​​​It is a debilitating brain disorder that significantly affects the quality of life of patients, their families and their caregivers alike.

Parkinson's disease (PD) results from a gradual loss of nerve cells (neurons) that produce dopamine. This causes an imbalance in the brain, leading to symptoms of tremor, slowness of movement, gait problems and cognitive decline. It also affects patients' mood and behaviour. Many PD patients experience depression, psychosis, sleep disturbances and dementia. Some of these symptoms can appear up to 10 years before the symptoms related to movement are observed.

It can be treated with various drugs and surgery to some extent, yet there is no cure. More than 200 years after it was first described, scientists are still trying to establish its exact causes. Both genetic and environmental factors play a role.

Now researchers at the University of Stellenbosch's Faculty of Medicine and Health Sciences (FMHS) hope their research will help to shed some new light on this disease. Their efforts focus on African populations.

The Parkinson's Disease Research Group at the FMHS forms part of an international consortium trying to unravel the genetic clues to the origin of this disease. The group, headed by Prof Soraya Bardien of the Division of Molecular Biology and Human Genetics and Prof Jonathan Carr of the Division of Neurology, is examining the genetic causes of PD in the South African population.

It is the only group doing this kind of research in the country and one of only two on the continent examining the genetic causes of PD.

Innovative approach

The scientists use cutting-edge techniques, including studying skin cells (fibroblasts) that could potentially be "reprogrammed" into stem cells and subsequently into neurons. This innovative approach enables them to get tissue from PD patients without actually having to use brain tissue.

The team also uses whole exome sequencing, a technique that involves the simultaneous screening of approximately 20 000 genes. This is used to investigate protein-coding regions of the human genome to uncover genetic influences on the disease that are currently unknown. Specialised protein techniques allow them to study the biological known pathways in which the known PD-causing genes are involved. Their research has already yielded important information about this disease.

To date, several PD-causing genes have been identified worldwide, and research about their function have provided novel insights in the development of this disease. The group has been looking at some of the known genes linked to the disease. Dr William Haylett, a member of the group, explains: "Seven or eight of them have been established in other populations. We are interested in finding new ones in South African and African populations."

In search of effective medication

The genetic defects that cause PD in most South African patients appear to be different from those found in American, Asian and European populations, says Bardien. Drug treatments developed overseas will thus not necessarily be applicable to local patients.

She explains: "Our group has shown that mutations in the known PD-causing genes are not common causes of the disorder in South African patients. However, a few pathogenic mutations were found, including one patient in whom we found a triplication of the entire SNCA gene." This particular gene is one of the known ones responsible for early-onset PD and mutations are very rare. "This suggests that the genetic causes of PD in local populations are unique and further studies are urgently needed."

According to Bardien genetic research is important, as it may contribute to the design of more effective drug therapies for PD in future. "Currently, existing drugs for the disease have horrible side-effects and are also not totally effective. After a while, it becomes less effective and doctors try to delay prescriptions until the patients really need it."

Haylett and PhD student Annika Neethling have been studying two of the genes known to cause PD in other populations. Neethling looked at the LRRK2 gene that causes mid- to late-onset PD. The parkin gene, the focus of Haylett's work, is the second largest gene in the human genome and mutations play a role in the early-onset form of the disease. Both genes appear to play a role in maintaining the health and function of mitochondria.

What happens in the mitochondria – the tiny batteries of cells – is important. "Mitochondria undergo a lot of wear and tear throughout their lifespan. They have to be replenished at a constant rate and the parkin gene is involved in that process," Bardien explains.

Surprising findings

Neethling, now in the final stages of her PhD, has identified a novel variant of the LRRK2 gene. "We think it causes the disease in a South African family that we studied." This variant significantly affects the functions of the LRRK2 protein. Mitochondria of cells carrying this novel variant use more oxygen and produce less energy. "This indicates that even though mitochondria are working hard to produce energy for the cell, the compensatory mechanisms are not able to manage the high energy demand," Neethling explains. "We think it is too active in the PD patients and doing more than what it should be doing. The mitochondria are working too hard. In the end, they just can't cope."

 Haylett's work has provided similar surprises. He has been looking at mitochondrial dysfunction in parkin-mutant fibroblasts. These fibroblasts also have a higher mitochondrial respiratory rate, as well as more fragmented mitochondrial networks and increased cellular growth. "These unanticipated findings suggest a compensatory mechanism preserves mitochondrial function and quality control in the absence of parkin in fibroblasts, which warrants further investigation.

"Furthermore, the interesting compensatory effect observed here may have important implications for therapeutic strategies aimed at supporting mitochondrial function in PD patients."

The parkin mutation appears to be present in approximately a tenth of patients with early-onset PD. In South Africa it was present in only 3% of the patients they studied. "It is much rarer than what we anticipated. At the moment we only know of eight patients in South Africa with this mutation," Haylett says.

Bardien concludes: "We are only starting to scratch the surface to understand the genetic causes of PD and biological pathways in the cells. Continued research may reveal important clues to help find more effective treatments. This is a complex disease for which there will be no single cure.

"Given that ageing is a major risk factor and projections indicate there will be more people aged 60 years and older in sub-Saharan Africa than in North America by 2050, there is a need for more research on genetic and environmental susceptibility factors for PD in Africa."

Caption: Members of the Parkinson's Disease Research Group at Stellenbosch University, Profs Helena Kuivaniemi, Jonathan Carr, and Soraya Bardien, wit Dr William Haylett and Annika Neethling.

Photo: Damien Schumann