Scientific project


Team 6 joined the JPArc INSERM research center in 2010 with the aim to better understand Parkinson’s disease (PD) from its early stages using several complementary approaches:

First, the team developed a descriptive approach from the information collected in patients to study their clinical symptoms, and the protective or deleterious factors of PD. It has set up several cohorts of familial and sporadic PD patients, other neurodegenerative disorders and controls. It showed for instance the benefice of estrogen and of treatments decreasing lipids which are associated with delays of PD onset (Mutez et al., 2009). This last result was confirmed with the use of an experimental model of PD (Kreisler et al., 2010).

Second, in order to better understand the initial mechanisms involved in the development of PD, the team focused on several familial cases with a dominant autosomal transmission. The team highlighted the deleterious roles of some PD-related genes, among which SNCA encoding the a-synuclein. This protein aggregates into Lewy bodies, a neuropathological hallmark of PD. team showed that the sole overexpression of this gene is sufficient to cause the disease in some rare cases of PD harboring an extra copy of this gene probably due to a non allelic homologous recombination mechanism between the Line-1 sequences identified at the break junctions (Chartier-Harlin et al., 2004, Mutez et al., 2010). The team also participated in collaborative researches demonstrating for instance that the LRRK2 gene, known for its involvement in familial and sporadic cases, displays numerous variants conferring a susceptibility to PD (Ross et al., 2011). These data underline that some genes of familial PD cases may also confer susceptibility for sporadic patients. Recently, the work of the team led to the identification of a mutation c.3614G>A (p.Arg1205His) of EIF4G1 (eukaryotic translation initiation factor 4-gamma 1) segregating with the disease in a familial form of PD (Chartier-Harlin et al., 2011). This protein is the backbone of the RNA translation initiation complex. Ongoing functional studies indicate that this mutation seems to alter its binding to eIF3e and increases the vulnerability of mutant cells towards reactive oxidative species. These first data suggest the involvement of EIF4G1 mutation in familial parkinsonism.

Third, the team conducted transcriptome approaches with the aim to establish an overview of deregulated biological networks in PD. Testing this approach in blood samples of controls and PD patients carrying LRRK2 G2019S mutation revealed that peripheral blood mononuclear cells represent an interesting model enabling the identification of similarly deregulated biological networks than in dopaminergic neuroblastoma cell lines invalidated for LRRK2. In addition, a principal component analysis showed that a PD transcriptome profile can be shared by asymptomatic carriers (Mutez et al., 2011). In addition, this study shows that PD does not only affect the nervous system but is also a systemic disorder.

In parallel, the team developed experimental models of exposure to low doses of the pesticide rotenone, a potent inhibitor of mitochondrial respiratory chain complex I. The team has demonstrated a synergistic effect of several deleterious factors such as a gestational stress combined to chronic low doses of rotenone in the offspring. In addition, the team also study the model developed by Pan-Montojo et al., 2012, showing that the intra-gastric administration of cumulative low doses of this pesticide leads to α-synuclein aggregation in the enteric nervous system propagating to the mesencephalon after a longer exposition according to a similar scheme as described in humans (Braak et al., 2003). Altogether, those transcriptome experiments realized in different tissues from these models and in blood cells collected from patients at different stages of the disease show a common dysfunction of PI3K/AKT/mTOR cell survival pathways and immunity processes. Interestingly, these analyses highlighted early perturbations of eIF2 and endocytosis-lysosomal pathways reminiscent of mechanisms observed in prion disorders. In addition, the team identified several transcripts as potential biomarker for PD.

Through national and international collaborations, the current project of our team is in the continuity of those results and consists in: 1) enlarging the cohorts of patients in the early stages of the disease and achieving their characterization at different levels (phenotype, genotype, metabolism) in order to carry on the search for biomarkers in previously identified signalization pathways and to test them in other related disorders; 2) better understanding the role of some early deregulated pathways in experimental models reflecting both genetic and environmental factors of PD.