Deviant lysosomal Ca2+ signalling in neurodegeneration. An introduction.

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.