Early synaptic dysfunction in Parkinson's disease: Insights from animal models

Tommaso Schirinzi, Graziella Madeo, Giuseppina Martella, Marta Maltese, Barbara Picconi, Paolo Calabresi, Antonio Pisani

Research output: Contribution to journalReview articlepeer-review


The appearance of motor manifestations in Parkinson's disease (PD) is invariably linked to degeneration of nigral dopaminergic neurons of the substantia nigra pars compacta. Traditional views on PD neuropathology have been grounded in the assumption that the prime event of neurodegeneration involves neuronal cell bodies with the accumulation of metabolic products. However, this view has recently been challenged by both clinical and experimental evidence. Neuropathological studies in human brain samples and both in vivo and in vitro models support the hypothesis that nigrostriatal synapses may indeed be affected at the earliest stages of the neurodegenerative process. The mechanisms leading to either structural or functional synaptic dysfunction are starting to be elucidated and include dysregulation of axonal transport, impairment of the exocytosis and endocytosis machinery, altered intracellular trafficking, and loss of corticostriatal synaptic plasticity. The aim of this review is to try to integrate different lines of evidence from both pathogenic and genetic animal models that, to different extents, suggest that early synaptic impairment may represent the key event in PD pathogenesis. Understanding the molecular and cellular events underlying such synaptopathy is a fundamental step toward developing specific biomarkers of early dopaminergic dysfunction and, more importantly, designing novel therapies targeting the synaptic apparatus of selective, vulnerable synapses.

Original languageEnglish
Pages (from-to)802-813
Number of pages12
JournalMovement Disorders
Issue number6
Publication statusPublished - Jun 1 2016


  • Parkinson's disease
  • Presymptomatic stage
  • Substantia nigra
  • Synaptopathy

ASJC Scopus subject areas

  • Clinical Neurology
  • Neurology


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