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.
Highlights
Parkinson’s disease (PD), the most common neurodegenerative disorder, is characterized by the loss of nigrostriatal dopamine neurons and the formation of intracellular Lewy bodies (LBs), which consist primarily of α-synuclein and ubiquitin[1]
Great progress has been made toward understanding the pathogenesis of familial PD, mainly due to the discovery of specific mutations, whereas little is understood about the mechanisms underlying idiopathic PD pathogenesis
We carried out detailed observations of Atg7-deficient mice, and observed a loss of autophagy in dopaminergic neurons, resulting in Lewy pathology and motor dysfunctions associated with aging
Summary
Parkinson’s disease (PD), the most common neurodegenerative disorder, is characterized by the loss of nigrostriatal dopamine neurons and the formation of intracellular Lewy bodies (LBs), which consist primarily of α-synuclein (hereafter referred to as synuclein) and ubiquitin[1]. The identification of PD-related genes and risk factors has implicated several pathways in PD etiology, with growing evidence suggesting a link between dysfunctional intracellular protein catabolism and PD pathogenesis. Given that highly aggregated proteins are deposited in nigral neurons in PD, dysfunctions of proteolytic systems, i.e., the ubiquitin–proteasome system and autophagy–lysosomal pathway, seem to contribute to the final neurodegenerative process. The phenotypes of mice harboring brain-specific deletion of Atg[5] or Atg[7] reveal the critical role of autophagy in the removal of aggregated proteins[7,8], Friedman et al.[9] demonstrated that DA neuron-specific autophagy deficiency leads to the restrictive presynaptic accumulation of synuclein in the dorsal striatum, suggesting that impaired autophagy plays a role in PD pathogenesis. In order to understand the effects of autophagy impairment on DA neurons, we characterized conditional knock-out mice harboring a tyrosine hydroxylase (TH) neuron–specific deletion of Atg[7] and observed their age-related pathological and motor phenotypes
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