Neurodegenerative Diseases Unit of the Lyon Laboratory

Head of Unit: Thierry Baron

Deputy Head of Unit: Anne-Gaëlle Morignat

The Neurodegenerative Diseases Unit is a team of 10 employees, including five scientists/engineers, four laboratory technicians and a secretarial service. For several years, it has been studying animal diseases associated with protein folding defects, historically represented by prion diseases. The unit has a facility of around 500 m2 hosting conventional and containment level L3 laboratories.

Reference activities

The unit is the National Reference Laboratory for the diagnosis and surveillance of prion diseases in ruminants.

Research activities

Historically, the unit's work has been dedicated to the study of prion "strains" and their biological and molecular differentiation. Most of the work undertaken has dealt with methods for the molecular phenotyping of pathological prion proteins. This work is still ongoing, with an emphasis on prion disease in elks, which recently appeared in Northern Europe. The objective is to determine the origin of the prion responsible for this disease, in particular through comparisons with other ruminant prion diseases, especially in sheep.

More recently, these methodologies based on protein biochemistry and histopathology (study of tissue) combined with in vitro methods have been used to study human neurodegenerative diseases, in particular Parkinson's. This work is largely carried out using animal models of Parkinson's or Alzheimer's disease.

Part of this work involves the molecular characterisation of alpha-synuclein aggregation; alpha-synuclein is a protein found in lesions in Parkinson's disease and similar disorders. The work aims to determine how neuropathological lesions spread in the central and peripheral nervous systems as these diseases progress and to what extent protein aggregation characteristics can be useful for early diagnosis, or to explain why some diseases differ in terms of the nature of the lesions and their clinical expression.

A second part focuses on the role of pesticide exposure in Parkinson's disease. Its goal is to better understand how much this exposure is a risk factor for this disease. The work currently being conducted mainly focuses on a persistent insecticide responsible for major human contamination – chlordecone – and on the effect of low-dose pesticide mixtures in food. Among other mechanisms potentially involved, the team is seeking to understand to what extent a pesticide could initiate and/or promote the spread of protein aggregation.

Main research projects, from the last five years and ongoing

SynStrain (2023-2025)

Funding: CIFRE thesis supported by the French Blood Agency (EFS) in Occitanie and the PCCEI joint research unit (UMR)

This thesis project is aiming to use different in vivo (ANSES) and in vitro (EFS Occitanie - UMR PCCEI) approaches to characterise the diversity of alpha-synuclein aggregates involved in the various human diseases associated with this protein. The question of the maintenance of strain characteristics will be studied using amplification products obtained in vitro from human multiple system atrophy or from the brains of transgenic mouse models of Parkinson's disease. In a second phase, the possibility of using a transgenic model that also has a disease such as Alzheimer's will be assessed to study another human disease, dementia with Lewy bodies (DLB).

ParkSang (2023)

Investigation of biomarkers in neuronal extracellular vesicles from blood plasma in a transgenic mouse model of Parkinson's disease

Funding: ANSES

There are currently no biological markers for the diagnosis and monitoring of Parkinson's disease, in particular on samples that can easily be taken from the patient, such as blood. The aim of this project is to search for such biomarkers in a model of Parkinson's disease in transgenic mice. The project will take blood samples and isolate extracellular vesicles of neuronal origin present in plasma, in order to search for pathological alpha-synuclein, a major component of brain lesions, and for microRNAs characteristic of the disease.

DEEP (2022-2024)

Impact of chronic exposure to a mixture of low doses of pesticides on the onset of Parkinson's disease and type 2 diabetes in mouse models, and study of the links between these two diseases

Funding: National Research Programme for Environmental and Occupational Health 2021

Parkinson's disease is promoted in humans by type 2 diabetes. One of the project partners showed that a mixture of pesticides administered to mice in the diet for 12 months at the acceptable daily doses for humans leads to overweight, glucose intolerance and hyperglycaemia, which are characteristic of type 2 diabetes. Our project aims to assess the effects of daily exposure to this pesticide mixture on metabolic disorders and Parkinson's disease in a transgenic mouse model of Parkinson's, and to investigate the pathological mechanisms common to both chronic diseases.

IAPPAS (2022-2024)

Impact of chronic exposure to a mixture of low doses of pesticides on the development of type 2 diabetes and Parkinson's disease: aiming for the discovery of common mechanisms of alteration

Funding: Francophone Diabetes Society

The project aims to assess the effects of daily exposure to a mixture of pesticides on metabolic disorders and Parkinson's disease in a transgenic mouse model expressing both human alpha-synuclein, the protein implicated in Parkinson's disease, and human pancreatic polypeptide, which is involved in type 2 diabetes.

SynCoV (2022)

Does SARS-CoV-2 facilitate the aggregation of human alpha-synuclein, a key protein in Parkinson's disease?

Funding: ANSES

Parkinson's syndromes in humans can be promoted by viral infections, especially respiratory viruses. This project aimed to assess the neuropathological effects of experimental infection with a strain of SARS-CoV-2 virus, which causes COVID-19 in humans, in a transgenic mouse model of Parkinson's disease. In particular, we looked for evidence of viral neurotropism and neuroinflammation associated with the experimental challenge, and clues for a possible increase in the aggregation of human alpha-synuclein expressed by these mice, a major feature of Parkinson's disease.

Chlorpark (2020-2022)

Can chlordecone have an adverse effect on the mouse nigrostriatal system, the preferential target in Parkinson's disease?

Funding: ANSES

Chlordecone is a major organochlorine insecticide contaminating the environment, animals and humans in the French Caribbean. This substance's acute neurotoxicity is known in humans and has been determined experimentally in rodents. However, it is not known whether chronic exposure to this substance could lead to degeneration of neurons in the brain regions affected by Parkinson's disease. The project intended to assess this possibility through chronic exposure of mice to this substance.