Université de Strasbourg

Fellows seminar - Alterations in genes or their packaging leading to human diseases

December 19, 2023
From 14:30 until 17:00


In this joint seminar relating to the life sciences, two USIAS projects will be presented. The three fellows who are involved in them, all from the Institute of Genetics and Molecular and Cellular Biology (IGBMC) of the University of Strasbourg, will speak about their findings, and reflect on the implications and applications of their research.

Connecting phenotype to genotype: hereditary cerebellar ataxia and mitochondrial dysfunction

By Christelle Golzio and Hélène Puccio, 2019 Fellows

Ataxia is a term for disorders that affect co-ordination, balance and speech, resulting from damage to a part of the brain called the cerebellum – the “little brain” at the back of the head. This can be caused by injury or an underlying disease, or it can be genetic and hereditary. Cerebellar ataxia (CA) refers to a group of degenerative genetic diseases that are characterised by progressive damage of the cerebellum. The recent progress in next-generation sequencing has opened up new perspectives in the hunt for the gene(s) and mechanisms involved. Problems with mitochondrial function is one of the common factors that is emerging.

Autosomal Recessive Cerebellar Ataxia 2 (ARCA2) is linked to mutations in the gene encoding for the protein COQ8A, a mitochondrial protein involved in Coenzyme Q biosynthesis. However, the link between different types of mutations found (genotype) and the disorder (phenotype) could not be established.

To study developmental defects in human genetic diseases, the zebrafish is widely used. It shares 70% of its genome with the human genome and is easy to manipulate genetically However, this model has only been used in few instances to study neurodegenerative cerebellar ataxia, and never for ARCA2.  

In their project, Christelle Golzio and Hélène Puccio departed from the current paradigm that ARCA2 is a disease due to a loss of function mechanism and is considered strictly as a neurodegenerative disorder. Instead, they hypothesize a developmental component. In addition to fundamental insights into the development of the cerebellum and the mechanisms at work, the disease models generated in the USIAS project can become the basis for in vivo screen of candidate therapeutic molecules for treatment of this serious progressive disorder.

Epigenetics and genome packaging

By Patrick Schultz, 2021 Fellow

The level of gene expression, also known as transcription, controls all aspects of life and must be precisely regulated in response to changes in the environment and cellular signals. Transcription is carried out by molecular machines, RNA polymerases, designed to copy the genetic information encoded by DNA into RNA, which is then translated into proteins. A host of regulatory molecules help to adjust gene expression. Remodelers make DNA accessible to the transcription machinery by modifying the way in which DNA is packaged in the cell. The way DNA is organised in the form of chromatin predisposes a particular cell type to express its own set of genes, giving it its cellular identity. The molecular machines that control chromatin structure are often mutated during the development of cancers and constitute therapeutic targets.

One of the goals of our team is to describe the architecture of these molecular edifices in order to understand how they function, and how these molecular structures are disrupted by mutations found in patients. We purify these molecular assemblies from cultured human cells and use molecular electron microscopy imaging technologies to observe these molecular edifices, describe their shape, study their interactions and their movement over time.

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