The parkinsonian LRRK2 R1441G mutation shows macroautophagy-mitophagy dysregulation concomitant with endoplasmic reticulum stress

Autophagy is a mechanism responsible for the degradation of cellular components to maintain their homeostasis. However, autophagy is commonly altered and compromised in several diseases, including neurodegenerative disorders. Parkinson’s disease (PD) can be considered a multifactorial disease becaus...

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Published in:Cell biology and toxicology 2022-10, Vol.38 (5), p.889-911
Main Authors: Yakhine-Diop, Sokhna M. S., Rodríguez-Arribas, Mario, Canales-Cortés, Saray, Martínez-Chacón, Guadalupe, Uribe-Carretero, Elisabet, Blanco-Benítez, Mercedes, Duque-González, Gema, Paredes-Barquero, Marta, Alegre-Cortés, Eva, Climent, Vicente, Aiastui, Ana, López de Munain, Adolfo, Bravo-San Pedro, José M., Niso-Santano, Mireia, Fuentes, José M., González-Polo, Rosa A.
Format: Article
Language:English
Subjects:
Aging
Autophagy
Basal ganglia
Biochemistry
Biomedical and Life Sciences
Cell Biology
Cell viability
Central nervous system diseases
Endoplasmic reticulum
Environmental factors
Genetic factors
Homeostasis
Kinases
Life Sciences
LRRK2 protein
Mitochondria
Mitophagy
Movement disorders
MPP
Mutation
Neurodegeneration
Neurodegenerative diseases
Original Article
Parkinson's disease
Pathogenesis
Pharmacology/Toxicology
Proteins
Toxins
Transgenic animals
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Summary:Autophagy is a mechanism responsible for the degradation of cellular components to maintain their homeostasis. However, autophagy is commonly altered and compromised in several diseases, including neurodegenerative disorders. Parkinson’s disease (PD) can be considered a multifactorial disease because environmental factors, genetic factors, and aging are involved. Several genes are involved in PD pathology, among which the LRRK2 gene and its mutations, inherited in an autosomal dominant manner, are responsible for most genetic PD cases. The R1441G LRRK2 mutation is, after G2019S, the most important in PD pathogenesis. Our results demonstrate a relationship between the R1441G LRRK2 mutation and a mechanistic dysregulation of autophagy that compromises cell viability. This altered autophagy mechanism is associated with organellar stress including mitochondrial (which induces mitophagy) and endoplasmic reticulum (ER) stress, consistent with the fact that patients with this mutation are more vulnerable to toxins related to PD, such as MPP + . Graphical abstract
ISSN:0742-2091
1573-6822
DOI:10.1007/s10565-021-09617-w