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

Authors
Jang, YongwooLee, ByeongjunKim, HyungsupJung, SeungmoonLee, Sung HoonLee, So-YoungJeon, Ji HyunKim, In-BeomLee, Seo-HoKim, Byung-JuKim, Uh-HyunLee, YunjongKim, Sung MinJeon, DaejongOh, Uhtaek
Issue Date
2019-05
Publisher
SPRINGER
Citation
MOLECULAR NEUROBIOLOGY, v.56, no.5, pp.3819 - 3832
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
INCLUSION-BODIES; OXIDATIVE STRESS; CHANNELS; RIBOSE; LIPOFUSCIN; CONTRIBUTES; ACTIVATION; REVEALS; SYSTEM; KINASE; ADPR; AMP; Autophagy; Protein aggregation; TRPM2
ISSN
0893-7648
URI
https://pubs.kist.re.kr/handle/201004/120034
DOI
10.1007/s12035-018-1309-0
Appears in Collections:
KIST Article > 2019
Files in This Item:
There are no files associated with this item.
Export
RIS (EndNote)
XLS (Excel)
XML

qrcode

Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.

BROWSE