Mitochondrial dysfunction in the pathogenesis of Parkinsons disease: elucidating disease mechanisms and identifying therapeutic targets

Parkinson disease (PD) is one of the most common neurodegenerative disorders with an increasing prevalence and a world-wide socioeconomic impact. The need for understanding and treating this debilitating disorder has never been more urgent. We believe that dysfunction of mitochondria, the energy factories of the cell, plays a decisive and central role in causing PD. Mitochondria are controlled through a complex genetic system involving a constant cross-talk between the cell nucleus (chromosomes), which is inherited from both parents and the mitochondria's own genetic material (mitochondrial DNA, mtDNA), which we only inherit from our mothers. We are studying this complex communication between the nucleus and mitochondria in material form large groups of patients and healthy controls. Specifically, we are studying how mitochondrial function is changed in the brain of patients with PD and what are the genetic mechanisms (risks) underlying these changes. Our current work has elucidated new mechanisms by which impaired mitochondrial function contributes to PD and we believe that our findings are highly relevant for the development of future treatments. Specifically, we have discovered that mitochondria from neurons (i.e. brain cells) of healthy individuals compensate for DNA damage which accumulates with aging, by increasing their total DNA content (mtDNA copy number). This compensatory mechanism fails in PD resulting in high levels of mtDNA damage and mitochondrial dysfunction leading to energy failure and death of nerve cells in the areas of the brain that are most vulnerable to PD. Our findings were published in the journal Nature Communications (Dölle et al., PMID: 27874000). One important aspect of these findings is that there are compounds that can boost the production of mtDNA and mitochondria in general and may therefore correct this defect. We have conducted a retrospective epidemiological project using the Norwegian prescription registry, where we studied the incidence of PD among individuals using one type of medication (glitazones) known to boost mitochondria. We found that individuals using glitazone medication for diabetes (high blood sugar) had a significantly lower incidence of PD compared to persons with diabetes using other drugs. Therefore, compounds boosting mitochondrial numbers and function may be beneficial for PD. Other studies have also corroborated our findings. Our study was published in the journal Movement Disorders (Brakedal et al., PMID: 28861893). The cause of failing communication between the nucleus and mitochondria in PD remains unknown. We hypothesized that this defect may be, at least partly, due to inherited factors. To answer this question, we compared the entire genetic material (DNA) from more than 1,000 individuals with PD and healthy controls. Our findings show that rare inherited mutations in the genes controlling mitochondrial function influence the susceptibility to PD. These findings provide a new link between heredity and PD and advance our understanding of how the genetic background predisposes to complex disorders. The study is in press in the journal Movement Disorders (Gaare et al.). Our goal with these experiments is to elucidate the "missing link" between environment, genetics and the risk to develop PD. Moreover, we intend to use this knowledge to identify novel therapeutic targets. We anticipate that our findings will advance the understanding and treatment of PD.

Parkinsons disease (PD) is one of the most common neurodegenerative disorders with an increasing prevalence and a world-wide socioeconomic impact. The need for understanding and treating this debilitating disorder has never been more urgent. We will elucidate the complex genetic aetiology and molecular pathogenesis of PD through mitochondrial dysfunction. I suggest that neurodegeneration in PD is driven by mitochondrial dysfunction resulting from a two-hit pathogenic process at the level of two genomes. Combinations of inherited genetic defects in nuclear-encoded mitochondrial genes acting on susceptible mitochondrial DNA (mtDNA) backgrounds disrupt normal mitochondrial function and lead to increased somatic mitochondrial mutagenesis in neurons. This causes a gradual build-up of mtDNA damage leading to respiratory dysfunction and neuronal death. The studies are based on unique patient materials. ParkVest is one of the best characterized PD cohorts word-wide. It comprises 200 Norwegian patients with PD who have been prospectively followed-up since 2004. Patient brains are systematically collected post-mortem. The Italian sample comprises ~2,000 PD patients and as many healthy controls. Initially we will define the complete exome in the ParkVest cohort using a combination of Next Generation Sequencing and chip-based arrays. Exome data will be processed by an innovative, pathway-targeted analysis focussing on groups of nuclear-encoded mitochondrial genes and mtDNA sequences. Top genetic hits will be replicated by targeted resequencing in the large Italian cohort. Subsequently, we will study the brains of the ParkVest patients and translate the genetic findings into biological mechanisms at the level of the neuron. By combining high sample quality, large size and innovative genetic and molecular analyses these studies will elucidate part of the missing heritability in PD and identify novel pathomechanisms explaining neurodegeneration at the molecular level.