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Loss of autophagy in dopaminergic neurons causes Lewy pathology and motor dysfunction in aged mice.


ABSTRACT: Inactivation of constitutive autophagy results in the formation of cytoplasmic inclusions in neurons, but the relationship between impaired autophagy and Lewy bodies (LBs) as well as the in vivo process of formation remains unknown. Synuclein, a component of LBs, is the defining characteristic of Parkinson's disease (PD). Here, we characterize dopamine (DA) neuron-specific autophagy-deficient mice and provide in vivo evidence for LB formation. Synuclein deposition is preceded by p62 and resulted in the formation of inclusions containing synuclein and p62. The number and size of these inclusions were gradually increased in neurites rather than soma with aging. These inclusions may facilitate peripheral failures. As a result, DA neuron loss and motor dysfunction including the hindlimb defect were observed in 120-week-old mice. P62 aggregates derived from an autophagic defect might serve as "seeds" and can potentially be cause of LB formation.

SUBMITTER: Sato S 

PROVIDER: S-EPMC5809579 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Loss of autophagy in dopaminergic neurons causes Lewy pathology and motor dysfunction in aged mice.

Sato Shigeto S   Uchihara Toshiki T   Fukuda Takahiro T   Noda Sachiko S   Kondo Hiromi H   Saiki Shinji S   Komatsu Masaaki M   Uchiyama Yasuo Y   Tanaka Keiji K   Hattori Nobutaka N  

Scientific reports 20180212 1


Inactivation of constitutive autophagy results in the formation of cytoplasmic inclusions in neurons, but the relationship between impaired autophagy and Lewy bodies (LBs) as well as the in vivo process of formation remains unknown. Synuclein, a component of LBs, is the defining characteristic of Parkinson's disease (PD). Here, we characterize dopamine (DA) neuron-specific autophagy-deficient mice and provide in vivo evidence for LB formation. Synuclein deposition is preceded by p62 and resulted  ...[more]

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