Conference Agenda

A complex cascade of electrophysiological and molecular events inducing aberrant plasticity in the cortico-basal ganglia system, at striatal and cortical level, plays a key role in the pathophysiology of motor complications in advanced stages of Parkinson’s disease (PD). Indeed, as the disease progresses, the adverse effects of dopaminergic therapy and fluctuations of therapeutic response emerge and worsen dramatically the quality of life of patients, thus representing the major eligibility criteria for advanced PD therapies. While synaptic and molecular adaptations that occur in motor complications, such as levodopa-induced dyskinesias (LIDs), have been well studied in the striatum, less is known about plastic changes taking place in the other parts of cortico-basal ganglia loop. However, in recent years, significant advances have been made in defining alterations of synaptic plasticity throughout the whole motor network, especially the motor cortex, through the increasing use of non-invasive brain stimulation methods, as transcranial stimulation either magnetic or electric can modulate excitability and network organization of the motor cortex. Growing and accumulating evidence from human studies using neurophysiological approaches indicate a pivotal role of maladaptive plasticity within the sensorimotor loop, the motor cortex as well as the basal ganglia-SMA circuits in the pathogenesis of motor complications in PD. Therefore, reversing brain plasticity abnormalities may restore normal functioning and ameliorate clinical deficits in PD. Based on these assumptions, neuromodulation could represent a promising treatment for LIDs. While DBS is a consolidated therapy for advanced PD patients with dyskinesias, future studies should clarify the role of NIBS, not only in treatment but also in delay or prevention of LIDs in PD.

Short- (STP) and long-term potentiation (LTP)-like cortical plasticity mechanisms are impaired in patients with Parkinson’s disease (PD), as demonstrated using specific transcranial magnetic stimulation (TMS) protocols. Moreover, the abnormality in cortical oscillatory activities, including increased beta and impaired gamma oscillations, is another well-known feature of PD patients, which relates to the cardinal motor symptoms of the disease. Until a few years ago, it was unknown whether these two neurophysiological changes were independent or whether there was a relationship between them. Recent experimental evidence obtained by combining different non-invasive brain stimulation techniques (e.g., TMS and transcranial alternating current stimulation - tACS) has demonstrated that these phenomena are likely interconnected and play a clinically relevant role in patients. In particular, impaired STP- and LTP-like plasticity mechanisms in PD have been shown to be sensitive to changes in specific brain rhythms, i.e., beta and gamma, respectively. Notably, the interaction between plasticity mechanisms and cortical oscillatory activities in PD is not significantly influenced by changes in central dopaminergic levels. Furthermore, recent data suggest that changes in cortical plasticity mechanisms may reflect compensatory phenomena against motor dysfunction in PD, including beta-related bradykinesia. This talk will first summarize previous neurophysiological data showing STP- and LTP-like plasticity impairment and altered cortical oscillatory activities in PD patients. Then, it will report some recent experimental studies supporting the hypothesis of significant interactions between these two phenomena and their possible clinical relevance. Finally, it will provide concluding remarks and take-home messages.

Loss of synaptic connections, namely “synaptopathy” is a key determinant of the clinical-pathological progression of Parkinson’s disease (PD), occurring since early, preclinical stages to later, advanced phases and accounting for the huge and heterogeneous burden of motor and non-motor symptoms. Impairment in multiple biological pathways underlie synaptopathy, including a-synuclein and other proteins pathology, mitochondrial dysfunction and oxidative stress, neuroinflammation. Most of the evidence in this field comes from PD animal models, being that the human brain is not accessible in vivo. However, in the last decade, translational studies proved the reliability of human peripheral tissues as a model to dissect the pathogenesis of neurodegenerative diseases. Therefore, the analysis of the cerebrospinal fluid (CSF), the blood, either as plasma/serum or cellular component, the skin fibroblasts, and other accessible mucosa now allows for tackling in vivo, directly in patients, the main molecular cascades involved in PD, including those related to synaptopathy. Here, we will overview available evidence on the synaptopathy biomarkers assay in human fluids of PD patients at various disease stages, together with the most novel findings on the pathogenic mechanisms contributing to synaptic loss and neurodegeneration obtained from peripheral human tissues.

Parkinson's disease (PD) is characterized by the degeneration of dopaminergic nigrostriatal neurons, which causes disabling motor disorders. Scientific findings support the role of epigenetics mechanism in the development and progression of many neurodegenerative diseases, including PD. In this field, some studies highlighted an upregulation of Enhancer of zeste homolog 2 (EZH2) in the brains of PD patients, indicating the possible pathogenic role of this methyltransferase in PD. The aim of this study was to evaluate the neuroprotective effects of GSK-343, an EZH2 inhibitor, in an in vivo model of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic degeneration. Specifically, nigrostriatal degeneration was induced by MPTP intraperitoneal injection. GSK-343 was administered intraperitoneally daily at doses of 1 mg/kg, 5 mg/kg and 10 mg/kg, mice were killed 7 days after MPTP injection. Our results demonstrated that GSK-343 treatment significantly improved behavioral deficits and reduced the alteration of PD hallmarks. Furthermore, GSK-343 administration significantly attenuated the neuroinflammatory state through the modulation of canonical and non-canonical NF-κB/IκBa pathway as well as the cytokines expression and glia activation, also reducing the apoptosis process. In conclusion, the obtained results provide further evidence that epigenetic mechanisms play a pathogenic role in PD demonstrating that the inhibition of EZH2, mediated by GSK-343, could be considered a valuable pharmacological strategy for PD.