With diabetes medication against Parkinson’s disease

Mitochondria (in red) overlayed by a neuron (in green); Credits: J. Fitzgerald

For some patients, suffering from a specific type of Parkinson, a diabetic medication could help to stop disease progression.

 

Parkinson’s is a neurodegenerative disease with several different genetic and environmental factors leading to this etiologically heterogeneous syndrome. Despite these known causing factors, current therapies aim at treating symptoms but causative therapies have not yet been developed. In some patients, a disturbance in the mitochondrial function is associated with this disease. e:Med scientists from Tübingen of the demonstrator alliance ‘MitoPD’ (= mitochondrial Parkinson’s diseases) investigate this mechanism of mitochondrial dysfunction in Parkinson’s. Now, they figured out a causative therapy that employs a diabetes medication which specifically rescues a loss-of-function-mutation associated with Parkinson’s.

In genetic screens of patient cohorts and further in genetic models and patient-derived cells, the scientists studied the underlying pathways that lead to the mitochondrial dysfunction found in Parkinson’s patients. They discovered that a specific heat-shock protein, TRAP1, plays a central role in energy metabolism and the pathogenesis of MitoPD. If this protein is overactive, it can compensate several other MitoPD-associated mutations upstream of this pathway. However, in patients with a loss-of-function mutation of TRAP1, the metabolic homeostasis of the mitochondria is disrupted leading to cell death and eventually to Parkinson’s. Interestingly, this factor plays a role also in other indications such as cancer.

 

Metformin mechanism, © Rotermund et al, Front Endocrinol, 2018

Knowing that the diabetes medication metformin is beneficial for TRAP1-dependent ovarian cancer treatment, the scientists adapted the therapy on this Parkinson’s phenotype. Hence, they used fibroblasts derived from a Parkinson’s patient with this specific mutation. They tested metformin treatment on these cells and showed that this medication could rescue the mitochondrial dysfunction caused by TRAP1 mutation and thus prevents mitochondrial dysfunction which is implicated in neuronal cell death. As this medication is already approved for other indications, patients with this specific mutation could potentially benefit from this therapy.

However, it is important to stratify patients in order to match disease phenotype and suitable and effective therapy. Since metformin acts by slowing cell respiration and inhibiting gluconeogenesis, it may only help a specific subset of patients and may even be detrimental in some cases. More work and clinical trials are needed to test whether this drug could be beneficial or related medications such as Rapamycin are more promising in this context because of less off-target effects. At the moment, metformin is most useful as a tool to study MitoPD and the contribution of aging to Parkinson’s pathogenesis, of which very little is currently known.

 

Artikle:

Fitzgerald, J.C., Zimprich, A., Carvajal Berrio, D.A., Schindler, K.M., Maurer, B., Schulte, C., Bus, C., Hauser, A.-K., Kübler, M., Lewin, R., Bobbili, D.R., Schwarz, L.M., Vartholomaiou, E., Brockmann, K., Wüst, R., Madlung, J., Nordheim, A., Riess, O., Martins, L.M., Glaab, E., May, P., Schenke-Layland, K., Picard, D., Sharma, M., Gasser, T., Krüger, R., 2017. Metformin reverses TRAP1 mutation-associated alterations in mitochondrial function in Parkinson’s disease. Brain 140, 2444–2459. doi.org/10.1093/brain/awx202

Rotermund, C., Machetanz, G., Fitzgerald, J.C., 2018. The Therapeutic Potential of Metformin in Neurodegenerative Diseases. Front. Endocrinol. 9. In press doi.org/10.3389/fendo.2018.00400

 

Contact:

Dr. Julia Fitzgerald, Hertie Institute for Clinical Brain Research, Tübingen, MitoPD