Expanding the Toolbox: Novel Modulators of Endolysosomal Cation Channels

Rautenberg, Susanne; Keller, Marco; Leser, Charlotte; Chen, Cheng‐Chang; Bracher, Franz

doi:10.1007/164_2022_605

Cited by 6 publications

(1 citation statement)

References 129 publications

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“…4 A,B). To determine whether these Ca 2+ sparks were TRPML1 mediated, neurons were pre-treated with the TRPML1 inhibitor GW405833, a close analogue of ML-SI1 ( Rautenberg et al, 2022 ). Upon TRPML1 inhibition, the number of spontaneous Ca 2+ sparks were significantly reduced ( P <0.001, Fig.…”

Section: Resultsmentioning

confidence: 99%

The synthetic TRPML1 agonist ML-SA1 rescues Alzheimer-related alterations of the endosomal-autophagic-lysosomal system

Somogyi

Kirkham

Lloyd-Evans

et al. 2023

Journal of Cell Science

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Abnormalities in the endosomal-autophagic-lysosomal (EAL) system are an early event in Alzheimer's disease (AD) pathogenesis. However, the mechanisms underlying these abnormalities are unclear. The transient receptor potential channel mucolipin 1(TRPML1), a vital endosomal-lysosomal Ca2+ channel whose loss of function leads to neurodegeneration, has not been investigated with respect to EAL pathogenesis in late onset AD (LOAD). Here, we identify pathological hallmarks of TRPML1 dysregulation in LOAD neurons, including increased perinuclear clustering and vacuolation of endolysosomes. We reveal that iPSC human cortical neurons expressing APOE e4, the strongest genetic risk factor for LOAD, have significantly diminished TRPML1-induced endolysosomal Ca2+ release. Furthermore, we found that blocking TRPML1 function in primary neurons by depleting the TRPML1 agonist PI(3,5)P2. via PIKfyve inhibition, recreated multiple features of EAL neuropathology evident in LOAD. This included increased endolysosomal Ca2+ content, enlargement and perinuclear clustering of endolysosomes, autophagic vesicle accumulation, and early endosomal enlargement. Strikingly, these AD-like neuronal EAL defects were rescued by TRPML1 reactivation using its synthetic agonist ML-SA1. These findings implicate defects in TRPML1 in LOAD EAL pathogenesis and present TRPML1 as a potential therapeutic target.

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Section: Resultsmentioning

confidence: 99%