title: Mutant alpha-synuclein causes age-dependent neuropathology in monkey brain.
abstract: Parkinson's disease (PD) is an age-dependent neurodegenerative disease that often occurs in those over age 60. Although rodents and small animals have been used widely to model PD and investigate its pathology, their short life span makes it difficult to assess the aging-related pathology that is likely to occur in PD patient brains. Here, we used brain tissues from rhesus monkeys at 2-3, 7-8, and >15 years of age to examine the expression of Parkin, PINK1, and α-synuclein, which are known to cause PD via loss- or gain-of-function mechanisms. We found that α-synuclein is increased in the older monkey brains, whereas Parkin and PINK1 are decreased or remain unchanged. Because of the gain of toxicity of α-synuclein, we performed stereotaxic injection of lentiviral vectors expressing mutant α-synuclein (A53T) into the substantia nigra of monkeys and found that aging also increases the accumulation of A53T in neurites and its associated neuropathology. A53T also causes more extensive reactive astrocytes and axonal degeneration in monkey brain than in mouse brain. Using monkey brain tissues, we found that A53T interacts with neurofascin, an adhesion molecule involved in axon subcellular targeting and neurite outgrowth. Aged monkey brain tissues show an increased interaction of neurofascin with A53T. Overexpression of A53T causes neuritic toxicity in cultured neuronal cells, which can be attenuated by transfected neurofascin. These findings from nonhuman primate brains reveal age-dependent pathological and molecular changes that could contribute to the age-dependent neuropathology in PD.
authors.affiliation: State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Weili
authors.identifier: http://orcid.org/0000-0001-6830-5204
authors.initials: W
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China, Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia 30322, and.
authors.forename: Guohao
authors.initials: G
authors.lastname: Wang
authors.affiliation: Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia 30322, and.
authors.forename: Chuan-En
authors.initials: CE
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Xiangyu
authors.initials: X
authors.lastname: Guo
authors.affiliation: State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Yin
authors.affiliation: State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Jinquan
authors.initials: J
authors.lastname: Gao
authors.affiliation: State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China.
authors.forename: Zhuchi
authors.initials: Z
authors.lastname: Tu
authors.affiliation: Kunming Institute of Zoology, the Chinese Academy of Sciences, Kunming, Yunnan 650223, China.
authors.forename: Zhengbo
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Kunming Institute of Zoology, the Chinese Academy of Sciences, Kunming, Yunnan 650223, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Wu
authors.affiliation: Kunming Institute of Zoology, the Chinese Academy of Sciences, Kunming, Yunnan 650223, China.
authors.forename: Xintian
authors.initials: X
authors.lastname: Hu
authors.affiliation: Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia 30322, and.
authors.forename: Shihua
authors.initials: S
authors.lastname: Li
authors.affiliation: State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China, Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia 30322, and xli2@emory.edu.
authors.forename: Xiao-Jiang
authors.initials: XJ
authors.lastname: Li
mesh_terms: D000375:Aging / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology*; D000882:Haplorhini; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation / Q000235:genetics; D009410:Nerve Degeneration / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D051844:alpha-Synuclein / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D051844:alpha-Synuclein
keywords: Parkinson's; aging; degeneration; neurite; primate