtubule-binding region (MTBR) and can cause memory deficits, behavioral anomalies. Inhibition of HDAC6 via gene therapy can be an effective therapy to treat Alzheimer's disease and other associated dementias.
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