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

Yongwoo Jang1,2,3, Byeongjun Lee4, Hyungsup Kim4

  • 1College of Pharmacy, Seoul National University, Seoul, 02862, South Korea.

Molecular Neurobiology
|September 15, 2018
PubMed

Insights

The TRPM2 enzyme

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Biochemistry

Background:

  • TRPM2 functions as a cation channel and an enzyme hydrolyzing ADP-ribose (ADPR).
  • While NUT9 pyrophosphatase handles ADPR in organs, it's deficient in the brain.
  • The brain's ADPR catabolism mechanism and TRPM2's role remain unclear.

Purpose of the Study:

  • To investigate the enzymatic role of TRPM2 in ADPR catabolism within the brain.
  • To understand the consequences of TRPM2 deficiency on ADPR levels and neuronal function.

Main Methods:

  • Utilized Trpm2 knockout (Trpm2-/-) mice to study ADPR catabolism.
  • Assessed ADPR and AMP levels, autophagosome formation, protein aggregation, synaptic structure, and neuronal function.

Main Results:

  • Genetic ablation of Trpm2 disrupted ADPR catabolism, leading to ADPR accumulation and decreased AMP.
  • Trpm2-/- mice showed reduced autophagosome formation, protein aggregation, and synaptic abnormalities in the hippocampus.
  • These mice exhibited learning/memory deficits, increased neuronal excitability, and imbalanced synaptic transmission.

Conclusions:

  • TRPM2's enzymatic function is critical for ADPR catabolism in the brain.
  • TRPM2 dysfunction contributes to neurodegeneration, protein aggregation, and cognitive impairment.
  • This study clarifies conflicting reports on TRPM2's role in neuroprotection versus neurodegeneration.
Keywords:
ADPRAMPAutophagyProtein aggregationTRPM2

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