title: Mutations in LRRK2 potentiate age-related impairment of autophagic flux.
abstract: Autophagy is thought to play a pivotal role in the pathophysiology of Parkinson's disease, but little is known about how genes linked to PD affect autophagy in the context of aging. We generated lines of C. elegans expressing reporters for the autophagosome and lysosome expressed only in dopaminergic neurons, and examined autophagy throughout the lifespan in nematode lines expressing LRRK2 and α-synuclein. Dopamine neurons exhibit a progressive loss of autophagic function with aging. G2019S LRRK2 inhibited autophagy and accelerated the age-related loss of autophagic function, while WT LRRK2 improved autophagy throughout the life-span. Expressing α-synuclein with G2019S or WT LRRK2 caused age-related synergistic inhibition of autophagy and increase in degeneration of dopaminergic neurons. The presence of α-synuclein particularly accentuated age-related inhibition of autophagy by G2019S LRRK2. This work indicates that LRRK2 exhibits a selective, age-linked deleterious interaction with α-synuclein that promotes neurodegeneration.
authors.affiliation: Departments of Pharmacology, Boston University School of Medicine, Boston, MA, 02118, USA.
authors.forename: Shamol
authors.initials: S
authors.lastname: Saha
authors.affiliation: Departments of Pharmacology, Boston University School of Medicine, Boston, MA, 02118, USA.
authors.forename: Peter E A
authors.initials: PE
authors.lastname: Ash
authors.affiliation: Departments of Pharmacology, Boston University School of Medicine, Boston, MA, 02118, USA.
authors.forename: Vivek
authors.initials: V
authors.lastname: Gowda
authors.affiliation: Departments of Pharmacology, Boston University School of Medicine, Boston, MA, 02118, USA.
authors.forename: Liqun
authors.initials: L
authors.lastname: Liu
authors.affiliation: Departments of Medicine, Boston University School of Medicine, Boston, MA, 02118, USA.
authors.forename: Orian
authors.initials: O
authors.lastname: Shirihai
authors.affiliation: Departments of Pharmacology, Boston University School of Medicine, Boston, MA, 02118, USA. bwolozin@bu.edu.|Departments of Neurology, Boston University School of Medicine, 72 East Concord St., Boston, MA, 02118, USA. bwolozin@bu.edu.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Wolozin
mesh_terms: D000375:Aging / Q000502:physiology*; D019943:Amino Acid Substitution; D000818:Animals; D030801:Animals, Genetically Modified; D001343:Autophagy / Q000502:physiology*; D017173:Caenorhabditis elegans / Q000235:genetics / Q000502:physiology*; D059290:Dopaminergic Neurons / Q000502:physiology*; D049452:Green Fluorescent Proteins / Q000032:analysis / Q000235:genetics; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008164:Luminescent Proteins / Q000032:analysis / Q000235:genetics; D008247:Lysosomes / Q000378:metabolism; D020125:Mutation, Missense; D010588:Phagosomes / Q000378:metabolism; D017354:Point Mutation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000502:physiology*; D051844:alpha-Synuclein / Q000235:genetics / Q000502:physiology* / Q000633:toxicity; D000097573:Red Fluorescent Protein
chemical_list: D049452:Green Fluorescent Proteins; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D008164:Luminescent Proteins; D017346:Protein Serine-Threonine Kinases; D051844:alpha-Synuclein; D000097573:Red Fluorescent Protein; C495280:LRRK2 protein, human