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Mol Neurobiol. 2019 May;56(5):3819-3832. doi: 10.1007/s12035-018-1309-0. Epub 2018 Sep 13.

Trpm2 Ablation Accelerates Protein Aggregation by Impaired ADPR and Autophagic Clearance in the Brain.

Author information

1
College of Pharmacy, Seoul National University, Seoul, 02862, South Korea.
2
Department of Psychiatry and Program in Neuroscience, McLean Hospital, Harvard Medical School, Belmont, MA, 02478, USA.
3
Department of Biomedical Engineering, Hanyang University, Seoul, 04763, South Korea.
4
Sensory Research Center, Brain Science Institute, Korea Institute of Science and Technology, 5 Hwarang-ro 14-gil, Seongbuk-gu, Seoul, 02792, South Korea.
5
Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology, Daejeon, 305-701, South Korea.
6
College of Pharmacy, Chung-ang University, Seoul, 06974, South Korea.
7
Department of Anatomy, College of Medicine, Catholic University of Korea, Seoul, 137-701, South Korea.
8
Department of Biochemistry, College of Medicine, Chonbuk National University, Jeonju, South Korea.
9
Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon, 446-746, South Korea.
10
Department of Active Aging Industry, Hanyang University, Seoul, 04763, South Korea.
11
Department of Neurology, Comprehensive Epilepsy Center, Biomedical Research Institute, Seoul National University Hospital, Seoul, 110-744, South Korea.
12
College of Pharmacy, Seoul National University, Seoul, 02862, South Korea. utoh@kist.ac.kr.
13
Sensory Research Center, Brain Science Institute, Korea Institute of Science and Technology, 5 Hwarang-ro 14-gil, Seongbuk-gu, Seoul, 02792, South Korea. utoh@kist.ac.kr.

Abstract

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.

KEYWORDS:

ADPR; AMP; Autophagy; Protein aggregation; TRPM2

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