TRPML1: A novel therapeutic target to remediate endolysosomal pathology in Alzheimer’s disease

Abstract

Background TRPML1 (transient receptor potential channel mucolipin 1) is an essential endosomal‐lysosomal Ca2+ channel whose loss of function can cause neurodegeneration. Defects in the endosomal‐autophagic‐lysosomal (EAL) are a primary feature of Alzheimer’s disease (AD) pathogenesis, and many late‐onset AD (LOAD) risk genes, including APOE4, functionally converge on the EAL system, although the underlying mechanisms remain unclear. Dysfunctional TRPML1 activity has been reported in genetic models of AD involving cells deficient in presenilin 1. Here, we hypothesised that TRPML1 malfunction underlies EAL defects in LOAD, and can be therapeutically targeted to remediate EAL defects in LOAD. Method Cell and molecular approaches were employed to investigate the integrity of endolysosomes in LOAD (n = 10) and matched control (n = 10) post‐mortem brain, and in APOE isoform expressing human cortical neurons derived from induced pluripotent stems cells. TRPML1 activity was manipulated in primary neurons to determine whether blocking TRPML1 could recreate EAL defects evident in LOAD and whether TRPML1 could be targeted therapeutically to protect against EAL defects in LOAD. Result We identified perinuclear clustering of enlarged LAMP‐1‐positive endolysosomes in post‐mortem LOAD hippocampal neurons, indicative of TRMPL1 dysregulation. Our results reveal for the first time that TRPML1 activity was significantly reduced in APOE4 expressing human cortical neurons derived from induced pluripotent stems cells, resulting in elevated endolysosomal Ca2+ content. Furthermore, depletion of the TRPML1 agonist, PI(3,5)P2 in primary neurons using YM201636, recreated many features of AD endolysosomal neuropathology. This included endolysosomal swelling, accumulation of autophagic vacuoles (AVs), and increased endolysosomal Ca2+ accumulation. Strikingly, the re‐activation of TRPML1 in YM201636‐treated cultures, using the synthetic small molecule agonist ML‐SA1, restored endolysosomal Ca2+ pool to its normal size, mitigated endolysosomal swelling, prevented the accumulation of AVs, and increased levels of non‐pathogenic alpha‐secretase derived C‐terminal fragments of the amyloid precursor protein (APP). Conclusion Together, these finding implicate defects in TRPML1 in LOAD and present TRPML1 as a novel potential therapeutic target to remediate endolysosomal pathology in AD.

Role of Calcium Modulation in the Pathophysiology and Treatment of Alzheimer’s Disease

“…It was found to be downregulated in APP/PS1 transgenic mice, while the overexpression of this channel was associated with rescuing memory and recognition impairment and with attenuated neuronal apoptosis in APP/PS1 transgenic mice [321]. The activation of these channels in postmortem late-onset AD (LOAD) hippocampal neurons using the agonist ML-SA1 was shown to restore endolysosomal calcium pools to normal levels, decrease endolysosomal swelling, and increase the levels of non-pathogenic fragments of APP [322]. Despite these promising results, few studies have examined TRPML1 regulation in AD models.…”