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Asada, A.

Publications and source records attributed to Asada, A..

2 recordsLinked to original sources
bioRxiv2020

Increasing glucose uptake into neurons antagonizes brain aging and promotes health and life span under dietary restriction in Drosophila

Brain neurons play a central role in organismal aging, but there is conflicting evidence about the roles of neuronal glucose availability, glucose uptake and metabolism in aging and extended lifespan. Here, we analyzed metabolic changes in the brain neurons of Drosophila during aging. Using a genetically-encoded fluorescent ATP biosensor, we found decreased ATP concentration in the neuronal somata of aged flies, which was correlated with decreased glucose content, expression of glucose transporter and glycolytic enzymes and mitochondrial quality. The age-associated reduction in ATP concentration did not occur in brain neurons with suppressed glycolysis or enhanced glucose uptake, suggesting these pathways contribute to reductions in ATP. Despite age-associated mitochondrial damage, increasing glucose uptake maintained ATP levels, suppressed age-dependent locomotor deficits and extended the life span. Increasing neuronal glucose uptake during dietary restriction resulted in the longest lifespans, suggesting an additive effect of enhancing glucose availability during a bioenergetic challenge on aging.

neuroscience↗
bioRxiv2020

MARK4 with an Alzheimer's disease-related mutation promotes tau hyperphosphorylation directly and indirectly and exacerbates neurodegeneration

Accumulation of the microtubule-associated protein tau is associated with Alzheimers disease (AD). In AD brain, tau is abnormally phosphorylated at many sites, and phosphorylation at Ser262 and Ser356 play critical roles in tau accumulation and toxicity. Microtubule-affinity regulating kinase 4 (MARK4) phosphorylates tau at those sites, and a double de novo mutation in the linker region of MARK4, {Delta}G316E317InsD, is associated with an elevated risk of AD. However, it remains unclear how this mutation affects phosphorylation, aggregation, and accumulation of tau and tau-induced neurodegeneration. Here, we report that MARK4{Delta}G316E317D increases the abundance of highly phosphorylated, insoluble tau species and exacerbates neurodegeneration via Ser262/356-dependent and -independent mechanisms. Using transgenic Drosophila expressing human MARK4 (MARK4wt) or a mutant version of MARK4 (MARK4{Delta}G316E317D), we found that co-expression of MARK4wt and MARK4{Delta}G316E317D increased total tau levels and enhanced tau-induced neurodegeneration, and that MARK4{Delta}G316E317D had more potent effects than MARK4wt. Interestingly, the in vitro kinase activities of MARK4wt and MARK4{Delta}G316E317D were similar. Blocking tau phosphorylation at Ser262 and Ser356 by alanine substitutions protected tau from the effects of MARK4wt, but not from MARK4{Delta}G316E317D. While both MARK4wt and MARK4{Delta}G316E317D increased the levels of oligomeric forms of tau, MARK4{Delta}G316E317D further boosted the levels of tau phosphorylated at several sites other than Ser262/356 and increased the detergent insolubility of tau in vivo. Together, these findings suggest that MARK4{Delta}G316E317D increases tau levels and exacerbates tau toxicity via an additional gain-of-function mechanism, and that modification in this region of MARK4 may impact disease pathogenesis.

neuroscience↗