Bioenergetics and mitochondrial dynamics in hereditary neuropathies

Julien Cassereau, Lecturer

julien.cassereau@univ-angers.fr

Keywords : GDAP1, MFN2, inherited neuropathies, bioenergetics, mitochondrial dynamics,

Project 1 : 

State of the art and objectives 

Amyotrophic Lateral Sclerosis (ALS) is a degenerative disease mainly affecting motor neurons leading to a progressive and diffuse paralysis. ALS is the third neurodegenerative disease, affecting 6000 persons in France, 150 000 in the world. Despite the advances in the fields of neurology and neuroscience, the pathological mechanisms of the disease remain unknown. In recent years, there has been increasing interest in mitochondrial bioenergetics impairment and cytosolic protein aggregations, as key pathological actors of the disease.

The aim of our project is to study energy and protein metabolisms in sporadic ALS in order to highlight pathological mechanisms, identify potential biomarkers, and test new therapies.

We are prospectively collecting primary skin fibroblasts from sporadic ALS patients and healthy controls with the aim of analyzing cell growth, bioenergetics, mitochondrial dynamics, free-radicals production, cytoplasmic inclusions, cytoskeleton structure, and stress response.

Main results from the last 5 years

• Metabolomics signature in ALS patients’ derived fibroblasts.

• Ultrastructural characterization of sporadic ALS patients’ derived fibroblasts.

People involved

Dr Philippe CODRON (MD-PhD).

Dr Arnaud Chevrollier (PhD)

Main publications and patents from the 5 last years

• Veyrat-Durebex C, Bris C, Codron P, Bocca C, Chupin S, Corcia P, Vourc’h P, Hergesheimer R, Cassereau J, Funalot B, Andres C, Lenaers G, Couratier P, Reynier P, Blasco H. Metabo-Lipidomics of Fibroblasts and Mitochondrial-Endoplasmic Reticulum Extracts from ALS Patients Show Alterations in Purine, Pyrimidine, Energetic, and Phospholipid Metabolisms. In submission, Brain.
• Codron P, Cassereau J, Vourc'h P, Veyrat-Durebex C, Blasco H, Kane S, Procaccio V, Letournel F, Verny C, Lenears G, Reynier P, Chevrollier A. Primary fibroblasts derived from sporadic amyotrophic lateral sclerosis patients do not show ALS cytological lesions. Amyotroph Lateral Scler Frontotemporal Degener. 2018 Jan;31:1-11.
• Codron P, Cassereau J, Eyer J, Letournel F. Neuronal Intermediate Filaments in Amyotrophic Lateral Sclerosis. In: Foyaca-Sibat H, Ibañez-Valdés L de F, editors. Update on Amyotrophic Lateral Sclerosis. InTech; 2016. DOI: 10.5772/6316.

Collaborations

• Department of Neurology, ALS reference center, University Hospital of Angers, Angers, France
• Department of Neurobiology and Neuropathology, University Hospital of Angers, Angers, France
• Department of Biochemistry and Molecular Biology, University Hospital of Tours, Tours, France
• School of Medicine, INSERM U930, Francois-Rabelais University, Tours, France

Acknowledgements for the financial supports

• Dr P. CODRON : Poste d’accueil INSERM 2017-2019 pour Médecins, Pharmaciens, Odontologistes (63.500€). Rémunération pour une durée de deux ans en tant que chercheur rattaché à l’unité INSERM 1083 CNRS 6015 dans le cadre de la réalisation d’une thèse de Sciences.
• Dr P. CODRON : Appel d’offre interne CHU d’Angers (18.600€). Budget alloué pour le projet de recherche Fibro-ALS étudiant la structure histologique et le métabolisme énergétique de lignées fibroblastiques issues de patients atteints de formes sporadique de Sclérose Latérale Amyotrophique.
• Dr P. CODRON : Médaille d’Or CHU d’Angers (24.000€) Rémunération pour une durée d’un an en tant que chercheur rattaché à l’unité INSERM 1083 CNRS 6015 dans le cadre de la réalisation d’une thèse de Sciences.

Project 2 : 

State of the art and objectives

Charcot-Marie-Tooth disease (CMT) is a hereditary sensorimotor peripheral neuropathy with an estimated prevalence of 1 / 2,500, with more than 80 genes identified. For a decade, advances in genetics have improved the understanding of the pathophysiological mechanisms, but there are probably still several functions to be discovered, and their involvement in the pathophysiological processes at the origin of the neurodegenerative phenomena remain uncertain. The role of mitochondria in the axonal form of the disease is better known and new genes are regularly described. The main objective of my work is to study the mitochondrial energetic metabolism of fibroblast cells from patients suffered from CMT4A / 2K by ganglioside-induced differentiation-associated protein 1 (GDAP1) gene mutations, or CMT2A by mitofusin 2 (MFN2) mutations.

Studies of the energetic metabolism of these cells revealed a significant bioenergetic alteration and the study of the mechanisms responsible for this bioenergetic alteration has highlighted new avenues for the understanding of the pathophysiology of these hereditary neuropathies.

Main results from the last 5 years

• MFN2 mutation can result in mitochondrial network hyper-fusion.
• GDAP1 mutations are associated with mitochondrial complex I defect.
• GDAP1 may play a protective role against oxidative stress.

People involved

Dr Philippe CODRON (MD-PhDS).

Main publications and patents from the 5 last years

• Codron P, Chevrollier A, Kane MS, Echaniz-Laguna A, Latour P, Reynier P, Bonneau D, Verny C, Procaccio V, Lenaers G, Cassereau J. Increased mitochondrial fusion in a autosomal recessive CMT2A family with mitochondrial GTPase mitofusin 2 mutations. J Peripher Nerv Syst. 2016;21:365-369.
• Kane MS, Paris A, Codron P, Cassereau J, Procaccio V, Lenaers G, Reynier P, Chevrollier A. Current mechanistic insights into the CCCP-induced cell survival response. Biochem Pharmacol. 2017 22;148:100-110
• Cassereau J, Codron P, Funalot B. Inherited peripheral neuropathies due to mitochondrial disorders. Rev Neurol. 2014 May;170:366-74.
• Chevrollier A, Cassereau J, Ferre M, Alban J, Desquiret-Dumas V, Gueguen N, Amati-Bonneau P, Procaccio V, Bonneau D, Reynier P. Standardized mitochondrial analysis gives new insights into mitochondrial dynamics and OPA1 function. Int J Biochem Cell Biol. 2012,44(6):980-8

Collaborations

• Neuromuscular diseases reference center, University Hospital of Angers, Angers, France
• Department of Genetics , University Hospital of Bordeaux , France (Pr Goizet)
• Department of Neurology, University Hospital of Strasbourg, Strasbourg, France (Dr Echaniz-Laguna)
• Department of Neurogenetics, University Hospital of Lyon, Bron, France (Pr Latour)
• Neuromuscular Unit, Neurology Department, Hospital Universitari de Bellvitge, Institut de Investigacions Biome`diques de Bellvitge (IDIBELL), L’Hospitalet de Llobregat, Barcelona, Spain (Dr Casasnovas)

Acknowledgements for the financial supports

Dr P. CODRON : Année Recherche Université d’Angers (22.000€). Rémunération pour une durée d’un an en tant que chercheur rattaché à l’unité INSERM 1083 CNRS 6015 dans le cadre de la réalisation d’un Master 2 en Neurosciences.