The Upshot of LRRK2 Inhibition to Parkinson's Disease Paradigm.
Mutations in leucine-rich repeat kinase 2 gene (LRRK2) are implicated in autosomal dominant familial and sporadic Parkinson's disease (sPD). Given its relative frequency in PD and its putative function in several cellular pathways that are known to be impaired in the disease, we wanted to tackle LRRK2 physiological role and to address its potential as a PD therapeutic target. We investigated the impact of pharmacological inhibition of LRRK2 kinase activity in control and PD cell function. We provide evidence that physiologically LRRK2, through its kinase activity, regulates mitochondrial fission events and facilitates autophagic degradation by modulating lysosomal cellular localization. Upon LRRK2 inhibition, normal fission decreases, leading to the elongation of mitochondrial network which contributes to a poor degradation of deficient mitochondria. Moreover, LRRK2 inhibition promotes lysosomal perinuclear clustering, through Rab7 that further hinders autophagosomes degradation. These events induce a decrease in the autophagic flow, which contributed directly to a decreased proteolytic degradation of damaged mitochondria. These data resembled the results observed in sPD cells. Interestingly, the LRRK2 kinase activity is increased in sPD cells, and despite its inhibition recovers mitochondrial cellular localization, it did not improve microtubule network-dependent trafficking. Our results provide novel insights into the multiple mechanisms that dictate the association between LRRK2 and mitophagy in sPD, and contribute with new findings that could have important therapeutic implications.
CNC-Centro de Neurociências e Biologia Celular, Universidade de Coimbra, Coimbra, Portugal.
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Esteves
CNC-Centro de Neurociências e Biologia Celular, Universidade de Coimbra, Coimbra, Portugal.
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G-Fernandes
CNC-Centro de Neurociências e Biologia Celular, Universidade de Coimbra, Coimbra, Portugal.
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Santos
Hospitais da Universidade de Coimbra, 3000, Coimbra, Portugal.
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Januário
CNC-Centro de Neurociências e Biologia Celular, Universidade de Coimbra, Coimbra, Portugal. cardoso.sandra.m@gmail.com.|Institue of Biology, Faculty of Medicine, Universidade de Coimbra, Coimbra, Portugal. cardoso.sandra.m@gmail.com.
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Cardoso
D000368:Aged; D000369:Aged, 80 and over; D001343:Autophagy / Q000502:physiology*; D005260:Female; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D010300:Parkinson Disease / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D021381:Protein Transport; D059748:Proteolysis
C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases
DRP1; LRRK2; Mitochondrial dynamics; Parkinson’s disease; Rab7