05:08pm Wednesday 16 August 2017

Lack of energy at the basis of Parkinson’s Disease – the molecular mechanism unraveled

Vanessa Morais and Bart De Strooper (VIB Center for the Biology of Disease, KU Leuven)  demonstrated how a defect in the PINK1 gene causes Parkinson’s disease. By mapping this process at the molecular level, they have provided ultimate proof that a deficient energy production process in cells leads to Parkinson’s disease.

What exactly did you discover?
Vanessa: We study the link between PINK1, mitochondria and Parkinson’s disease using as model organisms fruit flies and mice with a defective PINK1 gene, which as a result exhibit symptoms of Parkinson’s disease. We discovered that the defect in PINK1 led to the absence of phosphorylation of NdufA10, a core component of Complex I of the electron transport chain in mitochondria, resulting in decreased electrochemical potential and ATP generation. When we rescued the PINK1 deficiency with phosphomimetics of NdufA10, we were able to restore ATP generation in both mice cells and patient-derived stem cell lines, as well as synaptic deficits in the PINK1 Drosophila model. This leads us to believe that repairing the phosphorylation of Complex I should be considered for treating Parkinson’s disease.

It is not the first time the link between a defect in energy production and Parkinson’s has been
mentioned. Why do you think the Science reviewers called your results revolutionary?
Parkinson’s disease has, in fact, been linked to defects in energy production for several decades.
However, the underlying mechanism was never been fully understood. In our study, we were able to
pinpoint the cause of the energy defects observed in PINK1-mutated Parkinson’s disease patients as being the reduced phosphorylation event in the Complex I subunit NdufA10. These findings are
revolutionary because they open the avenue to a better comprehension of the disorder at the cellular level and of the disease mechanisms involved in the PINK1 loss-of-function scenario, while shedding light on a completely new pathway in the regulation of Complex I activity, which is one of the most crucial mechanism in living beings.

Your work built on findings obtained through collaboration within VIB. Can you say more about how the different labs were involved?
Phosphoproteomic screens performed with Kris Gevaert and Pieter-Jan de Bock led to the identification of the PINK1-mediated phosphorylation of NdufA10, the major building block of this study. The relevance of this modification was further analyzed in an in vivo context using the Drosophila melanogaster model, with the help of Patrik Verstreken and his colleagues, during which it was validated that PINK1 regulates mitochondrial function and synaptic activity by  phosphorylating Complex I. In fact, this story is part of a longstanding collaboration with Patrik Verstreken. Think of the Science paper by Melissa Vos and colleagues published in 2012, about the link between vitamin K2 and Parkinson’s. We now know that vitamin K2 bypasses the deficit we identified here.

When/how did Parkinson’s disease become such an important research focus in your lab/dept?
Bart: By accident! We were working on proteases, such as presenilin, involved in Alzheimer’s disease and became interested in a protein called PARL (Presenilin associated rhomboid like). This protein turned out to be present in the mitochondria and to process Pink1. When the mutations in Pink1 were identified, it was natural to explore this in more depth.

Morais et al.
Science 2014

 


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