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000281869 1001_ $$aRedl, Stefan$$b0
000281869 245__ $$aThe E193K LRRK2 mutation interferes with the autophagosome processing through the impairment of the LRRK2-Dynein-1 complex.
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000281869 520__ $$aParkinson'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.
000281869 536__ $$0G:(DE-HGF)POF4-352$$a352 - Disease Mechanisms (POF4-352)$$cPOF4-352$$fPOF IV$$x0
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000281869 650_7 $$2Other$$aAutophagy
000281869 650_7 $$2Other$$aDynein-1 complex
000281869 650_7 $$2Other$$aLRRK2 protein
000281869 650_7 $$2Other$$aOrganelle morphometry
000281869 650_7 $$2Other$$aParkinson´s disease
000281869 650_7 $$2Other$$aUltrastructure
000281869 650_7 $$0EC 2.7.11.1$$2NLM Chemicals$$aLeucine-Rich Repeat Serine-Threonine Protein Kinase-2
000281869 650_7 $$0EC 2.7.11.1$$2NLM Chemicals$$aLRRK2 protein, human
000281869 650_7 $$0EC 3.6.4.2$$2NLM Chemicals$$aDyneins
000281869 650_2 $$2MeSH$$aLeucine-Rich Repeat Serine-Threonine Protein Kinase-2: genetics
000281869 650_2 $$2MeSH$$aLeucine-Rich Repeat Serine-Threonine Protein Kinase-2: metabolism
000281869 650_2 $$2MeSH$$aHumans
000281869 650_2 $$2MeSH$$aAutophagosomes: metabolism
000281869 650_2 $$2MeSH$$aFibroblasts: metabolism
000281869 650_2 $$2MeSH$$aAutophagy: genetics
000281869 650_2 $$2MeSH$$aMutation
000281869 650_2 $$2MeSH$$aParkinson Disease: genetics
000281869 650_2 $$2MeSH$$aParkinson Disease: metabolism
000281869 650_2 $$2MeSH$$aParkinson Disease: pathology
000281869 650_2 $$2MeSH$$aDyneins: metabolism
000281869 650_2 $$2MeSH$$aDyneins: genetics
000281869 650_2 $$2MeSH$$aProtein Binding
000281869 7001_ $$0P:(DE-2719)2811552$$aZweydorf, Felix$$b1
000281869 7001_ $$0P:(DE-2719)2811291$$aGloeckner, Christian J$$b2$$udzne
000281869 7001_ $$aPosadas, Inmaculada$$b3
000281869 7001_ $$aCeña, Valentín$$b4
000281869 7001_ $$aHess, Michael W$$b5
000281869 7001_ $$aPiccoli, Giovanni$$b6
000281869 7001_ $$aPérez-Carrión, María Dolores$$b7
000281869 773__ $$0PERI:(DE-600)2615211-3$$a10.1038/s41598-025-26716-4$$gVol. 15, no. 1, p. 39117$$n1$$p39117$$tScientific reports$$v15$$x2045-2322$$y2025
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