TY  - JOUR
AU  - Höfs, Lennart
AU  - Geißler-Lösch, David
AU  - Falkenburger, Björn H
TI  - PLEKHM1 Overexpression Impairs Autophagy and Exacerbates Neurodegeneration in rAAV-α-Synuclein Mice.
JO  - Cells
VL  - 14
IS  - 17
SN  - 2073-4409
CY  - Basel
PB  - MDPI
M1  - DZNE-2025-01109
SP  - 1340
PY  - 2025
AB  - The aggregation of α-synuclein (αSyn) is a central feature of Parkinson's disease (PD) and other synucleinopathies. The efficient clearance of αSyn depends largely on the autophagy-lysosomal pathway. Emerging genetic evidence highlights the role of pleckstrin homology and RUN domain-containing M1 protein (PLEKHM1), a critical regulator of autophagosome-lysosome fusion, in the pathogenesis of multiple neurodegenerative diseases. This study investigates the possible effects of increased PLEKHM1 expression on αSyn pathology and neurodegeneration in mice. We utilized a mouse model of PD that is based on A53T-αSyn overexpression, achieved by the stereotactic injection of recombinant adeno-associated viral vectors (rAAV) into the substantia nigra. Additionally, this study explores the effect of PLEKHM1 overexpression on the autophagy-lysosomal pathway under physiological conditions, using transgenic autophagy reporter mice. PLEKHM1 overexpression facilitated the αSyn-induced degeneration of dopaminergic somata in the substantia nigra and degeneration of dopaminergic axon terminals in the striatum. In concert with αSyn expression, PLEKHM1 also potentiated microglial activation. The extent of αSyn pathology, as reported by staining for phosphorylated αSyn, was not affected by PLEKHM1. Using RFP-EGFP-LC3 autophagy reporter mice, rAAV-mediated PLEKHM1 overexpression reduced lysosomal and autolysosomal area, increased LAMP1-LC3 colocalization, and decreased the autolysosome-to-autophagosome ratio. Concurrently, PLEKHM1 overexpression in both genotypes caused p62 accumulation, accompanied by reduced overlap with lysosomal and autophagosomal markers but increased colocalization with autolysosomal markers, indicating impaired cargo degradation during late-stage autophagy. Taken together, elevated PLEKHM1 levels exacerbate neurodegeneration in αSyn-overexpressing mice, possibly by impairing autophagic flux. Now, with in vivo evidence complementing genetic data, alterations in PLEKHM1 expression appear to compromise autophagy, potentially enhancing neuronal vulnerability to secondary insults like αSyn pathology.
KW  - Animals
KW  - Autophagy: genetics
KW  - alpha-Synuclein: metabolism
KW  - alpha-Synuclein: genetics
KW  - Dependovirus: genetics
KW  - Dependovirus: metabolism
KW  - Mice
KW  - Lysosomes: metabolism
KW  - Disease Models, Animal
KW  - Mice, Transgenic
KW  - Substantia Nigra: metabolism
KW  - Substantia Nigra: pathology
KW  - Parkinson Disease: pathology
KW  - Parkinson Disease: metabolism
KW  - Parkinson Disease: genetics
KW  - Mice, Inbred C57BL
KW  - Dopaminergic Neurons: metabolism
KW  - Dopaminergic Neurons: pathology
KW  - Male
KW  - RFP-EGFP-LC3 mice (Other)
KW  - alpha-synuclein (Other)
KW  - autophagic flux (Other)
KW  - autophagy (Other)
KW  - lysosomes (Other)
KW  - mouse model (Other)
KW  - alpha-Synuclein (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:40940751
C2  - pmc:PMC12427628
DO  - DOI:10.3390/cells14171340
UR  - https://pub.dzne.de/record/281362
ER  -