The Convergence of Alpha-Synuclein, Mitochondrial, and Lysosomal Pathways in Vulnerability of Midbrain Dopaminergic Neurons in Parkinson's Disease

Abstract

Parkinson's disease (PD) is the second most common neurodegenerative disease, characterized by progressive bradykinesia, rigidity, resting tremor, and gait impairment, as well as a spectrum of non-motor symptoms including autonomic and cognitive dysfunction. The cardinal motor symptoms of PD stem from the loss of substantia nigra (SN) dopaminergic (DAergic) neurons, and it remains unclear why SN DAergic neurons are preferentially lost in PD. However, recent identification of several genetic PD forms suggests that mitochondrial and lysosomal dysfunctions play important roles in the degeneration of midbrain dopamine (DA) neurons. In this review, we discuss the interplay of cell-autonomous mechanisms linked to DAergic neuron vulnerability and alpha-synuclein homeostasis. Emerging studies highlight a deleterious feedback cycle, with oxidative stress, altered DA metabolism, dysfunctional lysosomes, and pathological alpha-synuclein species representing key events in the pathogenesis of PD. We also discuss the interactions of alpha-synuclein with toxic DA metabolites, as well as the biochemical links between intracellular iron, calcium, and alpha-synuclein accumulation. We suggest that targeting multiple pathways, rather than individual processes, will be important for developing disease-modifying therapies. In this context, we focus on current translational efforts specifically targeting lysosomal function, as well as oxidative stress via calcium and iron modulation. These efforts could have therapeutic benefits for the broader population of sporadic PD and related synucleinopathies.

Keywords: Parkinson’s disease; alpha-synuclein; calcium; dopamine; iron; mitochondria; synapse.

FIGURE 1

PD-linked SNCA mutations and interactions with DA metabolites, calcium, or iron promoting pathological aSyn oligomerization and/or aggregation. PD-linked SNCA missense mutations that increase the oligomerization and/or fibrillization of aSyn in vitro are shown in red (otherwise black). DA and oxidation derivatives bind non-specifically to the C-terminus (aa 125–129), further stabilized by long-range electrostatic interactions with E83 of the NAC region (intermittent gray line). Also, DOPAL/DOPAL-Q adducts with N-terminal aSyn lysines are formed at the 1–60 domains (purple line). Fe²⁺ (ferrous) and Fe³⁺ (ferric) iron bind to adjacent regions at the C-terminus of aSyn (blue line; Fe²⁺: aa P120-A124 and P128-S129; Fe³⁺: aa P120-M127). Moreover, a calcium-binding motif has been mapped to the C-terminus of aSyn (green line; aa 109–140). Calcium also promotes calpain I-mediated cleavage of aSyn, with three major cleavage sites depicted (green arrows; monomeric aSyn: after aa 57; fibrillar aSyn: after aa 114 and 122).

FIGURE 2

Potential model of the intersection of PD vulnerability pathways with DA metabolism at presynapse, promoting aSyn aggregation. Pre-synaptic calcium influx (via Ca_v1.3 calcium channels) drives mitochondrial oxidative phosphorylation (OxPhos), energetically supporting DA sequestration (thick green arrow) and consecutively neurotransmission. Synaptic vesicles (SVs) are loaded with DA neurotransmitter by VMAT-2, which transports cytosolic DA into the SV in exchange of H⁺ provided by the action of the H⁺-ATPase. Following release, synaptic vesicle endocytosis (SVE) replenishes SVs; however, PD-linked deficits in this pathway can limit the SV availability (thick red line). Because of ongoing DA biosynthesis (TH-catalyzed conversion of tyrosine to L-DOPA), impairment of DA sequestration into SVs leads to the accumulation of DA in the cytosol (thick red line). Subsequent build-up of oxidized DA metabolites (yellow highlight) in the cytosol disturbs aSyn homeostasis and leads to neurotoxicity. Specifically, cytosolic DA oxidation, catalyzed by iron (Fe³⁺), can lead to increased oxidized DA derivatives (oxDA), as well as increased levels of the neurotoxic metabolite DOPAL, catalyzed by MAO, further oxidized to DOPAL-Q (thick red arrows). aSyn oligomerization by DOPAL/-Q entails formation of adducts, whereas binding of DA-Q, calcium, and iron also promote the formation of aSyn oligomers/aggregates. Neuronal detoxification from DOPAL is mediated by ALDH1A1, which catalyzes its conversion to the non-toxic metabolite DOPAC (thin green arrow). Moreover, DA-Q and iron are removed from the cytosol over time by sequestration to the dark pigment neuromelanin at the soma (black intermittent arrow), enclosed within membranes, which can be neuroprotective under physiological conditions.

FIGURE 3

Mitochondrial oxidative stress, lysosomal dysfunction, and pathological aSyn are major converging pathways in the vulnerability of SNpc DAergic neurons in PD. Calcium influx via Ca_v1.3 channels during pacemaking and the metabolism of DA to DOPAL by mitochondrially-anchored MAO support mitochondrial energy production under physiological conditions. However, these mechanisms could also represent a dual source of sustained mitochondrial oxidative stress (mito ROS) over a long period, contributing to PD SNpc vulnerability. Moreover, DA metabolism and neurotoxic DA metabolites including DA/DOPAL quinones exacerbate oxidative stress and are linked to pathological aSyn modifications and GCase inhibition (green arrows). In turn, GCase is reciprocally linked to pathological aSyn via its lipid substrate glucosylceramide (GluCer). GCase deficiency increases GluCer levels, therefore stabilizing oligomeric aSyn intermediates (red arrow), whereas pathological aSyn inhibits GCase lysosomal activity or trafficking (blue arrow). As part of this vicious feedback cycle, both GCase and pathological aSyn contribute to oxidative stress (intermittent red arrow) via intersecting with DA metabolism. These major pathways may render SNpc DAergic neurons more vulnerable to the influence of PD-linked factors, such as aging, environment, and genetics.