Parkinson’s disease (PD) is a neurodegenerative disorder characterized by severe motor and cognitive symptoms and by the massive loss of vulnerable neuronal population in the brain. Beside the neuronal damage, PD is characterized by the formation of intra-neuronal aggregates called Lewy bodies. These fibrillar inclusions are mainly constituted of a presynaptic protein, α-synuclein. Increasing body of evidences from neuropathological, animal models and in vitro studies, suggests that α-synuclein spreads from one brain region to another via prion-like mechanisms. This prion-like behavior has emerged as a new modulator of α-synuclein toxicity and may contribute to the disease progression.

The general aim of our project is to decorticate the cellular and molecular bases of α-synuclein prion-like propagation. More specifically we will seek to:

1. Dissecting and monitoring how α-syn aggregation disrupts physiological functions of dopaminergic neurons leading to their loss: Focus on protein quality control and synaptic transmission.

Converging lines of evidence from neuropathological studies suggest that failure of protein degradation pathways, the ubiquitin-proteasome system (UPS) and the lysosome-autophagy pathway (LAP), represents a key step in the pathological cascade of PD and related disorders. However, the molecular mechanisms leading to protein degradation dysfunction remain unknown. Immunohistochemical and proteomic analysis of post-mortem PD tissues revealed the presence of proteins implicated in the degradation pathways within the LBs, as well as UPS catalytic subunits (i.e. 26S subunit). These observations suggest that LBs may sequester these proteins preventing them from achieving their physiological role, thus leading to protein degradation loss-of-function pathology. In this project, we seek to investigate how LB formation traps the protein degradation machinery and how it affects real-time protein turnover.

2. Investigate how α-syn aggregation affects DA synaptic function and morphology.

Synaptic transmission is the process by which the information spreads between neurons and between brain regions. This process is very dynamic (synaptic plasticity) allowing for information storage (memory), and it is tightly regulated to maintain stable communication between neurons and prevent the nervous system from descending into chaos. This process is referred to as synaptic homeostasis. PD and related disorders are usually associated with the abnormal accumulation of α-syn aggregates at the synaptic terminal and at the dendritic neuritis. Moreover, in vivo imaging of synaptic functions in the brain of patients suffering from PD and related disorders have revealed compelling evidence for presynaptic neurotransmitter deficiencies, indicating that LBs-induced neuronal dysfunction may start at the synaptic terminal and result in a failure of synaptic transmission. Using our model of LIPA-induced LBs formation, we will seek to investigate and to monitor, in live imaging, how LBs affect synaptic activity in the dopaminergic neurons. More specifically, we will address the following questions: 1) How LBs affect the synaptic morphology and 2) how LBs disturb the synaptic transmission (neurotransmitter release and electrophysiological activity).

3. Impact of SARS‐CoV‐2 infection on the development and progression of neurodegenerative diseases

Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is associated with severe respiratory complications. Interestingly, some patients with COVID‐19 also showed neurological symptoms, such as headache, nausea and vomiting, suggesting that SARS-CoV-2 may also invade the central nervous system (CNS) and exacerbate neurological diseases. Previous studies have reported that some strains of the family of respiratory viruses can infect the brain, with sometimes devastating neurological consequences. However, the questions of whether the new SARS‐CoV‐2 can invade the CNS and how it impacts neuronal development, health and function remain unexplored. Moreover, the long-term impact of COVID-19 and related inflammatory conditions on neuronal vulnerability in the context of neurodegenerative disorders remains to be elucidated. Answers to these questions are crucial to help prevent potential future pandemic of neurological and neurodegenerative disorders. In the present project, we will investigate the effects of SARS-Cov2 infection on the CNS, with a focus on the increased susceptibility to develop neurodegenerative diseases such as Parkinson’s disease (PD). By combining unique mouse models of COVID-19 with a wide range of sophisticated imaging techniques, we will address the following questions: should we expect a pandemic of neurological diseases after the COVID-19 outbreak and how can we prepare for such a scenario?

The expected results will enable us to bring new insight into the etiology of PD and how the disease starts and progresses. Moreover, the cellular and animal model of α-synuclein propagation will help us identify the pathogenic α-synuclein prion-like strains and it will offer a unique opportunity to develop new therapeutic strategies to halt or slow down the progression of PD.