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Unraveling the molecular mechanisms leading to cellular dysfunction in diseases linked to defects in mitochondrial iron-sulfur cluster metabolism

Objective

The project aims at unraveling the molecular pathophysiology of recessive ataxias, a heterogeneous set of severely disabling neurodegenerative disorders due to loss of function of proteins involved either in mitochondrial/metabolic pathways or DNA repair. Friedreich ataxia, the most common form, is due to partial loss of function of frataxin, a mitochondrial protein involved in iron-sulfur cluster (ISC) biogenesis. Furthermore, the rare X-linked sideroblastic anemia with cerebellar ataxia is caused by mutation in ABCb7, an ATP-binding cassette transporter of the mitochondrial inner membrane necessary for cytosolic ISC export. ISC are versatile co-factors of proteins involved in electron transport, enzyme catalysis and regulation of gene expression. The synthesis and insertion of ISC into apoproteins involve complex machineries that are still poorly understood in the mammalian cell. The objectives of this proposal are: 1) to elucidate ISC biogenesis and metabolism in the mammalian cell, with an emphasis on the role of frataxin and ABCb7; 2) to better understand the molecular pathways that are involved in neuronal dysfunction due to defects in mitochondrial ISC metabolism. These objectives will be accomplished by a multidisciplinary approach combining molecular and biochemical approaches to study the ISC assembly machineries, bioinformatic and proteomic studies to identify new Fe-S proteins, the development and pathological analysis of animal and cellular models to dissect the molecular mechanisms, and transcriptomic analysis to uncover the common pathways among recessive ataxias. A specific focus of the proposal will be the involvement of DNA damage response pathways in neuronal dysfunction, as several DNA repair enzymes have recently been identified as Fe-S proteins and thus might be directly affected by frataxin and ABCb7 deficiency. This proposal should lead to the identification of different pathways for therapeutic intervention for these devastating disorders.

Field of science

  • /natural sciences/biological sciences/genetics and heredity/mutation
  • /medical and health sciences/basic medicine/physiology/pathophysiology
  • /natural sciences/biological sciences/biochemistry/biomolecules/proteins
  • /social sciences/social and economic geography/transport
  • /natural sciences/biological sciences/biochemistry/biomolecules/proteins/enzymes

Call for proposal

ERC-2007-StG
See other projects for this call

Funding Scheme

ERC-SG - ERC Starting Grant

Host institution

CENTRE EUROPEEN DE RECHERCHE EN BIOLOGIE ET MEDECINE
Address
Rue Laurent Fries 1
67404 Illkirch Graffenstaden
France
Activity type
Research Organisations
EU contribution
€ 1 449 924
Principal investigator
Hélène Monique Sadoulet Puccio (Dr.)
Administrative Contact
Steve Brooks (Dr.)

Beneficiaries (1)

CENTRE EUROPEEN DE RECHERCHE EN BIOLOGIE ET MEDECINE
France
EU contribution
€ 1 449 924
Address
Rue Laurent Fries 1
67404 Illkirch Graffenstaden
Activity type
Research Organisations
Principal investigator
Hélène Monique Sadoulet Puccio (Dr.)
Administrative Contact
Steve Brooks (Dr.)