Aging and Parkinson's disease: Different sides of the same coin?

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. © 2017 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Keywords: Parkinson's disease; aging; lysosome; microglia; nonhuman primates; oxidative stress; proteasome.

FIG. 1

The pattern of ageing-related changes in markers of cellular mechanisms. With advancing age, DA neurons in the ventral tier of the substantia nigra (vtSN)—the population that is most vulnerable to degeneration in PD—show changes with aging. a–d: Age-related decline in tyrosine hydroxylase staining (shown in red) in vtSN neurons, but not in vental tegmental area (VTA) neurons. e,f: Accumulation of cytoplasmic α-synuclein (shown in brown). Tyrosine hydroxylase staining is shown in gray. Arrows show examples of cytoplasmic α-synuclein in aged vtSN. g,h: Increased numbers of Marinesco bodies, characterized by cytoplasmic inclusions of ubiquitin (shown in red). Tyrosine hydroxylase staining is shown in gray. The inset (in part h) is a higher magnification view of a tyrosine hydroxylase immunoreactive neuron of the vtSN exhibiting multiple Marinesco bodies. i,j: No accumulation of lipofuscin (shown in green). Tyrosine hydroxylase staining is shown in red, colocalization of lipofuscin and tyrosine hydroxylase is shown in yellow. Note that virtually all lipofuscin staining in the vtSN is not in dopamine neurons, whereas colocalization is apparent in aged VTA neurons. k,l: Accumulation of 3-nitrotyrosine (shown in green). m,n: Greater microglial reactivity in aged vtSN neurons than in aged VTA neurons, shown by greater staining for human leukocyte antigen (HLA) class II histocompatibility antigen, antigen D related (DR) α-chain (HLA-DRA; a marker for microglia), shown in brown. UPS, ubiquitin–proteasome system. From Ref. with permission.

FIG. 2

Age-related accumulation of alpha synuclein within the human substantia nigra.

FIG. 3

The nigrostriatal dopamine system in aging and PD share important biological features. DA neurodegeneration in PD presents a complex biology of interacting factors. Many of these factors also are present during aging of this system, exhibiting the same direction of change while varying in the magnitude of change. In normal aging, threats to dopamine neuron viability are expressed as impaired function of the system, whereas additional contributions of genetic, environmental, and other unknown factors exaggerate aging-related changes to reach the threshold for dopamine neurodegeneration and symptomatic PD. The multiple shared features of dopamine neuron biology in aging and PD lead to the hypotheses that aging actively creates a pre-PD state and that aging-related changes are the pathological foundation on which the degeneration in PD is built.