DS0402 - Décryptage des fonctions biologiques élémentaires et de leur intégration

Deciphering TMEM165_CDG (Congenital Disorders of Glycosylation), from cellular mechanisms understanding to cure (SOLV_CDG) – SOLV_CDG

Submission summary

A group of inherited human disorders named Congenital Disorders of Glycosylation (CDG) dramatically illustrates the fundamental involvement of glycosylation in the intricate design of life. Congenital Disorders of Glycosylation (CDG) are a rapidly growing and heterogeneous group of rare, autosomal recessive inborn diseases of metabolism in which the biosynthesis of glycoproteins and/or glycolipids is affected. To date, over 100 human genetic disorders have been shown to result from mutations in glycosylation related genes. However and over the past few years, the discovery of deficiencies causing glycosylation abnormalities that are not directly linked to glycosylation pathway has led to a completely new field of investigations for the CDG research community.
Recently, our group has discovered TMEM165 as a novel deficient protein involved in CDG. Intriguingly and while the functions of TMEM165 are not known so far, the TMEM165 deficient CDG patients present bone anomalies highly suggesting a direct involvement of TMEM165 in bone homeostasis.
The entire goal of this project named SOLV-CDG is to decipher the molecular, cellular, physiological and pathological mechanisms of TMEM165 and provide potential cure for TMEM165 deficient CDG patients. To reach the objectives, three main workpackages are proposed:

(i) The first one aims at: (1) understanding the TMEM165 dysfunction on Golgi glycosylation processes, Golgi/ Lysosomal Ca2+ and pH homeostasis, and Golgi vesicular trafficking. (2) conduct pilot high throughput screen for proof of principle and potentially identify therapeutic compounds.
(ii) The second aims at characterizing the transport function of wt and mutated forms of TMEM165.
(iii) The third one aims at discovering the molecular mechanisms by which deficiencies in TMEM165 lead to skeletal abnormalities.

To achieve these objectives, this project plans to develop and characterize cellular and animal models, which are relevant and mandatory tools to understand the pathogenesis of the different types of CDG and are a requisite for evaluation of potential drugs. Novel methodologies will also be developed to particularly study the glycosylation processes, to assess the transport function of TMEM165 and to identify therapeutic compounds.

In conclusion, this project is a collaborative research project gathering three teams with complementary expertise in multidisciplinary fields. Eventually, this project, dedicated to TMEM165, offers us a new and mostly unexplored way to better understand the molecular mechanisms of Golgi glycosylation itself, its link with bone homeostasis and the development of tools to identify therapeutic compounds.

Project coordination

François Foulquier (Structural and Functional Glycobiology Unit)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

UGSF Structural and Functional Glycobiology Unit
Université Paris Descartes Laboratoire de Dynamique Membranaire et Maladies Neurologiques
IMoPA, MolCelTEG Ingénierie Moléculaire et Physiopathologie Articulaires

Help of the ANR 542,568 euros
Beginning and duration of the scientific project: September 2015 - 48 Months

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