Abstract: Filled with more than 60 different types of hydrolases, the acidic organelle lysosome governs cellular digestion by removing damaged organelles and catabolic products (Xu and Ren, 2015). Beyond the canonical role in the intracellular degradative pathways, lysosome precedes nutrient sensing, autophagy, immune cell signaling, metabolism and membrane repair. Of note, most of these necessary functions are Ca2+-dependent. In this respect, lysosome is now being considered as a dynamic organelle deputed to Ca2+ storing and homeostasis (Patel and Muallem, 2011). Accordingly, lysosomal channels and transporters regulate not only lysosomal ion homeostasis, membrane potential, catabolite export, membrane trafficking, and nutrient sensing, but also the whole cellular Ca2+ homeostasis (Xu and Ren, 2015). Interestingly, dysfunction of lysosomal channels may underlie the pathogenesis of many lysosomal storage diseases, other metabolic disorders and some neurodegenerative diseases (Xu and Ren, 2015). Furthermore, lysosomes continuously communicate and exchange ions with the main intracellular calcium stores, including endoplasmic reticulum (ER) and mitochondria (Tedeschi et al., 2019a). In this respect, we have recently demonstrated a functional interplay between these tiny organelles and the ER through the unique ER Ca2+ sensor, STIM1 (Tedeschi et al., 2021). Therefore, it is not surprising that lysosomal dysfunction, determining organellar Ca2+ dyshomeostasis, may underlie various neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). It has been recently postulated that channelopathy-like mechanisms may contribute to disease progression via pathological alterations in motor neuron intrinsic biophysical properties (Deardorff et al., 2021). In line with this view, we have demonstrated the involvement of a cation-permeable channel localized on lysosomal membrane and belonging to the mammalian mucolipin transient receptor potential (TRP) subfamily, TRPML1 or mucolipin-1, in the pathogenesis of amyotrophic lateral sclerosis/Parkinson-dementia complex (ALS/PDC), a Guamanian form of the disease (Tedeschi et al., 2019b). In this study we found that a progressive downregulation of TRPML1 occurs in motor neurons exposed to the cyanobacterial neurotoxin beta-methylamino-L-alanine (L-BMAA), mainly involved in the disease etiology through an oral ingestion (Dunlop et al., 2021). On the other hand, an early pharmacological stimulation of TRPML1 can efficiently rescue motor neurons from L-BMAA toxicity by counteracting ER stress and autophagy impairment (Tedeschi et al., 2019b). Therefore, we suggest that boosting autophagy via TRPML1 activation could represent a new therapeutic avenue to explore in searching for new effective drugs in ALS.