DOPAL initiates αSynuclein-dependent impaired proteostasis and degeneration of neuronal projections in Parkinson’s disease

Abstract

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.

Prodromal Parkinson's disease and the catecholaldehyde hypothesis: Insight from olfactory bulb organotypic cultures

“…Particularly impaired by catecholaldehyde exposure was the ubiquitination pathway, fundamental in controlling proteostasis. The disrupted UPS signaling could be one of the contributing causes, together with protein modifications particularly on lysine residues, of DOPAL‐induced α‐synuclein aggregation, the signs of which were observed in our model and have been reported in other studies 24–28,66,67 . However, the evidence of α‐synuclein aggregation in our model was far from being convincing, possibly due to species‐specific differences between rodent and human, already reported in the case of dopamine‐modified synuclein, detectable only in human and not rodent model of PD 68 .…”

“…17 After optimizing culture conditions for postnatal OB slices, we were able to detect neurodegeneration and cell death in tissue treated with as little as 50 μM of DOPAL, a concentration higher than the reported physiological values of 2-3 μM, but possibly not too far from the levels of DOPAL in Parkinsonian brains, where the exposure is sustained for years and not days. 56 The dopamine metabolite's toxicity has already been proven in various in vitro models 27,[56][57][58][59][60] and even assessed in vivo, 29,61 but the focus to date has mainly been on neuronal cells, particularly the midbrain dopaminergic population. Therefore, ours is the first study of the effect of DOPAL in olfactory bulb cultures, and its relevance lies in the following considerations.…”

“…23 Here, we describe the induction of ex vivo prodromal PD-like pathology using 3,4-dihydroxyphenylacetaldehyde (DOPAL), a metabolite of dopamine which is present within the OB under normal physiological conditions. DOPAL is at the center of the catecholaldehyde hypothesis of PD progression, and it has been shown to potently oligomerize α-synuclein [24][25][26][27] and induce neurodegeneration. [28][29][30] Interestingly, the DOPAL/dopamine ratio was higher in brain tissue samples derived from PD patients 31,32 and exposure to pesticides, a well-established risk factor for PD, has also been shown to inhibit aldehyde dehydrogenase activity, the enzyme responsible for DOPAL degradation.…”

Oxidative Stress and Neuroinflammation in Parkinson’s Disease: The Role of Dopamine Oxidation Products

“…More specifically, a strong decrease in the number of vesicles per synapse was observed in neurons treated with DOPAL, with a reduction of the fraction of synaptic vesicles in the ready-releasable pool and an increase in the vesicles size of the resting pool, suggesting that αSyn-DOPAL oligomers may preferentially damage the vesicles ready to be released at the synapse, possibly because oligomer formation occurs in the subcellular region where αSyn is known to participate in synaptic vesicle recycling [ 91 ]. More recently, proteostasis impairment has been indicated as a major contributing factor to DOPAL-triggered αSyn neurotoxicity [ 93 ]. In particular, DOPAL-induced αSyn accumulation among the neuronal compartments was observed, as well as impaired αSyn clearance in primary neuronal cultures.…”

“…In particular, DOPAL-induced αSyn accumulation among the neuronal compartments was observed, as well as impaired αSyn clearance in primary neuronal cultures. Investigators also assessed the differential impact of the αSyn-DOPAL interplay in diverse neuronal districts, revealing altered synaptic integrity, overwhelmed degradative pathways in neuronal projections, and reduced axonal arborization [ 93 ].…”