TY  - JOUR
AU  - Redl, Stefan
AU  - Zweydorf, Felix
AU  - Gloeckner, Christian J
AU  - Posadas, Inmaculada
AU  - Ceña, Valentín
AU  - Hess, Michael W
AU  - Piccoli, Giovanni
AU  - Pérez-Carrión, María Dolores
TI  - The E193K LRRK2 mutation interferes with the autophagosome processing through the impairment of the LRRK2-Dynein-1 complex.
JO  - Scientific reports
VL  - 15
IS  - 1
SN  - 2045-2322
CY  - [London]
PB  - Springer Nature
M1  - DZNE-2025-01240
SP  - 39117
PY  - 2025
AB  - 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.
KW  - Leucine-Rich Repeat Serine-Threonine Protein Kinase-2: genetics
KW  - Leucine-Rich Repeat Serine-Threonine Protein Kinase-2: metabolism
KW  - Humans
KW  - Autophagosomes: metabolism
KW  - Fibroblasts: metabolism
KW  - Autophagy: genetics
KW  - Mutation
KW  - Parkinson Disease: genetics
KW  - Parkinson Disease: metabolism
KW  - Parkinson Disease: pathology
KW  - Dyneins: metabolism
KW  - Dyneins: genetics
KW  - Protein Binding
KW  - Autophagy (Other)
KW  - Dynein-1 complex (Other)
KW  - LRRK2 protein (Other)
KW  - Organelle morphometry (Other)
KW  - Parkinson´s disease (Other)
KW  - Ultrastructure (Other)
KW  - Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 (NLM Chemicals)
KW  - LRRK2 protein, human (NLM Chemicals)
KW  - Dyneins (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:41203815
C2  - pmc:PMC12594833
DO  - DOI:10.1038/s41598-025-26716-4
UR  - https://pub.dzne.de/record/281869
ER  -