Protein aggregation is found occurring in the vast majority of degenerative diseases but its role remains controversial. Part of the literature suggests that this aggregation leads to cell death through sequestering of essential proteins by illicit interactions or to the inhibition of the proteasome. On the opposite, other published data indicate that aggregation could represent a protective mechanism ensuring survival of cells by the isolation of some of their toxic components from the rest of the cell. While studying the cell death process in the presence of toxic proteins that aggregate we have detected a phenomenon of compensatory proliferation that allows replacing dead cells of a tissue and thus tissue homeostasis. Therefore, our group studies both cell death and compensatory proliferation associated with protein aggregation in Drosophila thanks to two models:

1)   fruit flies expressing the human Sca3 gene that is responsible for spinocerebellar ataxia type 3, a polyglutamine disease also known as Machado-Joseph disease. We are developing methods that combine genetics and biochemistry to identify the nature of the toxic molecule, and thus define whether it is a soluble or aggregated form of the Sca3 protein that triggers cell death.

In Drosophila as in mammals only the mutated protein is toxic and forms insoluble aggregates. We have shown that mutated Sca3 sequesters normal Sca3 inside insoluble aggregates. To address the question of the toxic form of mutated Sca3, we have estimated the quantity of soluble and insoluble Sca3 per cell in the presence of a suppressor (either Hsp70 or normal Sca3 protein) or enhancer (Sca7, a polyglutamine protein responsible for spinocerebellar ataxia type 7) of the Sca3-induced toxicity, as well as along ageing. Our results suggest that soluble Sca3 would not be the toxic specie but aggregates would be.

We are now testing whether Sca3 can affect degradation systems in vivo as suggested by data of the literature that were obtained in vitro and in cellulo.

2)  flies overexpressing the dpsn gene that encodes a 6 to 8 transmembrane domains-bearing Drosophila presenilin. First, to validate this model, we have shown that dpsn overexpression-induced cell death was associated with protein aggregation and could be modulated by Hsp70. We could also identify several components of this cell death pathway.

Our data show that the adult phenotype induced by the overexpression of dpsn in the wing tissue is naturally diminished by a phenomenon of proliferation that involves the Jun kinase (JNK) pathway. Dpsn overexpression-induced apoptosis in this proliferative tissue triggers compensatory proliferation.

In mammals, as in other models developed to study this phenomenon in Drosophila, compensatory proliferation is controlled by the JNK pathway. However, contrary to what is observed in compensatory proliferation in the mammalian liver, the p38 MAPK pathway is not involved in our system, thus showing that the control of compensatory proliferation may depend on the tissue, organism and death signal it is associated to.

Identity of the components of the JNK pathway that are regulating this proliferation remain poorly studied. Thus we have focused on this matter and shown that the whole core of the JNK pathway is implicated. We could also identify the MAP3K that is responsible for the activation of the pathway.

When the JNK pathway is overactivated or when dpsn-induced cell death is inhibited, overproliferation can be observed and non-cell autonomous apotosis is observed, meaning that cells adjacent to the domain expressing Dpsn die.

We are now identifying the signals that are responsible for the activation of the JNK pathway through the identified MAP3K.

Modifying the balance between apoptosis and compensatory proliferation is a potential source for cancer in mammals. This is well established in the case of liver cancer. However, the role of this coupling between cell death and proliferation remains poorly described. Because it necessitates to work on whole organisms, the signalling and apoptosis pathways involved in triggering compensatory proliferation are mostly studied in Drosophila. Our work should allow a better understanding of this equilibrium.