Pathophysiological Role of Transient Receptor Potential Mucolipin Channel 1 in Calcium-Mediated Stress-Induced Neurodegenerative Diseases.

Giorgio Santoni,Consuelo Amantini,Maria Beatrice Morelli,Oliviero Marinelli,Massimo Nabissi,Federica Maggi

doi:10.3389/fphys.2020.00251

Giorgio Santoni, Consuelo Amantini + Show 4 more

Open Access

https://doi.org/10.3389/fphys.2020.00251

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Abstract

Mucolipins (TRPML) are endosome/lysosome Ca2+ permeable channels belonging to the family of transient receptor potential channels. In mammals, there are three TRPML proteins, TRPML1, 2, and 3, encoded by MCOLN1-3 genes. Among these channels, TRPML1 is a reactive oxygen species sensor localized on the lysosomal membrane that is able to control intracellular oxidative stress due to the activation of the autophagic process. Moreover, genetic or pharmacological inhibition of the TRPML1 channel stimulates oxidative stress signaling pathways. Experimental data suggest that elevated levels of reactive species play a role in several neurological disorders. There is a need to gain better understanding of the molecular mechanisms behind these neurodegenerative diseases, considering that the main sources of free radicals are mitochondria, that mitochondria/endoplasmic reticulum and lysosomes are coupled, and that growing evidence links neurodegenerative diseases to the gain or loss of function of proteins related to lysosome homeostasis. This review examines the significant roles played by the TRPML1 channel in the alterations of calcium signaling responsible for stress-mediated neurodegenerative disorders and its potential as a new therapeutic target for ameliorating neurodegeneration in our ever-aging population.

Highlights

Neurodegenerative diseases entail progressive destruction and loss of neural cells and impairment of both motor and cognitive functions
Mitochondrial function and resistance to oxidative stress are compromised during the aging phase, and this is a starting point for the onset of neurodegenerative diseases (Cenini et al, 2019)
Given that lysosomes are the major contributors to autophagic recycling of mitochondria, to misfolded protein and to damaged organelles, it may be that defects in lysosome function affect mitochondrial recycling, cause accumulation of fragmented mitochondria, and block the ability to buffer cytoplasmic Ca2+, and that these processes in turn sensitize cells to pro-apoptotic signals

Summary

INTRODUCTION

Neurodegenerative diseases entail progressive destruction and loss of neural cells and impairment of both motor and cognitive functions. Zhang et al demonstrated that endogenous ROS are able to regulate lysosomal activities through the TRPML1 channel, which functions as a “ROS sensor” (Zhang et al, 2016). In this way, lysosomal Ca2+ release induces nuclear translocation of transcription factor EB (TFEB) (Medina et al, 2015), followed by autophagosome and lysosome biogenesis, induction of autophagic flux and re-establishment of redox homeostasis. In lysosomes of ADA mutant B-lymphocytes, adenosine accumulation impairs TRPML1 activity and triggers lysosome enlargement and dysfunction (Zhong et al, 2017) These data suggest that the lack of TRPML1 activity could lead to an increased susceptibility to oxidative stress and cell death. Rigorous experiments should be conducted to further explore the possible role of TRPML1 as a therapeutic target in PD

AMYOTROPHIC LATERAL SCLEROSIS

MUCOLIPIDOSIS TYPE IV

DISCUSSION