Project 1. The synergistic interplay between αSynuclein and DOPAL in the vulnerability of nigrostriatal neurons in Parkinson’s Disease. A full understanding of Parkinson’s Disease (PD) etiopathogenesis is still an unsolved puzzle. Among the various determinants of the preferential vulnerability of the nigrostriatal pathway, a pivotal role has been addressed to the endotoxicity associated with dopamine dyshomeostasis. An altered dopamine metabolism generates increasing levels of the reactive catabolite DOPAL, with serious consequences on neuronal proteostasis and down-stream toxic effects. Interestingly, αSynuclein (αSyn), whose buildup is a recurrent trait of PD pathology, is particularly affected by DOPAL modification. By combining cellular and in vivo models, we provided evidence that DOPAL-induced αSyn oligomerization hinders neuronal resilience, compromises synaptic integrity, and overwhelms protein quality control pathways, thus leading to a progressive dopaminergic neuron loss. Finally, we are currently testing the hypothesis that the presence of DOPAL-modified αSyn in patients’ biofluids might serve as a specific biomarker for the early diagnosis of PD.

Project 2. Dopamine signaling on striatal astrocytes. Dopamine signaling contributes to several physiological functions in the central nervous system and disturbances of dopaminergic transmission may lead to neuropsychiatric or neurodegenerative disorders, including Parkinson’s disease (PD). Indeed, PD is characterized by the progressive degeneration of dopaminergic neurons in the Substantia Nigra pars compacta, resulting in the loss of striatal dopamine content with serious consequences on the neuronal networks that regulate the initiation of movements of the body. Although the role of dopamine on neurons is well described, its influence on non-neuronal glial cells, such as astrocytes, oligodendrocytes and microglia, remains poorly understood. Astrocytes are complex and highly differentiated cells, recently proposed to play active roles in the brain pathophysiology, being key players in the ‘tripartite synapse’. Considering that different cell types cooperate in the brain physiology, the working hypothesis is to untangle the role of dopamine as a modulator of non-neuronal astrocytic functions at the striatum, to further comprehend the astrocyte-mediated pathological events occurring in PD.

Project 3.Study of SARS-CoV-2 infection as potential risk factor in Parkinson disease onset.

During these last two years, links between SARS-CoV-2 viral infection and the pathogenesis of neurodegenerative diseases has been a main topic of research. Given the neurotropism of this virus, it exists the possibility that SARS-CoV-2 viral particles could reach the neurons in the brain affecting the physiological functions of the central nervous system. Hence, we might expect this pandemic to be followed by a higher incidence of neurodegenerative diseases in the future, as it has been described in the past for similar viral infections. In this study, we focus on the role that SARS-CoV-2 viral infection might have on αSynuclein (αSyn) aggregation, a hallmark of Parkinson’s disease pathogenesis. Specifically, we are currently exploring the effect that virus-mimicking particles, as well as SARS-CoV-2-related Spike and N-protein, might have on αSyn aggregation both in vitro assays (real-time quaking-induced conversion RT-QuIC, transmission electron microscopy, atomic force microscopy) and in αSyn-inducible neuroblastoma cellular model.

1. Neurodegeneration
   1. Synuclein
2. bbbb
3. cccc