TRP Channels as Emerging Therapeutic Targets for Neurodegenerative Diseases.

Chansik Hong,Byeongseok Jeong,Jinsung Kim,Young-Cheul Shin,Insuk So,Hyung Joon Park,Ji Yeon Chung,Jung Eun Lee

doi:10.3389/fphys.2020.00238

Abstract

The development of treatment for neurodegenerative diseases (NDs) such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis is facing medical challenges due to the increasingly aging population. However, some pharmaceutical companies have ceased the development of therapeutics for NDs, and no new treatments for NDs have been established during the last decade. The relationship between ND pathogenesis and risk factors has not been completely elucidated. Herein, we review the potential involvement of transient receptor potential (TRP) channels in NDs, where oxidative stress and disrupted Ca2+ homeostasis consequently lead to neuronal apoptosis. Reactive oxygen species (ROS) -sensitive TRP channels can be key risk factors as polymodal sensors, since progressive late onset with secondary pathological damage after initial toxic insult is one of the typical characteristics of NDs. Recent evidence indicates that the dysregulation of TRP channels is a missing link between disruption of Ca2+ homeostasis and neuronal loss in NDs. In this review, we discuss the latest findings regarding TRP channels to provide insights into the research and quests for alternative therapeutic candidates for NDs. As the structures of TRP channels have recently been revealed by cryo-electron microscopy, it is necessary to develop new TRP channel antagonists and reevaluate existing drugs.

Highlights

Neurodegenerative disorders (NDs) are one of the most devastating types of chronic diseases and lead to a significant social and medical burden on society
Since transient receptor potential (TRP) channels are non-selective, Ca2+-permeable channels that can be opened at resting membrane potential in response to various stimuli, we focused on TRP channels
We identified that the expression level of endogenous TRPC1 in striatal cells of the Huntington’s disease (HD) model was decreased compared to wildtype cells, indicating that HD cells could be more susceptible to oxidative stress due to the activity of the dominant homomeric TRPC5 (Figure 2D; Hong et al, 2015)

Summary

INTRODUCTION

Neurodegenerative disorders (NDs) are one of the most devastating types of chronic diseases and lead to a significant social and medical burden on society. OAG-induced Ca2+ transients were inhibited in MPP+treated murine striatal astrocytes, and the same was observed in HEK293 cells overexpressing TRPC3 (Streifel et al, 2014) These studies suggest that an increased Na+ influx of TRPC3 due to oxidative stress may reduce Ca2+ influx and contribute to the treatment of PD. In a recent zebrafish study, TRPM7 mutation suppressed dopamine-dependent developmental transitions and increased sensitivity to the neurotoxicity of MPP+ (Decker et al, 2014), and expression of the channel-dead variant of TRPM7 in SH-SY5Y cells increased cell death These studies suggest that the role of Mg2+ influx and TRPM7 in dopaminergic neurons is important and could be a therapeutic target for PD. Most of the brain lesions in ND present alongside several

Increase neuronal apoptosis by activation induced oxidative stress

CONCLUSION