Home > Publications Database > PLEKHM1 Overexpression Impairs Autophagy and Exacerbates Neurodegeneration in rAAV-α-Synuclein Mice. > print

001     281362
005     20251012002039.0
024 7 _ |a 10.3390/cells14171340
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037 _ _ |a DZNE-2025-01109
041 _ _ |a English
082 _ _ |a 570
100 1 _ |a Höfs, Lennart
|0 P:(DE-2719)9002445
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245 _ _ |a PLEKHM1 Overexpression Impairs Autophagy and Exacerbates Neurodegeneration in rAAV-α-Synuclein Mice.
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520 _ _ |a 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.
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650 _ 7 |a RFP-EGFP-LC3 mice
|2 Other
650 _ 7 |a alpha-synuclein
|2 Other
650 _ 7 |a autophagic flux
|2 Other
650 _ 7 |a autophagy
|2 Other
650 _ 7 |a lysosomes
|2 Other
650 _ 7 |a mouse model
|2 Other
650 _ 7 |a alpha-Synuclein
|2 NLM Chemicals
650 _ 2 |a Animals
|2 MeSH
650 _ 2 |a Autophagy: genetics
|2 MeSH
650 _ 2 |a alpha-Synuclein: metabolism
|2 MeSH
650 _ 2 |a alpha-Synuclein: genetics
|2 MeSH
650 _ 2 |a Dependovirus: genetics
|2 MeSH
650 _ 2 |a Dependovirus: metabolism
|2 MeSH
650 _ 2 |a Mice
|2 MeSH
650 _ 2 |a Lysosomes: metabolism
|2 MeSH
650 _ 2 |a Disease Models, Animal
|2 MeSH
650 _ 2 |a Mice, Transgenic
|2 MeSH
650 _ 2 |a Substantia Nigra: metabolism
|2 MeSH
650 _ 2 |a Substantia Nigra: pathology
|2 MeSH
650 _ 2 |a Parkinson Disease: pathology
|2 MeSH
650 _ 2 |a Parkinson Disease: metabolism
|2 MeSH
650 _ 2 |a Parkinson Disease: genetics
|2 MeSH
650 _ 2 |a Mice, Inbred C57BL
|2 MeSH
650 _ 2 |a Dopaminergic Neurons: metabolism
|2 MeSH
650 _ 2 |a Dopaminergic Neurons: pathology
|2 MeSH
650 _ 2 |a Male
|2 MeSH
700 1 _ |a Geißler-Lösch, David
|0 0009-0006-8332-2145
|b 1
700 1 _ |a Falkenburger, Björn H
|0 P:(DE-2719)2814178
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773 _ _ |a 10.3390/cells14171340
|g Vol. 14, no. 17, p. 1340 -
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910 1 _ |a Deutsches Zentrum für Neurodegenerative Erkrankungen
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