Parkinson's disease is characterized by the progressive degeneration of dopaminergic neurons within the substantia nigra pars compacta and the presence of protein aggregates in surviving neurons. The LRRK2 G2019S mutation is one of the major determinants of familial Parkinson's disease cases and leads to late-onset Parkinson's disease with pleomorphic pathology, including α-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 patients with Parkinson's disease carrying the G2019S variant, 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. Of note, the induction of autophagy cleared NSF aggregation and rescued motor and cognitive impairment observed in aged hG2019S bacterial artificial chromosome (BAC) mice. We suggest that LRRK2 G2019S pathological phosphorylation impacts on NSF biochemical properties, thus causing the formation of cytotoxic protein inclusions.

LRRK2 G2019S kinase activity triggers neurotoxic NSF aggregation

Morari M.;
2021

Abstract

Parkinson's disease is characterized by the progressive degeneration of dopaminergic neurons within the substantia nigra pars compacta and the presence of protein aggregates in surviving neurons. The LRRK2 G2019S mutation is one of the major determinants of familial Parkinson's disease cases and leads to late-onset Parkinson's disease with pleomorphic pathology, including α-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 patients with Parkinson's disease carrying the G2019S variant, 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. Of note, the induction of autophagy cleared NSF aggregation and rescued motor and cognitive impairment observed in aged hG2019S bacterial artificial chromosome (BAC) mice. We suggest that LRRK2 G2019S pathological phosphorylation impacts on NSF biochemical properties, thus causing the formation of cytotoxic protein inclusions.
2021
Pischedda, F.; Cirnaru, M. D.; Ponzoni, L.; Sandre, M.; Biosa, A.; Carrion, M. P.; Marin, O.; Morari, M.; Pan, L.; Greggio, E.; Bandopadhyay, R.; Sala...espandi
File in questo prodotto:
File Dimensione Formato  
pischedda et al june 2020.pdf

solo gestori archivio

Descrizione: preprint
Tipologia: Pre-print
Licenza: NON PUBBLICO - Accesso privato/ristretto
Dimensione 681.11 kB
Formato Adobe PDF
681.11 kB Adobe PDF   Visualizza/Apri   Richiedi una copia
BRAIN-2020-01856.R1_Proof.pdf

accesso aperto

Descrizione: Pre-print
Tipologia: Pre-print
Licenza: PUBBLICO - Pubblico con Copyright
Dimensione 28.33 MB
Formato Adobe PDF
28.33 MB Adobe PDF Visualizza/Apri
awab073.pdf

solo gestori archivio

Descrizione: Full text editoriale
Tipologia: Full text (versione editoriale)
Licenza: NON PUBBLICO - Accesso privato/ristretto
Dimensione 2.13 MB
Formato Adobe PDF
2.13 MB Adobe PDF   Visualizza/Apri   Richiedi una copia

I documenti in SFERA sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11392/2471966
Citazioni
  • ???jsp.display-item.citation.pmc??? 13
  • Scopus 19
  • ???jsp.display-item.citation.isi??? 17
social impact