Report

Teaser, summary, work performed and final results

Periodic Reporting for period 1 - SysMedPD (Systems Medicine of Mitochondrial Parkinson’s Disease)

Teaser

Parkinsons’s disease (PD) is a difficult and complex condition. Between 90–95% of Parkinson’s cases are sporadic, which means they have no family history. The remaining 5–10% are genetic and can be traced to familial heritage. The latest figures from the Parkinson’s...

Summary

Parkinsons’s disease (PD) is a difficult and complex condition. Between 90–95% of Parkinson’s cases are sporadic, which means they have no family history. The remaining 5–10% are genetic and can be traced to familial heritage. The latest figures from the Parkinson’s Disease Foundation report that approx. 8 million people are living with the disease globally. In Europe alone, the direct and indirect costs associated with the disease are in the region of €14 billion p.a. In countries with increasing life expectancy this is a growing burden with personal, social and economic consequences. Over the last two decades our knowledge of specific genetic risk factors that contribute to the cause of PD has increased greatly, however, this has failed to result in any treatment to slow down disease progression. Experts believe this is due to the fact that the cause of PD differs between individuals and ultimately that everybody’s Parkinson’s disease is different. The overall goal of SysMedPD is to reduce this variability by identifying patients that have a known gene abnormality that disrupts normal mitochondrial activity, the latter being a vital component of human cells that is responsible for energy production. The involvement of dysfunctional mitochondria in PD is well accepted and could contribute to a large proportion of both sporadic and familial PD cases. Therefore, identifying a particular subset of PD patients with a known cause will allow researchers to focus on new treatments to slow down the progression of that particular form of PD. The consortium will achieve this through a number of objectives:
- Clinical researchers will generate stem cells from skin samples obtained from patients with experimentally proven mitochondrial abnormalities.
- Researchers will grow the specific brain cells associated with PD (dopamine neurons) from these patient stem cells in 3D cell culture and test the effect of (a) particular drug(s) that has(ve) been shown to improve mitochondrial deficits.
- Researchers will also investigate the effect of the drug on human brain cells that have been transplanted into the brain of mice.
- Researchers will identify new improved methods of validating the data generated from the patient derived cells confirming PD with disrupted mitochondrial activity.
- PD relevant computational models will be constructed to assist with identification of promising novel therapies.

Work performed

The recruitment of PD patients into the SysMedPD study has been ongoing since the start of the project. Different groups of patients are being constructed based on the type and extent of their mitochondrial dysfunction. PD patients with a known mutation in a particular gene associated with mitochondrial dysfunction were included in the monogenic PD cohort which was established at the end of month 12. Experimental data obtained from this cohort is being used to identify groups of PD patients with and without mitochondrial deficits but do not have any known mutation i.e. idiopathic PD cohorts. Stem cell lines from the monogenic PD cohort have been made available to the consortium for preclinical research activities.
Researchers have developed a reproducible procedure that allows for growth of neurons from PD patient stem cells in an advanced 3D cell culture plate known as an OrganoPlate(TM). In addition, an industrial quality OrganoPlate(TM)is now available with improvements that make it compatible with laboratory automation and imaging systems. Further in-depth analysis has been performed on the mitochondria of brain dopamine neurons grown in the OrganoPlate(TM) from patients assigned to the monogenic PD cohort. This information will go towards identifying the therapeutic potential new drugs.

Researchers have confirmed the ability of existing electrochemical microsensors to measure chemical changes in the brain of freely moving mice. These microsensors, in parallel with other analytical techniques will be used to measure neurochemical and cellular characteristics from PD relevant neurons transplanted into the mouse. The transplantation of human cells into mice has been carried out and a good survival rate has been reported. The first implantation and recording from microsensors has occurred, after which the brains were removed from the mice and staining analysis was carried out. This analysis identified the microsensor was located slightly outside the transplanted human cells and improvements have been made during subsequent surgeries.
Researchers have been developing and optimising techniques to maximise the measurement of brain metabolites from different samples such as plasma, serum and tissue. These techniques will be applied to samples collected from patients categorised into the monogenic PD and idiopathic PD cohorts. In addition, these techniques will be applied to both OrganoPlate(TM) and other samples obtained from the brains of transplanted mice. Further development is being carried out on existing imaging and staining methods to improve analysis of mitochondrial function in PD relevant neurons grown in the OrganoPlate(TM).

Researchers have been constructing the specific metabolic pathways in a mitochondrion using a combination of experimental data, computational and mathematical modelling. They have also constructed a metabolic model of PD relevant neurons using experimental data obtained from human derived stem cells. Further modelling has been carried out on cell metabolism in the nigrostriatal pathway which is the particular network of brain cells that is dysfunctional in PD. The team intend to identify the particular pathways involved in generating energy during normal and PD states.

Final results

The establishment of a monogenic PD cohort has allowed patients to be separated into distinct groups based on the type and extent of their mitochondrial abnormalities. This approach enables the identification of a signature of mitochondrial PD that can eventually be applied to the idiopathic PD cohort and separate these more common patients into particular groups based on their differing mitochondrial deficits. This new method of grouping patients based on their degree of mitochondrial dysfunction is beyond the state of the art and will permit more impactful experimental research to be carried out.

Likewise, electrochemical recordings in freely moving mice are now possible over one or two weeks. Coupled with the transplantation of PD patient derived neurons and other analytical techniques, it is possible to collect neurochemical and cellular information from these particular PD brain cells as they would potentially exist in the diseased human brain. The further improvements to existing techniques for analysing data collected from patients, OrganoPlates(TM) and transplanted mice can provide researchers with access to a wealth of information that will assist in the identification of a new therapeutic drug. Identification of this drug will be accelerated through the novel computer and mathematical models that have been reconstructed with PD and mitochondrial relevant pathways at their core. Although the project is still too early on its lifetime to impact on society as a whole, it is nevertheless important to highlight some socio-economic impacts that have been achieved thus far. Most notably the establishment of the spin-out company BTech from Luxembourg which will act as a support for pharmaceutical companies in drug discovery.

Website & more info

More info: http://www.sysmedpd.eu.