ArticleJournal of cell science2023
The synthetic TRPML1 agonist ML-SA1 rescues Alzheimer-related alterations of the endosomal-autophagic-lysosomal system.
Article in Journal of cell science, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
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Who cites it
33 citing papers in PubMed, 44 citations in OpenAlex.
- How to Perform a Tracer Displacement BRET Assay for the TRPML1 Ion Channel.Bio-protocol · 2026Article
- TLDc proteins: Stress-responsive nexus regulators of redox signaling, V-ATPase dynamics, and organellar crosstalk in neurodegeneration.Redox biology · 2026Review
- Lysosomes and lysosomal dysfunction in ageing biology.Nature cell biology · 2026Review
- The Neuroprotective Effect of a Waste Byproduct Obtained From Pomegranate (Punica granatum).Phytotherapy research : PTR · 2026Review
- Two-pore channel-2 controls calmodulin-dependent STIM1 inactivation.Nature communications · 2026Article
- Intercompartmental communication in senescence.FEBS open bio · 2026Review
- Lysosomes as chemical and metabolic organizers of central nervous system injury and repair.Frontiers in chemistry · 2026Review
- One organelle to rule them all: enhancement of lysosomal activity as a therapeutic modality for protein misfolding neurodegenerative diseases.Frontiers in neuroscience · 2026Review
- Focusing on microglial mitochondria-lysosome crosstalk and neuroinflammation underlying depression: from molecular pathways to potential therapeutic interventions.Frontiers in immunology · 2026Review
- Amyloid-Frontiers in neuroscience · 2026Review
- Loss of Fanconi anemia proteins causes a reliance on lysosomal exocytosis.Cell death & disease · 2025Article
- Physiological functions and pharmacological targeting of transient receptor potential channels.Pharmacological reviews · 2025Review
- DMXL1 promotes recruitment of V1-ATPase to lysosomes upon TRPML1 activation.Nature structural & molecular biology · 2025Article
- Lysosomal ion channels and pain.Pain reports · 2025Review
- Lysosomes in the immunometabolic reprogramming of immune cells in atherosclerosis.Nature reviews. Cardiology · 2025Review
- Integrated transcriptomic and single-cell RNA sequencing identifies lysosomal ion channel genes as potential biomarkers for Alzheimer's disease.Frontiers in genetics · 2025Article
- Lysosomal Channels as New Molecular Targets in the Pharmacological Therapy of Neurodegenerative DiseasesCurrent neuropharmacology · 2025Review
- Tail Anchored protein insertion mediated by CAML and TRC40 links to neuromuscular function in mice.PLoS genetics · 2025Article
- Regulatory Mechanisms and Therapeutic Implications of Lysosomal Dysfunction in Alzheimer's Disease.International journal of biological sciences · 2025Review
- Endosomal traffic disorders: a driving force behind neurodegenerative diseases.Translational neurodegeneration · 2024Review
Corrections and comments
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Authors and funding
13 authors at 4 institutions in 2 countries.
Funding
Abstract
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, also known as MCOLN1), 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 induced pluripotent stem cell (iPSC)-derived human cortical neurons expressing APOE ε4, 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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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.