Abstract
Despite abundant epidemiological evidence in support of aging as the primary risk factor for PD, biological correlates of a connection have been elusive. In this article, we address the following question: does aging represent biology accurately characterized as pre-PD? We present evidence from our work on midbrain dopamine neurons of aging nonhuman primates that demonstrates that markers of known correlates of dopamine neuron degeneration in PD, including impaired proteasome/lysosome function, oxidative/nitrative damage, and inflammation, all increase with advancing age and are exaggerated in the ventral tier substantia nigra dopamine neurons most vulnerable to degeneration in PD. Our findings support the view that aging-related changes in the dopamine system approach the biological threshold for parkinsonism, actively producing a vulnerable pre-parkinsonian state.
Highlights
Evidence From Aging Nonhuman PrimatesWe revisited the association of aging and Parkinson’s disease (PD) by incorporating 2 main features into our experimental design
Despite abundant epidemiological evidence in support of aging as the primary risk factor for Parkinson’s disease (PD), biological correlates of a connection have been elusive
Returning to the original question of whether aging is pre-PD, the short answer is “yes.” At a simplistic level, there is no PD without aging
Summary
We revisited the association of aging and PD by incorporating 2 main features into our experimental design. Middle-aged monkey dtSN neurons that contained lipofuscin exhibited an intensity of TH staining comparable to young adult animals, appearing resistant to the normal aging-related decrease in expression of this phenotypic marker. This may represent more efficient removal of damaged or malfunctioning organelles (such as mitochondria) in degeneration-resistant DA neurons. During normal aging in nonhuman primates, the DA neurons most vulnerable to degeneration in PD display histological correlates of progressive loss of phenotype, the accumulation of ubiquitin-positive inclusions, inadequate lysosome function, increased oxidative/nitrative damage, and exaggerated neuroinflammation, all factors implicated in PD pathology. Aging and PD exhibit region-specific shared biology for these factors, suggesting that they exist along a shared continuum
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