Mitochondria drive autophagy pathology via microtubule disassembly: a new hypothesis for Parkinson disease.
Neurons are exquisitely dependent on quality control systems to maintain a healthy intracellular environment. A permanent assessment of protein and organelle "quality" allows a coordinated action between repair and clearance of damage proteins and dysfunctional organelles. Impairments in the intracellular clearance mechanisms in long-lived postmitotic cells, like neurons, result in the progressive accumulation of damaged organelles and aggregates of aberrant proteins. Using cells bearing Parkinson disease (PD) patients' mitochondria, we demonstrated that aberrant accumulation of autophagosomes in PD, commonly interpreted as an abnormal induction of autophagy, is instead due to defective autophagic clearance. This defect is a consequence of alterations in the microtubule network driven by mitochondrial dysfunction that hinder mitochondria and autophagosome trafficking. We uncover mitochondria and microtubule-directed traffic as main players in the regulation of autophagy in PD.
CNC-Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
Daniela M
DM
Arduíno
A Raquel
AR
Esteves
Sandra Morais
SM
Cardoso
D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy / Q000502:physiology*; D000071186:Beclin-1; D006801:Humans; D006822:Hybrid Cells; D008565:Membrane Proteins / Q000378:metabolism; D008870:Microtubules / Q000473:pathology*; D008928:Mitochondria / Q000502:physiology*; D008959:Models, Neurological; D009474:Neurons / Q000473:pathology / Q000502:physiology; D010300:Parkinson Disease / Q000209:etiology* / Q000473:pathology* / Q000503:physiopathology
D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D008565:Membrane Proteins