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

Anna Masato, Nicoletta Plotegher, Francesca Terrin, Michele Sandre, Gaia Faustini, Andrea Thor, Stephen Adams, Giulia Berti, Susanna Cogo, Federica De Lazzari, Camilla Maria Fontana, Paul Anthony Martinez, Randy Strong, Rina Bandopadhyay, Marco Bisaglia, Arianna Bellucci, Elisa Greggio, Luisa Dalla Valle, Daniela Boassa, Luigi Bubacco

Research output: Contribution to journalArticlepeer-review

20 Scopus citations

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.

Original languageEnglish (US)
Article number42
Journalnpj Parkinson's Disease
Volume9
Issue number1
DOIs
StatePublished - Dec 2023
Externally publishedYes

ASJC Scopus subject areas

  • Clinical Neurology
  • Neurology
  • Cellular and Molecular Neuroscience

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