Biology subjects

Iijima, K. M.

Publications and source records attributed to Iijima, K. M..

4 recordsLinked to original sources

bioRxiv2024

Axonal distribution of mitochondria maintains neuronal autophagy during aging via eIF2β

Neuronal aging and neurodegenerative diseases are accompanied by proteostasis collapse, while the cellular factors that trigger it have not been identified. Impaired mitochondrial transport in the axon is another feature of aging and neurodegenerative diseases. Using Drosophila, we found that genetic depletion of axonal mitochondria causes dysregulation of protein degradation. Axons with mitochondrial depletion showed abnormal protein accumulation and autophagic defects. Lowering neuronal ATP levels by blocking glycolysis did not reduce autophagy, suggesting that autophagic defects are associated with mitochondrial distribution. We found that eIF2{beta} was increased by the depletion of axonal mitochondria via proteome analysis. Phosphorylation of eIF2, another subunit of eIF2, was lowered, and global translation was suppressed. Neuronal overexpression of eIF2{beta} phenocopied the autophagic defects and neuronal dysfunctions, and lowering eIF2{beta} expression rescued those perturbations caused by depletion of axonal mitochondria. These results indicate the mitochondria-eIF2{beta} axis maintains proteostasis in the axon, of which disruption may underlie the onset and progression of age-related neurodegenerative diseases. HighlightsO_LILoss of axonal mitochondria impairs autophagy and accumulates proteins in the axon C_LIO_LILoss of axonal mitochondria increases eIF2{beta} and decreases p-eIF2 C_LIO_LINeuronal upregulation of eIF2{beta} induces autophagic defects and locomotor dysfunction C_LIO_LILowering eIF2{beta} rescues autophagic defects caused by loss of axonal mitochondria C_LI

cell biology↗

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↗

bioRxiv2019

Disruption of a RAC1-centred protein interaction network is associated with Alzheimer’s disease pathology and causes age-dependent neurodegeneration

The molecular biological mechanisms of Alzheimers disease (AD) involve disease-associated cross-talk through many genes and include a loss of normal as well as a gain of abnormal interactions among genes. A protein domain network (PDN) is a collection of physical bindings that occur between protein domains, and the states of the PDNs in patients with AD are likely to be perturbed compared to those in normal healthy individuals. To identify PDN changes that cause neurodegeneration, we analysed the PDNs that occur among genes co-expressed in each of three brain regions at each stage of AD. Our analysis revealed that the PDNs collapsed with the progression of AD stage and identified five hub genes, including Rac1, as key players in PDN collapse. Using publicly available gene expression data, we confirmed that the mRNA expression level of the RAC1 gene was downregulated in the entorhinal cortex (EC) of AD brains. To test the causality of these changes in neurodegeneration, we utilized Drosophila as a genetic model and found that modest knockdown of Rac1 in neurons was sufficient to cause age-dependent behavioural deficits and neurodegeneration. Finally, we identified a microRNA, hsa-miR-101-3p, as a potential regulator of RAC1 in AD brains. As the Braak neurofibrillary tangle (NFT) stage progressed, the expression levels of hsa-miR-101-3p were upregulated specifically in the EC. Furthermore, overexpression of hsa-miR-101-3p in the human neuronal cell line SH-SY5Y caused RAC1 downregulation. These results highlight the utility of our integrated network approach for identifying causal changes leading to neurodegeneration in AD.

genomics↗