title: Alteration of Upstream Autophagy-Related Proteins (ULK1, ULK2, Beclin1, VPS34 and AMBRA1) in Lewy Body Disease.
abstract: Autophagy is associated with the pathogenesis of Lewy body disease, including Parkinson's disease (PD) and dementia with Lewy bodies (DLB). It is known that several downstream autophagosomal proteins are incorporated into Lewy bodies (LBs). We performed immunostaining and Western blot analysis using a cellular model of PD and human brain samples to investigate the involvement of upstream autophagosomal proteins (ULK1, ULK2, Beclin1, VPS34 and AMBRA1), which initiate autophagy and form autophagosomes. Time course analysis of cultured cells transfected with flag-α-synuclein and synphilin-1 revealed upregulation of these upstream proteins with accumulation of LB-like inclusions. In human specimens, only mature LBs were positive for upstream autophagosomal proteins. Western blotting of fractionated brain lysates showed that upstream autophagosomal proteins were detected in the soluble and insoluble fraction in DLB, corresponding to the bands of phosphorylated α-synuclein. However, Western blot analysis of total brain lysates in PD and DLB showed that the increase of upstream autophagosomal proteins was only partial. The quantitative, qualitative and locational alteration of upstream autophagosomal proteins in the present study indicates their involvement in the pathogenesis of LB disease. Our data also suggest that misinduction or impairment of upstream autophagy might occur in the disease process of LB disease.
authors.affiliation: Department of Neuropathology, Institute of Brain Science, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Miki
authors.affiliation: Department of Neuropathology, Institute of Brain Science, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
authors.forename: Kunikazu
authors.initials: K
authors.lastname: Tanji
authors.affiliation: Department of Neuropathology, Institute of Brain Science, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Mori
authors.affiliation: Department of Neurology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Utsumi
authors.affiliation: Department of Neurology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Hidenao
authors.initials: H
authors.lastname: Sasaki
authors.affiliation: Department of Pathological Neuroscience, Center for Bioresource-Based Researches, Brain Research Institute, University of Niigata, Niigata, Japan.
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Kakita
authors.affiliation: Department of Pathology, Brain Research Institute, University of Niigata, Niigata, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Takahashi
authors.affiliation: Department of Neuropathology, Institute of Brain Science, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Wakabayashi
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000368:Aged; D000369:Aged, 80 and over; D001343:Autophagy / Q000502:physiology*; D000071189:Autophagy-Related Protein-1 Homolog / Q000378:metabolism; D000071183:Autophagy-Related Proteins / Q000378:metabolism*; D000071186:Beclin-1 / Q000378:metabolism; D058546:Class III Phosphatidylinositol 3-Kinases / Q000378:metabolism; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D020961:Lewy Body Disease / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism
chemical_list: C553334:AMBRA1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D000071183:Autophagy-Related Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D047908:Intracellular Signaling Peptides and Proteins; D058546:Class III Phosphatidylinositol 3-Kinases; D000071189:Autophagy-Related Protein-1 Homolog; D017346:Protein Serine-Threonine Kinases; C484754:ULK1 protein, human; C541703:Ulk2 protein, human
keywords: Lewy body; Lewy body disease; Parkinson's disease; autophagy; dementia with Lewy bodies