| First Author | H?fs L | Year | 2025 |
| Journal | Cells | Volume | 14 |
| Issue | 17 | PubMed ID | 40940751 |
| Mgi Jnum | J:382925 | Mgi Id | MGI:8246021 |
| Doi | 10.3390/cells14171340 | Citation | Hofs L, et al. (2025) PLEKHM1 Overexpression Impairs Autophagy and Exacerbates Neurodegeneration in rAAV-alpha-Synuclein Mice. Cells 14(17) |
| abstractText | The aggregation of alpha-synuclein (alphaSyn) is a central feature of Parkinson's disease (PD) and other synucleinopathies. The efficient clearance of alphaSyn 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 alphaSyn pathology and neurodegeneration in mice. We utilized a mouse model of PD that is based on A53T-alphaSyn 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 alphaSyn-induced degeneration of dopaminergic somata in the substantia nigra and degeneration of dopaminergic axon terminals in the striatum. In concert with alphaSyn expression, PLEKHM1 also potentiated microglial activation. The extent of alphaSyn pathology, as reported by staining for phosphorylated alphaSyn, 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 alphaSyn-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 alphaSyn pathology. |
