MITOCHONDRIAL DYSFUNCTION IN NEURODEGENERATIVE DISORDERS

Abstract: 

While the aetiology of human neurodegeneration remains unknown, mitochondrial dysfunction, glutamate toxicity and protein misfolding may play a critical role. Our data showing that deregulation of glutamate dehydrogenase2 (hGDH2) accelerates Parkinson disease (PD) onset and that SLC25 mutation produces ataxia have linked mitochondrial glutamate metabolism and/or transport processes to degeneration.

Also, over expression of hGDH1 accelerates age-dependent hippocampal changes, providing connection between GDH deregulation and Alzheimer's disease (AD). We have characterized mitochondrial systems (Mia40 and Erv1) responsible for transport and oxidative folding of proteins linked to amyotrophic lateral sclerosis (ALS). Here, we have assembled a multidisciplinary team of neurologists/neuroscientists and basic scientists to study specific mitochondrial metabolic enzymes and transport systems as these relate to human degenerations.

We will study the transport of hGDH1 and hGDH2 across mitochondrial membranes using both mammalian systems and S. cerevisiae and we will investigate whether the enzyme forms homo- or hetero-hexamers in vivo. In addition, we will study the role of hGDH1 and hGDH2 in cell function by creating a S. cerevisiae GDH knockout model with the organism's GDH genes replaced by the human genes. Regarding ALS, we will study the interaction of Mia40-Erv1 with the wild-type SOD1 and its mutants and will determine whether ALS-causing SOD1 mutations alter its oxidative folding.

The pathogenic role of SLC25 in ataxia will be explored by performing histological analyses in SLC25m/m mutant mice and by studying the expression profile and function of the SLC25 protein. Finally, we will sequence the genes GLUD1/GLUD2 (encoding hGDH1 and hGDH2, respectively), CHCHD4/GFER (human homologs of Mia40/Erv1) and SLC25 in patients with AD, ALS and ataxia. These efforts may identify novel targets for developing rational treatments to human degenerations.

Project info

Acronym:
MDND
Coordinating Institution:
University of Crete
Scientific Coordinator:
Plaitakis Andreas
Research Team 2 Leader:
Tokatlidis Ioannis
Research Team 3 Leader:
Douni Eleni

Stats

I.D.:
631
Mis:
377226
Duration (months):
42
Budget:
600 000.00
Diavgeia:
ΑΔΑ: Β4ΛΔ9-Ν4Ι

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