A full understanding of Parkinson’s Disease etiopathogenesis and of the causes of the preferential vulnerability of nigrostriatal dopaminergic neurons is still an unsolved puzzle. A multiple-hit hypothesis has been proposed, which may explain the convergence of familial, environmental and idiopathic forms of the disease. Among the various determinants of the degeneration of the neurons in Substantia Nigra pars compacta, in this review we will focus on the endotoxicity associated to dopamine dyshomeostasis. In particular, we will discuss the relevance of the reactive dopamine metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL) in the catechol-induced neurotoxicity. Indeed, the synergy between the catechol and the aldehyde moieties of DOPAL exacerbates its reactivity, resulting in modification of functional protein residues, protein aggregation, oxidative stress and cell death. Interestingly, αSynuclein, whose altered proteostasis is a recurrent element in Parkinson’s Disease pathology, is considered a preferential target of DOPAL modification. DOPAL triggers αSynuclein oligomerization leading to synapse physiology impairment. Several factors can be responsible for DOPAL accumulation at the pre-synaptic terminals, i.e. dopamine leakage from synaptic vesicles, increased rate of dopamine conversion to DOPAL by upregulated monoamine oxidase and decreased DOPAL degradation by aldehyde dehydrogenases. Various studies report the decreased expression and activity of aldehyde dehydrogenases in parkinsonian brains, as well as genetic variants associated to increased risk in developing the pathology. Thus, we discuss how the deregulation of these enzymes might be considered a contributing element in the pathogenesis of Parkinson’s Disease or a down-stream effect. Finally, we propose that a better understanding of the impaired dopamine metabolism in Parkinson’s Disease would allow a more refined patients stratification and the design of more targeted and successful therapeutic strategies.

Parkinson disease (PD) is a severe neurodegenerative disorder that affects around 2% of the population over 65 years old. It is characterized by the progressive loss of nigrostriatal dopaminergic neurons, resulting in motor disabilities of the patients. At present, only symptomatic cures are available, without suppressing disease progression. In this frame, the anti-diabetic drug metformin has been investigated as a potential disease modifier for PD, being a low-cost and generally well-tolerated medication, which has been successfully used for decades in the treatment of type 2 diabetes mellitus. Despite the precise mechanisms of action of metformin being not fully elucidated, the drug has been known to influence many cellular pathways that are associated with PD pathology. In this review, we present the evidence in the literature supporting the neuroprotective role of metformin, i.e., autophagy upregulation, degradation of pathological α-synuclein species, and regulation of mitochondrial functions. The epidemiological studies conducted in diabetic patients under metformin therapy aimed at evaluating the correlation between long-term metformin consumption and the risk of developing PD are also discussed. Finally, we provide an interpretation for the controversial results obtained both in experimental models and in clinical studies, thus providing a possible rationale for future investigations for the repositioning of metformin for PD therapy.

Dopamine dyshomeostasis has been acknowledged among the determinants of nigrostriatal neuron degeneration in Parkinson’s disease (PD). Several studies in experimental models and postmortem PD patients underlined increasing levels of the dopamine metabolite 3,4-dihydroxyphenylacetaldehyde (DOPAL), which is highly reactive towards proteins. DOPAL has been shown to covalently modify the presynaptic protein αSynuclein (αSyn), whose misfolding and aggregation represent a major trait of PD pathology, triggering αSyn oligomerization in dopaminergic neurons. Here, we demonstrated that DOPAL elicits αSyn accumulation and hampers αSyn clearance in primary neurons. DOPAL-induced αSyn buildup lessens neuronal resilience, compromises synaptic integrity, and overwhelms protein quality control pathways in neurites. The progressive decline of neuronal homeostasis further leads to dopaminergic neuron loss and motor impairment, as showed in in vivo models. Finally, we developed a specific antibody which detected increased DOPAL-modified αSyn in human striatal tissues from idiopathic PD patients, corroborating the translational relevance of αSyn-DOPAL interplay in PD neurodegeneration.

Fibrillary aggregated α-synuclein (α-syn) deposition in Lewy bodies (LB) characterizes Parkinson's disease (PD) and is believed to trigger dopaminergic synaptic failure and a retrograde terminal-to-cell body neuronal degeneration. We described that the neuronal phosphoprotein synapsin III (Syn III) cooperates with α-syn to regulate dopamine (DA) release and can be found in the insoluble α-syn fibrils composing LB. Moreover, we showed that α-syn aggregates deposition, and the associated onset of synaptic deficits and neuronal degeneration occurring following adeno-associated viral vectors-mediated overexpression of human α-syn in the nigrostriatal system are hindered in Syn III knock out mice. This supports that Syn III facilitates α-syn aggregation.

Dopamine dyshomeostasis is a driving factor of nigrostriatal degeneration in Parkinson's disease (PD). Accumulation of cytosolic dopamine at striatal projections results in the buildup of autoxidation products, which generates protein adducts and exacerbate oxidative stress. Moreover, an excessive rate of dopamine degradation results in accumulation of 3,4‐dihydroxyphenylacetaldehyde (DOPAL), a toxic metabolite which rapidly reacts with other proteins. These events lead to protein misfolding and cross‐linking as well as mitochondrial and lysosomal dysfunction, the main pathological mechanisms underscoring dopaminergic neuron loss in PD. In this issue of Journal of Neurochemistry, Vecchio et al. generated and characterized a new in vivo model of chronic dopamine accumulation through the overexpression of a hyperactive form of tyrosine hydroxylase (TH‐HI), the rate‐limiting step enzyme in dopamine biosynthesis. At 3–5 months of age, TH‐HI mice displayed increased striatal dopamine content, exacerbated dopamine catabolism, and augmented responses to amphetamine. This correlated with enhanced oxidative stress and DOPAL buildup, highlighting a catechol‐induced neurotoxic vicious cycle that may anticipate a parkinsonian‐like phenotype in aged mice. This novel TH‐HI animal model represents an exciting new tool to unravel the molecular mechanisms underlying dopamine disequilibrium, catecholamine autotoxicity, and neurodegeneration in PD. image