DOPAL initiates αSynuclein-dependent impaired proteostasis and degeneration of neuronal projections in Parkinson's disease PMID: 36966140

ADC Targets in Oncology

2026-04-10

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

NPJ Parkinsons Dis. 2023 Mar 25;9(1):42. doi: 10.1038/s41531-023-00485-1.

Anna Masato ¹ , Nicoletta Plotegher ¹ ² , Francesca Terrin ¹ , Michele Sandre ³ , Gaia Faustini ⁴ , Andrea Thor ⁵ ⁶ , Stephen Adams ⁷ , Giulia Berti ¹ , Susanna Cogo ¹ , Federica De Lazzari ¹ , Camilla Maria Fontana ¹ , Paul Anthony Martinez ⁸ ⁹ , Randy Strong ⁸ ⁹ , Rina Bandopadhyay ¹⁰ , Marco Bisaglia ¹ ² , Arianna Bellucci ⁴ , Elisa Greggio ¹ ² , Luisa Dalla Valle ¹ , Daniela Boassa ¹¹ ¹² , Luigi Bubacco ¹³ ¹⁴

Affiliations

1. Department of Biology, University of Padova, Padova, 35131, Italy.
2. Centro Studi per la Neurodegenerazione (CESNE), University of Padova, Padova, Italy.
3. Department of Neuroscience, University of Padova, Padova, 35131, Italy.
4. Department of Molecular and Translational Medicine, University of Brescia, Brescia, 25123, Italy.
5. Department of Neurosciences, University of California San Diego, La Jolla, CA, 92093-0608, USA.
6. National Center for Microscopy and Imaging Research, University of California San Diego, La Jolla, CA, 92093-0608, USA.
7. Department of Pharmacology, University of California San Diego, La Jolla, CA, 92093-0608, USA.
8. Department of Pharmacology and Barshop Institute for Longevity and Aging Studies, University of Texas Health Science Center at San Antonio, San Antonio, TX, 78229, USA.
9. South Texas Veterans Health Care Network, San Antonio, TX, 78229, USA.
10. Reta Lila Weston Institute of Neurological Studies, UCL Queen Square Institute of Neurology, London, WC1N 1PJ, UK.
11. Department of Neurosciences, University of California San Diego, La Jolla, CA, 92093-0608, USA. [email protected].
12. National Center for Microscopy and Imaging Research, University of California San Diego, La Jolla, CA, 92093-0608, USA. [email protected].
13. Department of Biology, University of Padova, Padova, 35131, Italy. [email protected].
14. Centro Studi per la Neurodegenerazione (CESNE), University of Padova, Padova, Italy. [email protected].

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.