Nitration of TRPM2 as a Molecular Switch Induces Autophagy During Brain Pericyte Injury

Area of Science:

• Neuroscience
• Cell Biology
• Biochemistry

Background:

• Neurovascular pericyte dysfunction contributes to blood-brain barrier breakdown.
• The precise molecular mechanisms driving pericyte injury remain largely unknown.

Purpose of the Study:

• To investigate the roles of the transient receptor potential melastatin-related 2 (TRPM2) channel and autophagy in brain pericyte injury.
• To elucidate the molecular pathways involved in pericyte damage induced by zinc oxide nanoparticles (ZnO-NP).

Main Methods:

• In vitro studies using human brain vascular pericytes exposed to ZnO-NP.
• In vivo studies utilizing TRPM2 knockout mice subjected to ZnO-NP-induced vascular injury.
• Mass spectrometry to identify tyrosine nitration sites on TRPM2.

Main Results:

• ZnO-NP exposure rapidly induced autophagy and increased TRPM2-S expression in pericytes.
• Tyrosine nitration of TRPM2 at Y1485 was identified as a key event.
• Overexpression of a non-nitrated TRPM2 mutant (Y1485S) attenuated ZnO-NP-induced autophagy and pericyte injury.
• TRPM2 knockout mice showed reduced autophagy and better pericyte preservation after ZnO-NP exposure.

Conclusions:

• Nitrosative stress-induced tyrosine nitration of TRPM2 is a novel mechanism causing autophagy disturbance during pericyte injury.
• TRPM2 plays a critical role in mediating ZnO-NP-induced brain pericyte damage.
• Targeting TRPM2 nitration may offer therapeutic strategies for blood-brain barrier protection.