title: NADPH oxidase promotes Parkinsonian phenotypes by impairing autophagic flux in an mTORC1-independent fashion in a cellular model of Parkinson's disease.
abstract: Oxidative stress and aberrant accumulation of misfolded proteins in the cytosol are key pathological features associated with Parkinson's disease (PD). NADPH oxidase (Nox2) is upregulated in the pathogenesis of PD; however, the underlying mechanism(s) of Nox2-mediated oxidative stress in PD pathogenesis are still unknown. Using a rotenone-inducible cellular model of PD, we observed that a short exposure to rotenone (0.5 μM) resulted in impaired autophagic flux through activation of a Nox2 dependent Src/PI3K/Akt axis, with a consequent disruption of a Beclin1-VPS34 interaction that was independent of mTORC1 activity. Sustained exposure to rotenone at a higher dose (10 μM) decreased mTORC1 activity; however, autophagic flux was still impaired due to dysregulation of lysosomal activity with subsequent induction of the apoptotic machinery. Cumulatively, our results highlight a complex pathogenic mechanism for PD where short- and long-term oxidative stress alters different signaling pathways, ultimately resulting in anomalous autophagic activity and disease phenotype. Inhibition of Nox2-dependent oxidative stress attenuated the impaired autophagy and cell death, highlighting the importance and therapeutic potential of these pathways for treating patients with PD.
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, United States.
authors.forename: Rituraj
authors.initials: R
authors.lastname: Pal
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States.
authors.forename: Lakshya
authors.initials: L
authors.lastname: Bajaj
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States.
authors.forename: Jaiprakash
authors.initials: J
authors.lastname: Sharma
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States.
authors.forename: Michela
authors.initials: M
authors.lastname: Palmieri
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States.
authors.forename: Alberto
authors.initials: A
authors.lastname: Di Ronza
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States.
authors.forename: Parisa
authors.initials: P
authors.lastname: Lotfi
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, United States.
authors.forename: Arindam
authors.initials: A
authors.lastname: Chaudhury
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, United States.
authors.forename: Joel
authors.initials: J
authors.lastname: Neilson
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States.
authors.forename: Marco
authors.initials: M
authors.lastname: Sardiello
authors.affiliation: Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, United States.
authors.forename: George G
authors.initials: GG
authors.lastname: Rodney
mesh_terms: D017209:Apoptosis; D001343:Autophagy; D045744:Cell Line, Tumor; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D008562:Membrane Glycoproteins / Q000378:metabolism*; D046912:Multiprotein Complexes / Q000378:metabolism*; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000378:metabolism*; D018384:Oxidative Stress; D010300:Parkinson Disease / Q000378:metabolism* / Q000473:pathology; D012402:Rotenone / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D008562:Membrane Glycoproteins; D046912:Multiprotein Complexes; D012402:Rotenone; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases