Impaired dopamine metabolism in Parkinson’s disease pathogenesis

Abstract

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.

Behavioral Tests in Neurotoxin-Induced Animal Models of Parkinson’s Disease

“…The remaining challenge is still understanding why changes in various proteins with altered or uncertain physiological functions congregate to comparable pathologic phenotypes, which are also observed in idiopathic PD [ 214 ]. Conversely, familial, environmental, and idiopathic PD forms present some differences from both the histopathological and clinical perspectives [ 215 ].…”

A Computational Model of Levodopa-Induced Toxicity in Substantia Nigra Pars Compacta in Parkinson’s Disease

“…The impaired DA metabolism causes oxidative stress (ROS), which in turn leads to PD pathogenesis (Masato et al, 2019). It was reported that abnormal activity of vesicular monoamine transporter 2 (VMAT2) leads to reduced vesicular DA storage and increased cytoplasmic DA which results in oxidative stress-induced degeneration of cell bodies (soma) and terminals (Caudle et al, 2007;Kariya et al, 2005;Mingazov and Ugryumov, 2019;Pifl et al, 2014).…”

β-synuclein promotes synaptic vesicle dopamine uptake and rescues dopaminergic neurons from MPTP-induced death

“…Three members of the synuclein family, α-, β-and γ-synuclein, are involved in various important molecular processes in presynaptic terminals. Gain-of-toxic-function is believed to be the main mechanism of the involvement of these proteins, α-synuclein in particular, in pathogenesis of Parkinson's disease and certain other neurodegenerative diseases collectively known as synucleinopathies, but the loss-offunction can also be a factor contributing to synaptic dysfunction associated with these diseases [1][2][3][4][5].…”