Deviant lysosomal Ca2+ signalling in neurodegeneration. An introduction

摘要

Lysosomes are key acidic Ca²⁺ stores. The principle Ca²⁺-permeable channels of the lysosome are TRP mucolipins (TRPMLs) and NAADP-regulated two-pore channels (TPCs). Recent studies, reviewed in this collection, have linked numerous neurodegenerative diseases to both gain and loss of function of TRPMLs/TPCs, as well as to defects in acidic Ca²⁺ store content. These diseases span rare lysosomal storage disorders such as Mucolipidosis Type IV and Niemann–Pick disease, type C, through to more common ones such as Alzheimer and Parkinson disease. Cellular phenotypes, underpinned by endo-lysosomal trafficking defects, are reversed by chemical or molecular targeting of TRPMLs and TPCs. Lysosomal Ca²⁺ channels therefore emerge as potential druggable targets in combatting neurodegeneration.