Oligomeric alpha-synuclein causes early synaptic dysfunction of the corticostriatal pathway associated with non-motor symptoms

  • NPJ Parkinsons Dis. 2025 Jul 29;11(1):220. doi: 10.1038/s41531-025-01075-z.
Laura Bellingacci  #  1 ,  Miriam Sciaccaluga  #  1  2  3 ,  Alfredo Megaro  4 ,  Antonella Cardinale  5 ,  Jacopo Canonichesi  4 ,  Maria De Carluccio  6  7 ,  Roberta Mastrantonio  8 ,  Cinzia Costa  4 ,  Massimiliano Di Filippo  4 ,  Alessandro Usiello  9  10 ,  Maria Teresa Viscomi  8  11 ,  Paolo Calabresi  6  11 ,  Alessandro Tozzi  12
Affiliations
  • 1. Physiology and Biochemistry Section, Department of Medicine and Surgery, University of Perugia, Perugia, Italy.
  • 2. Fondazione Malattie Rare Mauro Baschirotto BIRD Onlus, Longare (VI), Italy.
  • 3. Department of Life Science, Health and Health Professions, Link University, Rome, Italy.
  • 4. Neurology Section, Department of Medicine and Surgery, University of Perugia, Perugia, Italy.
  • 5. Telematic University San Raffaele, IRCCS San Raffaele, Rome, Italy.
  • 6. Neurology Section, Department of Neuroscience, Università Cattolica del Sacro Cuore, Rome, Italy.
  • 7. Department of Neurosciences and Neurorehabilitation, IRCCS San Raffaele, Rome, Italy.
  • 8. Department of Life Science and Public Health, Università Cattolica del Sacro Cuore, Rome, Italy.
  • 9. Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania "L. Vanvitelli", Caserta, Italy.
  • 10. CEINGE Biotecnologie Avanzate "Franco Salvatore", Naples, Italy.
  • 11. Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy.
  • 12. Physiology and Biochemistry Section, Department of Medicine and Surgery, University of Perugia, Perugia, Italy. [email protected].
  • # Contributed equally.
PMID: 40730592 DOI: 10.1038/s41531-025-01075-z
Abstract

In synucleinopathies, α-synuclein oligomers (OSyn) appear to be associated with neurodegeneration, neurotoxicity, and proinflammatory responses, even at low concentrations, suggesting their pivotal role in the pathogenesis of Parkinson's disease (PD). We utilized a rat model of synucleinopathy induced by intrastriatal injection of OSyn, aiming to elucidate events preceding the formation of fibrillary α-syn aggregates. Electrophysiological assessments and behavioral assays revealed several early alterations in OSyn rats, evident as early as 12 weeks post-OSyn injection. These included mild and variable reduction of motor activity, anxiety-like behavior, impaired bidirectional striatal long-term synaptic plasticity, and diminished spontaneous excitatory neurotransmission in the striatum. Furthermore, p-α-syn aggregates were detected in the cortex but not in the substantia nigra (SN). Confocal microscopy analysis revealed reduced vesicular glutamate transporter 1 (VGluT1) expression at striatal glutamatergic terminals. Chronic administration of the ampakine Tulrampator to OSyn Animals prevented impairment of long-term depression (LTD), spontaneous striatal neurotransmission, and VGluT1 levels. Tulrampator also ameliorated the anxiety-related behavioral phenotype, albeit without attenuating motor deficits, demonstrating its efficacy in mitigating early synaptic and emotional deficits induced by OSyn. These findings provide a basis for a novel drug treatment strategy aimed at mitigating or delaying early damage at cortico-striatal terminals induced by OSyn, thereby counteracting the pathophysiological processes underlying the onset of early non-motor symptoms in PD.

Products