Trpm2 Ablation Accelerates Protein Aggregation by Impaired ADPR and Autophagic Clearance in the Brain
- Trpm2 Ablation Accelerates Protein Aggregation by Impaired ADPR and Autophagic Clearance in the Brain
- 오우택; 이병준; 김형섭; Yongwoo Jang; Seungmoon Jung; Sung Hoon Lee; Ji Hyun Jeon; In-Beom Kim; Seo-Ho Lee; Byung-Ju Kim; Uh-Hyun Kim; Yunjong Lee; Sung Min Kim; Daejong Jeon; So-Young Lee
- Issue Date
- Molecular neurobiology
- VOL 56, NO 5-3832
- TRPM2 a cation channel is also known to work as an enzyme that hydrolyzes highly reactive, neurotoxic ADP-ribose (ADPR). Although ADPR is hydrolyzed by NUT9 pyrophosphatase in major organs, the enzyme is defective in the brain. The present study questions the role of TRPM2 in the catabolism of ADPR in the brain. Genetic ablation of Trpm2 results in the disruption of ADPR catabolism that leads to the accumulation of ADPR and reduction in AMP. Trpm2− /− mice elicit the reduction in autophagosome formation in the hippocampus. Trpm2− mice also show aggregations of proteins in the hippocampus, aberrant structural changes and neuronal connections in synapses, and neuronal degeneration. Trpm2− mice exhibit learning and memory impairment, enhanced neuronal intrinsic excitability, and imbalanced synaptic transmission. These results respond to long-unanswered questions regarding the potential role of the enzymatic function of TRPM2 in the brain, whose dysfunction evokes protein aggregation. In addition, the present finding answers to the conflicting reports such as neuroprotective or neurodegenerative phenotypes observed in Trpm2− mice.
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