2. Academic Validation
  3. Oligomeric alpha-synuclein causes early synaptic dysfunction of the corticostriatal pathway associated with non-motor symptoms

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

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. alessandro.tozzi@unipg.it.
  • # 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.

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