Increased HSC70‐4/HSPA8 regulated autophagy reduces tau‐mediated synaptic dysfunction

Abstract

Background Tau tangles are present in the brains of Alzheimer diseased (AD) patients and strategies that remove Tau oligomers and Tau tangles are tested in clinical trials. These anti‐Tau drugs may keep misfolded Tau from spreading and damaging additional neurons, but they may be inefficient at targeting soluble Tau early in the disease before tangles are formed and thus be relatively late to spare cognitive defects. Our research is therefore refreshing as it may tackle early Tau induced dysfunction. We have shown in Drosophila that the overexpression of the chaperone Hsc70‐4 promotes endosomal microautophagy at presynapses and regulates the turnover of synaptic proteins harboring pentapeptide motifs, biochemically related to the KFERQ sequence (Uytterhoeven, 2015). Intriguingly, Tau harbors two such motifs. Method We tested if increasing endosomal microautophagy by overexpressing Hsc70‐4 has an effect on Tau‐mediated synaptic defects . Result Indeed, increasing microautophagy reduces presynaptic Tau levels and presynaptic vesicle sequestrations at presynapses, two phenotypes previously shown by our lab to appear after expressing pathogenic Tau in the fly nervous system (Zhou, 2017 and McInnes, 2018). In addition, via lentiviral‐mediated overexpression of HSPA8, the human homologue of Hsc70‐4, we are able to increase HSPA8 regulated autophagy in human neurons. Conclusion Together, our work provides important molecular insight into the contribution of Hsc70‐4/HSPA8 regulated autophagy on AD disease onset and progression and may contribute to the development of methods and treatments to alleviate the defects in dementia.

Genomic Convergence in Hibernating Mammals Elucidates the Genetics of Metabolic Regulation in the Hypothalamus

“…Some pHibAR-Hub genes increase or decrease their expression in a particular cell type according to metabolic state. Hspa8 is a member of the heatshock protein 70 (HSP 70) family with roles in autophagy and protein-folding that breaks down functional amyloids in the brain (54), and has important roles in neuroprotective processes and effects on protein misfolding in neurodegenerative diseases (55)(56)(57)(58)(59)(60)(61). We found that Hspa8 expression is reduced in the 72hr FD condition in glia and GABA neurons, but not in glutamatergic or other neurons (Fig.…”

“…6E, F). Changes to Hspa8 expression can have neuroprotective effects (54,60) and influence the accumulation of protein aggregates involved in neurodegenerative processes (62). Importantly, hibernators evolved mechanisms for enhanced neuroprotection and resolving tauopathy (14), and we therefore performed a detailed analysis to understand the regulatory program of this candidate gene at the cellular level.…”