LRRK2 G2019S kinase activity triggers neurotoxic NSF aggregation
| Autor: | Michele Sandre, Francesca Pischedda, Maria Perez Carrion, Maria Daniela Cirnaru, Alice Biosa, Lifeng Pan, Elisa Greggio, Rina Bandopadhyay, Luisa Ponzoni, Mariaelvina Sala, Oriano Marin, Michele Morari, Giovanni Piccoli |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
autophagy Parkinson's disease Substantia nigra Biology Protein aggregation Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 Protein Aggregation Pathological NO 03 medical and health sciences aggregation LRRK2 Animals Autophagy Brain Humans Mutation N-Ethylmaleimide-Sensitive Proteins Parkinson Disease Phosphorylation 0302 clinical medicine Pathological Basal ganglia medicine Kinase activity LS5_2 Chemistry Pars compacta medicine.disease Protein Aggregation nervous system diseases Cell biology 030104 developmental biology Neurology (clinical) 030217 neurology & neurosurgery |
| Popis: | SummaryParkinson’s disease (PD) is characterized by the progressive degeneration of dopaminergic neurons within the substantia nigra pars compacta and the presence of protein aggregates in surviving neurons. LRRK2 G2019S mutation is one of the major determinants of familial PD cases and leads to late-onset PD with pleomorphic pathology, including alpha-synuclein accumulation and deposition of protein inclusions. We demonstrated that LRRK2 phosphorylates N-ethylmaleimide sensitive factor (NSF). We observed aggregates containing NSF in basal ganglia specimens from G2019S carrier PD patients and in cellular and animal models expressing the LRRK2 G2019S variant. We found that LRRK2 G2019S kinase activity induces the accumulation of NSF in toxic aggregates. Noteworthy, the induction of autophagy cleared NSF aggregation and rescued motor and cognitive impairment observed in aged hG2019S BAC mice. We suggest that LRRK2 G2019S pathological phosphorylation hampers substrate catabolism, thus causing the formation of cytotoxic protein inclusions.HighlightsLRRK2 phosphorylates NSF in vivoNSF aggregates in complementary LRRK2 G2019S modelsLRRK2 G2019S kinase activity induces NSF accumulation in toxic aggregatesAutophagy induction rescues hG2019S BAC mice motor and cognitive impairment |
| Databáze: | OpenAIRE |
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