期刊
MOLECULAR NEUROBIOLOGY
卷 56, 期 5, 页码 3819-3832出版社
SPRINGER
DOI: 10.1007/s12035-018-1309-0
关键词
ADPR; AMP; Autophagy; Protein aggregation; TRPM2
资金
- National Research Foundation of Korea [2011-0018358] Funding Source: Medline
- National Research Foundation of Korea [2011-0018358] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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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