2. Academic Validation
  3. The synthetic TRPML1 agonist ML-SA1 rescues Alzheimer-related alterations of the endosomal-autophagic-lysosomal system

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

  • J Cell Sci. 2023 Mar 15;136(6):jcs259875. doi: 10.1242/jcs.259875.
Aleksandra Somogyi 1 2 3,  Emily D Kirkham 4,  Emyr Lloyd-Evans 4,  Jincy Winston 5,  Nicholas D Allen 4,  John J Mackrill 6,  Karen E Anderson 7,  Phillip T Hawkins 7,  Sian E Gardiner 8,  Helen Waller-Evans 8,  Rebecca Sims 9,  Barry Boland 2 3,  Cora O'Neill 1 3
Affiliations

Affiliations

  • 1 School of Biochemistry and Cell Biology, BioSciences Institute, University College Cork, T12 YT20 Cork, Ireland.
  • 2 Department of Pharmacology and Therapeutics, Western Gateway Building, University College Cork, T12 XF62 Cork, Ireland.
  • 3 Cork Neuroscience Centre (CNSC), University College Cork, T12 YT20 Cork, Ireland.
  • 4 School of Biosciences, Sir Martin Evans building, Cardiff University, CF10 3AX Cardiff, UK.
  • 5 UK Dementia Research Institute, Hadyn Ellis Building, Cardiff University, CF24 4HQ Cardiff, UK.
  • 6 Department of Physiology, School of Medicine, University College Cork, T12 YT20 Cork, Ireland.
  • 7 The Babraham Institute, Babraham Research Campus, CB22 3AT Cambridge, UK.
  • 8 Medicines Discovery Institute, Main Building, Cardiff University, CF10 3AT Cardiff, UK.
  • 9 Division of Psychological Medicine and Clinical Neuroscience, Cardiff University, C14 4XN Cardiff, UK.
PMID: 36825945 DOI: 10.1242/jcs.259875
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.

Keywords

APOE; Alzheimer's disease; Ca2+; PIKfyve; Phosphoinositides; TRPML1.

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