title: Anti-aging treatments slow propagation of synucleinopathy by restoring lysosomal function.
abstract: Aging is the major risk factor for neurodegenerative diseases that are also associated with impaired proteostasis, resulting in abnormal accumulation of protein aggregates. However, the role of aging in development and progression of disease remains elusive. Here, we used Caenorhabditis elegans models to show that aging-promoting genetic variations accelerated the rate of cell-to-cell transmission of SNCA/α-synuclein aggregates, hallmarks of Parkinson disease, and the progression of disease phenotypes, such as nerve degeneration, behavioral deficits, and reduced life span. Genetic and pharmacological anti-aging manipulations slowed the spread of aggregates and the associated phenotypes. Lysosomal degradation was significantly impaired in aging models, while anti-aging treatments reduced the impairment. Transgenic expression of hlh-30p::hlh-30, the master controller of lysosomal biogenesis, alleviated intercellular transmission of aggregates in the aging model. Our results demonstrate that the rate of aging closely correlates with the rate of aggregate propagation and that general anti-aging treatments can slow aggregate propagation and associated disease progression by restoring lysosomal function.
authors.affiliation: a Department of Biomedical Sciences and Neuroscience Research Institute , Seoul National University College of Medicine , Seoul , Korea.|b Department of Biomedical Science and Technology , Konkuk University , Seoul , Korea.
authors.forename: Dong-Kyu
authors.initials: DK
authors.lastname: Kim
authors.affiliation: b Department of Biomedical Science and Technology , Konkuk University , Seoul , Korea.
authors.forename: Hee-Sun
authors.initials: HS
authors.lastname: Lim
authors.affiliation: c Department of Bioscience and Biotechnoloy and Institute of KU Biotechnology, Konkuk University , Seoul , Korea.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Kawasaki
authors.affiliation: c Department of Bioscience and Biotechnoloy and Institute of KU Biotechnology, Konkuk University , Seoul , Korea.
authors.forename: Yhong-Hee
authors.initials: YH
authors.lastname: Shim
authors.affiliation: d Department of Biochemistry , College of Medicine and Health Science, United Arab University , Al Ain , United Arab Emirates.
authors.forename: Nishant N
authors.initials: NN
authors.lastname: Vaikath
authors.affiliation: e Neurological Disorders Center, Qatar Biomedical Research Institute (QBRI), and College of Science and Engineering, Hamad Bin Khalifa University (HBKU), Education City, Qatar Foundation , Doha , Qatar.
authors.forename: Omar M A
authors.initials: OM
authors.lastname: El-Agnaf
authors.affiliation: f Department of Anatomy , School of Medicine, Konkuk University , Seoul , Korea.
authors.forename: He-Jin
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: a Department of Biomedical Sciences and Neuroscience Research Institute , Seoul National University College of Medicine , Seoul , Korea.
authors.forename: Seung-Jae
authors.initials: SJ
authors.lastname: Lee
mesh_terms: D000117:Acetylglucosamine / Q000494:pharmacology; D000375:Aging / Q000235:genetics / Q000502:physiology*; D000818:Animals; D017173:Caenorhabditis elegans / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D011992:Endosomes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D025821:Polyubiquitin / Q000378:metabolism; D066329:Protein Aggregates / Q000187:drug effects; D019076:Transgenes; D054875:Ubiquitination / Q000187:drug effects; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: D066329:Protein Aggregates; D051844:alpha-Synuclein; D025821:Polyubiquitin; D000117:Acetylglucosamine
keywords: C. elegans; Parkinson disease; SNCA/α-synuclein; aggregate propagation; aging; bimolecular fluorescence complementation; lysosome