Αlpha-Synuclein as a Mediator in the Interplay between Aging and Parkinson's Disease

Abstract

Accumulation and misfolding of the alpha-synuclein protein are core mechanisms in the pathogenesis of Parkinson's disease. While the normal function of alpha-synuclein is mainly related to the control of vesicular neurotransmission, its pathogenic effects are linked to various cellular functions, which include mitochondrial activity, as well as proteasome and autophagic degradation of proteins. Remarkably, these functions are also affected when the renewal of macromolecules and organelles becomes impaired during the normal aging process. As aging is considered a major risk factor for Parkinson's disease, it is critical to explore its molecular and cellular implications in the context of the alpha-synuclein pathology. Here, we discuss similarities and differences between normal brain aging and Parkinson's disease, with a particular emphasis on the nigral dopaminergic neurons, which appear to be selectively vulnerable to the combined effects of alpha-synuclein and aging.

Keywords: Parkinson’s disease; aging; alpha-synuclein; metabolism; mitochondria; nigral dopaminergic neurons; proteostasis.

Figure 1

Physiological and pathological roles of α-synuclein. Alpha-synuclein, in physiological conditions, is considered to exist in two forms, monomer and tetramer. Its role in neuronal homeostasis is mostly associated with molecular chaperone activity at the synapse, where it controls clustering [39,40,41] and release of synaptic vesicles [33,34,42], and at the mitochondrial membrane, where together with cardiolipin, it stabilizes electron transport chain proteins [47]. When misfolded and/or aggregated, α-synuclein inhibits the ubiquitin-proteasome system [52,53,54,55] as well as mitochondrial complex I activity [43,56,57], blocks mitochondrial fusion [58,59] and impairs autophagy [60,61,62].

Figure 2

The effect of aging on dopamine neurons. During aging, dopamine neurons of the substantia nigra pars compacta undergo a series of debilitating molecular changes, which compromise their physiological function. With time, a decrease in mitochondrial turnover occurs. As a consequence of this, accumulation of dysfunctional mitochondria is observed, which results in an increase in reactive oxygen species production [29]. Ubiquitin-proteasome and autophagic activities gradually decline with time [27,28], which leads to the deposition of neuronal pigments like neuromelanin or lipofuscin [114]. Aging has been correlated to a significant increase in protein levels of α-synuclein, promoting misfolding and neuronal toxicity [111].