Neuroprotection, etiology and treatment of Parkinson’s disease, mitochondrial cytopathies, abnormalities of the mitochondrial genome
Previous and Current Research
Our research groups focus on mitochondrial diseases; these include those arising from mitochondrial DNA abnormalities, and are varied in their clinical presentation. Mitochondrial cytopathies are generally based on abnormalties of the respiratory chain and/or b-oxidation of fatty acids. A field of particular interest is the interrelation between b-oxidation defects and respiratory chain function, which we characterise by analysing the relevant metabolic intermediates formed. Metabolic intermediate analysis will be a tool to further establish the effects of mtDNA mutations found in neurodegenerative diseases (Parkinson’s Disease and Alzheimers Disease) on the various pathways of cellular energy metabolism.
Parkinson’s Disease is of particular interest to us. We were the first to describe a complex I defect confined to the substantia nigra pars compacta of PD patients. We have recently found several new mutations of the mtDNA in blood and brain samples of PD patients. Using cybrids generated from those patients we will go on to investigate the biochemical effects of the mtDNA abnormalities and their relevance to PD. We would also like to investigate the link between mtDNA abnormalities and environmental risk factors, such as chronic exposure to neurotoxins, with respect to the development of PD. It is our aim to characterise persons at risk and find stratergies for clinical treatment.
Future Projects and Goals
Using primary mice cultures we study neuroprotection mechanisms of dopaminergic neurons. We have shown the dopamine agonists lisuride and pergolide increase the survival of neurones and the length of neuritic processes, thereby enlarging the number of synapses.
Dopamine agonists also protect neurons from MPP+ toxicity, the toxic metabolite of MPTP, which is currently the most widely used model of PD. Our future studies will focus on the mechanisms by which dopamine agonists act as neuroprotective agents. We would also like to establish a new model of PD by chronic rotenone treatment, where we hope to imitate the loss of dopaminergic neurons as observed in the brain of PD patients. Although the use of antioxidants (eg. Coenzyme Q10) is controversial, they may have neuroprotective effects on dopaminergic neurons. In view of increasing evidence that combination therapy is most effective in the treatment of PD, we hope to investigate the potential synergistic effects of both dopamine agonists and antioxidants. We will concentrate on the metabolic consequences of oxidative stress and its relationship with excitotoxicity. In particular glutamate toxicity will be studied in primary dopaminergic cultures, using fluorescent techniques to measure free radical production and mitochondrial membrane potential. Since toxicity can be induced by several mechanisms, we hope to study the deleterious effects of oxidised proteins (a-synuclein) and of an impaired ubiquitine-proteasome system (by direct or indirect inhibition). The protective effects of dopamine agonists and antioxidants on this induced toxicity will then be determined. Furthermore we wish to characterise the target genes which might be affected by DA agonists and antioxidants, contributing to their protective effect. We will perform this using microarray gene chip analysis. In addition we would like to investigate genes relevant for oxygen radical detoxification.
In the future we hope to develope a microarray gene chip for the detection of mitochondrial genome abnormalities. This will help to further elucidate the problem of phenotype-genotype correlation.
Gille G, Rausch WD, Hung ST, Moldzio R, Ngyuen A, Janetzky B, Engfer A, Reichmann H
Protection of dopaminergic neurons in primary culture by lisuride.
J Neural Transm., 109: 157–169 (2002)
Richter G, Sonnenschein A, Grünewald T, Reichmann H, Janetzky B
Mitochondrial mutations in Parkinson’s disease.
J Neural Transm., 109: 721–729 (2002)
Schaefer J, Pourfarzam M, Bartlett K, Jackson S, Turnbull DM
Fatty acid oxidation in peripheral blood cells – characterisation and use for the diagnosis of fatty acid oxidation.
Pediatr Res., 37: 354–360 (1995)
Janetzky B, Hauck S, Youdim MB, Riederer P, Jellinger K, Pantucek F, Zöchling R, Boissl KW, Reichmann H
Unaltered aconitase activitiy, but decreased complex I activity in substantia nigra pars compacta of patients with Parkinson’s disease.
Neurosci Lett., 169: 126–128 (1994)
Lestienne P, Nelson I, Riederer P, Reichmann H, Jellinger K
Mitochondrial DNA in postmortem brain from patients with Parkinson’s disease.
J. Neurochen., 56: 1819 (1991)