Home > Publications Database > The E193K LRRK2 mutation interferes with the autophagosome processing through the impairment of the LRRK2-Dynein-1 complex. > print

001     281869
005     20251127141829.0
024 7 _ |a 10.1038/s41598-025-26716-4
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041 _ _ |a English
082 _ _ |a 600
100 1 _ |a Redl, Stefan
|b 0
245 _ _ |a The E193K LRRK2 mutation interferes with the autophagosome processing through the impairment of the LRRK2-Dynein-1 complex.
260 _ _ |a [London]
|c 2025
|b Springer Nature
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520 _ _ |a Parkinson's disease (PD) is a neurodegenerative pathology characterized by movement-associated symptoms due to the selective loss of dopaminergic neurons in the substantia nigra pars compacta. Autophagy is an essential mechanism that restores homeostasis and promotes cell survival. Mutations in the Leucine-Rich Repeat Kinase 2 (LRRK2) gene are among the most common in the familial cases. The LRRK2 E193K mutation falls in the Armadillo (ARM) domain and modifies LRRK2 interactome. The role of LRRK2 in autophagy has been widely explored, but the impact of E193K mutation on autophagy remains unknown. We found that the E193K variant increases autophagy in primary fibroblasts obtained from an E193K carrier. By cryo-based electron microscopy we observed that E193K fibroblasts present a higher amount of phagophores/autophagosomes. We showed that LRRK2 binds to the Dynein-1 complex, an essential regulator of retrograde transport of autophagosomes. Noteworthy, the E193K mutation jeopardizes this interaction and increases the cellular sensitivity to 1-methyl-4-phenylpyridinium (MPP+) toxin in fibroblasts as well as in a heterologous cell model. Our study reveals that the LRRK2 E193K variant influences the autophagic regulation and suggests that the dysregulation of the LRRK2-Dynein-1 complex causes autophagic defects and, eventually, cell death.
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650 _ 7 |a Autophagy
|2 Other
650 _ 7 |a Dynein-1 complex
|2 Other
650 _ 7 |a LRRK2 protein
|2 Other
650 _ 7 |a Organelle morphometry
|2 Other
650 _ 7 |a Parkinson´s disease
|2 Other
650 _ 7 |a Ultrastructure
|2 Other
650 _ 7 |a Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
|0 EC 2.7.11.1
|2 NLM Chemicals
650 _ 7 |a LRRK2 protein, human
|0 EC 2.7.11.1
|2 NLM Chemicals
650 _ 7 |a Dyneins
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650 _ 2 |a Leucine-Rich Repeat Serine-Threonine Protein Kinase-2: genetics
|2 MeSH
650 _ 2 |a Leucine-Rich Repeat Serine-Threonine Protein Kinase-2: metabolism
|2 MeSH
650 _ 2 |a Humans
|2 MeSH
650 _ 2 |a Autophagosomes: metabolism
|2 MeSH
650 _ 2 |a Fibroblasts: metabolism
|2 MeSH
650 _ 2 |a Autophagy: genetics
|2 MeSH
650 _ 2 |a Mutation
|2 MeSH
650 _ 2 |a Parkinson Disease: genetics
|2 MeSH
650 _ 2 |a Parkinson Disease: metabolism
|2 MeSH
650 _ 2 |a Parkinson Disease: pathology
|2 MeSH
650 _ 2 |a Dyneins: metabolism
|2 MeSH
650 _ 2 |a Dyneins: genetics
|2 MeSH
650 _ 2 |a Protein Binding
|2 MeSH
700 1 _ |a Zweydorf, Felix
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700 1 _ |a Gloeckner, Christian J
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700 1 _ |a Posadas, Inmaculada
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700 1 _ |a Ceña, Valentín
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700 1 _ |a Hess, Michael W
|b 5
700 1 _ |a Piccoli, Giovanni
|b 6
700 1 _ |a Pérez-Carrión, María Dolores
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773 _ _ |a 10.1038/s41598-025-26716-4
|g Vol. 15, no. 1, p. 39117
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|t Scientific reports
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910 1 _ |a Deutsches Zentrum für Neurodegenerative Erkrankungen
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