A common mitochondrial pathogenesis for Parkinson’s disease: elucidating disease mechanisms and designing treatments
A common mitochondrial pathogenesis for Parkinson's disease: mitochondrial dysfunction in neurons
Both damage of the mitochondrial DNA (mtDNA) and mitochondrial respiratory chain (MRC) have been described as a consistent phenomenon in sporadic Parkinson’s disease, although their origin and role remain unknown. We have studied the role of mitochondrial dysfunction at the level of the single neuron in the PD brain.
Parkinson’s disease (PD) is the second most common neurodegenerative disease causing severe disability and death. While all roads in PD seem to go through mitochondria, the underlying mechanisms and sequence of events remain unresolved. The central hypothesis in this work is that mitochondrial dysfunction is a key factor in the pathogenesis of PD, and that understanding the underlying mechanisms will provide better options for treatment. We have shown that mtDNA in the substantia nigra in the PD brain have an increased deletion of mtDNA compared to age matched controls (Dölle et al, PMID: 27874000). Further more, while deletion of mtDNA in substantia nigra is a common phenomenon in aging, healthy individuals appear to correct for this deletion by increasing the number of mitochondria per neuron. This upregulation seems to be impaired in PD, and patients are not able to compensate for the increasing deletions resulting in a depletion of mtDNA. There is no difference in mtDNA point mutational load between PD and controls. Previous research has shown that the MRC is affected in PD, with decreased deficiency of the mitochondrial complex I in the substantia nigra, as well as the frontal cortex. The neurodegenerative process of PD, however, affects multiple brain regions, but whether complex I deficiency occurs outside of the substantia nigra remains controversial. We have performed a study (unpublished, in writing) showing that complex I is deficient throughout the PD brain, affecting the hippocampus, striatum and cerebellum as well as frontal cortex and substantia nigra. However, there is no correlation between mtDNA and complex I deficiency outside of the substantia nigra. Based on this, we conclude that semi-quantitative and functional deficiencies of complex I is not caused by damaged mtDNA. The role of complex I deficiency in the pathogenesis of PD remains unexplained. Moreover, it is unclear whether this is a primary pathogenic event compromising neuronal integrity and function, an adaptive response to disease-related stress, or merely a symptom of end-stage dysfunction in terminally ill neurons. Medications increasing mitochondrial biogenesis have been shown to have a protective effect on PD. Based on this, we hypothesize that increasing mitochondrial biogenesis may compensate for the accumulating damage to mtDNA in the substantia nigra and rescue neuronal dysfunction and death. For the following years of this PhD, we will focus cell models designed to test whether boosting the mitochondrial biogenesis can be protective in a cell model.
Defective mitochondrial DNA homeostasis in the substantia nigra in Parkinson disease.
Nat Commun 2016 Nov 22;7():13548. Epub 2016 nov 22
PMID: 27874000 - Inngår i doktorgradsavhandlingen