PLEKHM2 Loss of Function Impairs the Activity of iPSC-Derived Neurons via Regulation of Autophagic Flux

Pleckstrin Homology And RUN Domain Containing M2 (PLEKHM2) [delAG] mutation causes dilated cardiomyopathy with left ventricular non-compaction (DCM-LVNC), resulting in a premature death of PLEKHM2[delAG] individuals due to heart failure. PLEKHM2 is a factor involved in autophagy, a master regulator...

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Bibliographic Details
Published in:International journal of molecular sciences 2022-12, Vol.23 (24), p.16092
Main Authors: Ben-Zvi, Hadas, Rabinski, Tatiana, Ofir, Rivka, Cohen, Smadar, Vatine, Gad D
Format: Article
Language:English
Subjects:
Abnormalities
Alzheimer's disease
Autophagosomes - metabolism
Autophagy
Autophagy - genetics
Cardiomyopathy
Congestive heart failure
DCM-LVNC
Dilated cardiomyopathy
Fibroblasts
Flow cytometry
Homeostasis
Homology
Humans
Induced Pluripotent Stem Cells
Life sciences
Lysosomes - metabolism
Motor Neurons
Mutation
neurodegeneration
Neurological disorders
Neurons
Patients
Pleckstrin
PLEKHM2
Pluripotency
Proteins
Stem cells
Therapeutic targets
Ventricle
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Summary:Pleckstrin Homology And RUN Domain Containing M2 (PLEKHM2) [delAG] mutation causes dilated cardiomyopathy with left ventricular non-compaction (DCM-LVNC), resulting in a premature death of PLEKHM2[delAG] individuals due to heart failure. PLEKHM2 is a factor involved in autophagy, a master regulator of cellular homeostasis, decomposing pathogens, proteins and other cellular components. Autophagy is mainly carried out by the lysosome, containing degradation enzymes, and by the autophagosome, which engulfs substances marked for decomposition. PLEKHM2 promotes lysosomal movement toward the cell periphery. Autophagic dysregulation is associated with neurodegenerative diseases' pathogenesis. Thus, modulation of autophagy holds considerable potential as a therapeutic target for such disorders. We hypothesized that PLEKHM2 is involved in neuronal development and function, and that mutated PLEKHM2 (PLEKHM2[delAG]) neurons will present impaired functions. Here, we studied PLEKHM2-related abnormalities in induced pluripotent stem cell (iPSC)-derived motor neurons (iMNs) as a neuronal model. PLEKHM2[delAG] iMN cultures had healthy control-like differentiation potential but exhibited reduced autophagic activity. Electrophysiological measurements revealed that PLEKHM2[delAG] iMN cultures displayed delayed functional maturation and more frequent and unsynchronized activity. This was associated with increased size and a more perinuclear lysosome cellular distribution. Thus, our results suggest that PLEKHM2 is involved in the functional development of neurons through the regulation of autophagic flux.
ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms232416092