LAMTOR1 inhibition of TRPML1‐dependent lysosomal calcium release regulates dendritic lysosome trafficking and hippocampal neuronal function

Abstract

Lysosomes function not only as degradatory compartments but also as dynamic intracellular calcium ion stores. The transient receptor potential mucolipin 1 (TRPML1) channel mediates lysosomal Ca 2+ release, thereby participating in multiple cellular functions. The pentameric Ragulator complex, which plays a critical role in the activation of mTORC1, is also involved in lysosomal trafficking and is anchored to lysosomes through its LAMTOR1 subunit. Here, we report that the Ragulator restricts lysosomal trafficking in dendrites of hippocampal neurons via LAMTOR1-mediated tonic inhibition of TRPML1 activity, independently of mTORC1. LAMTOR1 directly interacts with TRPML1 through its N-terminal domain. Eliminating this inhibition in hippocampal neurons by LAMTOR1 deletion or by disrupting LAMTOR1-TRPML1 binding increases TRPML1-mediated Ca 2+ release and facilitates dendritic lysosomal trafficking powered by dynein. LAMTOR1 deletion in the hippocampal CA1 region of adult mice results in alterations in synaptic plasticity, and in impaired object-recognition memory and contextual fear conditioning, due to TRPML1 activation. Mechanistically, changes in synaptic plasticity are associated with increased GluA1 dephosphorylation by calcineurin and lysosomal degradation. Thus, LAMTOR1-mediated inhibition of TRPML1 is critical for regulating dendritic lysosomal motility, synaptic plasticity, and learning.

Lack of UBE3A-Mediated Regulation of Synaptic SK2 Channels Contributes to Learning and Memory Impairment in the Female Mouse Model of Angelman Syndrome

“…A few lines of transgenic mice with maternal UBE3a deficiency (AS mice) have been developed and tremendously contributed to our understanding of AS pathogenesis, as these mice exhibit several features of the human disease, including reduced brain size, abnormal electroencephalogram, learning and memory deficits, motor dysfunction [24][25][26][27][28], as well as impairment in long-term potentiation (LTP) of synaptic transmission [25,[29][30][31][32][33]. The influence of age and background strains on phenotypic syndromes and their severity across these mouse models has been well characterized [26,34,35].…”

Lysosomal Ca2+ as a mediator of palmitate-induced lipotoxicity

“…We have also studied the effect of inhibitors of TRPML1 or TRPM2. However, ML-SI1, ML-SI3 or N-(p-amylcinnamoyl)anthranilic acid inhibiting TRPML1, TRPML1/2/3 and TRPM2, respectively [ 42 – 44 ], did not inhibit PA-induced lipotoxic death of HepG2 cells (Oh S-J et al, unpublished results). Furthermore, Ned-19, an inhibitor of TPC1/2 which has been reported to be associated with ischemia-reperfusion injury [ 45 ], was also without effect (Oh S-J et al, unpublished results).…”

Alterations in Proteostasis Mechanisms in Niemann–Pick Type C Disease

“…TRPML1 may be an option as a therapeutic target in NPC because its overexpression reduces cholesterol accumulation, corrects lysosomal transport defects, and also has beneficial effects on other neurodegenerative diseases, such as Alzheimer's disease, by enhancing dynein-dependent lysosomal transport by promoting the release of lysosomal Ca 2+ . This argues for the importance of this receptor and the release of lysosomal Ca 2+ in lysosomal transport and neurodegenerative diseases [34,96,99].…”