名古屋市立大学大学院薬学研究科 分子生物薬学分野

Mechanism of endosome dynamics underlying neuronal integrity

Lipid transfer-mediated endosome maturation in neurons

Neuropsychiatric disorders are considered to be difficult to treat, because nerve cells are vulnerable and rarely regenerate, and also the connections between them in brain are complicated. We are studying molecular mechanism underlying neuronal integrity that leads to elucidation of the causes of neuropsychiatric disorders.

Recently, the involvement of lipids has been suggested as a causative mechanism of neuropsychiatric disorders. For example, abnormalities in the transport and metabolism of cholesterol have been implicated as a cause of a neurodegenerative disease, Alzheimer's disease. These findings suggest that the normal metabolism and distribution of lipids in neurons is important for maintaining neuronal integrity. Based on these backgrounds, we have been focusing on lipid transport and metabolism as one of the causative mechanisms of neuropsychiatric disorders.

Intracellular transport and metabolism of lipids are mediated by intracellular organelles. For example, Lipids undergo modifications such as hydroxylation and esterification in the endoplasmic reticulum. In addition, Lipids are transported through endosomes and degraded in lysosomes. Thus, the endoplasmic reticulum (ER), endosomes, and lysosomes play a role in lipid regulation. Recently, it has been shown that endosomes and lysosomes communicate with the ER at the sites called membrane contact sites (MCSs), where different organelles come close and molecular information is mutually exchanged.

We found that lipids are transferred from the ER to endosomes at MCSs, which promotes endosome maturation and leads to the maintenance of neuronal integrity. Endosome maturation is a series of processes in which molecules in endosomes are degraded by lysosomal enzymes through fusion of endosomes and lysosomes. Endosome maturation plays an important role in maintaining cellular homeostasis, but the mechanism or function of it has not been well understood. We have shown that one of the causative mechanisms of neurodegeneration is defects in lipid transfer-dependent endosome maturation 【Shirane et al, Nature Commun., 2020】.

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This work began with the analysis of protrudin-binding proteins using proteomics to identify novel lipid transport complexes. This complex contained molecules responsible for a variety of neuropsychiatric disorders, suggesting that it is a complex that plays an important role in maintaining the neuronal health. The relationship between the components in the complex and neuropsychiatric disorders is as follows: Protoludin is associated with neurodegenerative disorder HSP and psychiatric disorders such as depression, VAP is associated with neurodegenerative disorder ALS, PDZD8 is associated with psychiatric disorder PTSD (trauma), and Rab7 is associated with neurological disorder CMT. And we have demonstrated that PDZD8 in this complex has lipid transport activity for the first time. We hope to further elucidate the detailed mechanism of this novel lipid-transfer complex to elucidate the cause of neuropsychiatric disorders.

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