The Complex Genetics behind Neurodegeneration and Susceptibility to Parkinson’s disease

Sammanfattning: Parkinson’s disease (PD) is the second most common neurodegenerative disorder and affects over 1% of people above the age of 65. This progressive and debilitating disease is usually thought of as a motor disease, with symptoms such as muscle rigidity, slowness of movement, and tremor at rest.PD can be familial, where a single inherited gene mutation causes the disease, but most cases of PD (90%) are idiopathic and complex, with both genetic and environmental components contributing to disease etiology. Both forms are characterized by degeneration of dopaminergic neurons in the midbrain and by the accumulation of a protein called alpha-synuclein (α-syn) inside neurons. The complexity of idiopathic PD makes it challenging to have a full understanding of its possible causes. Current treatments can only temporarily alleviate symptoms by compensating for the loss of dopamine, but do nothing to slow the progression of the disease. Therefor, there is a need for new therapeutic strategies that can halt, or even prevent disease progression. In order to achieve this, a better understanding of the genetic risk factors contributing to PD is necessary.This thesis is aimed at reaching this goal by investigating genetic susceptibility to neurodegeneration in three different rodent models modeling idiopathic PD, with naturally-occurring variation as a key factor.We first explored differences between six rat strains after exposure to PD-like conditions produced by overexpression of α-syn in the substantia nigra pars compacta to determine strain-dependent susceptibility to neurodegeneration. Our results do indeed show differences among strains in response to this model, both in terms of dopaminergic cell loss and in terms of movement behavior. We can therefor conclude that there are genetic risk factors involved in the susceptibility to α-syn accumulation in these rats, and further genetic analyses can be used to determine such factors.Then we applied a method called linkage analysis to determine which loci are responsible for the phenotypic difference between two mouse strains that have a partial knockout of Engrailed 1, a gene important for dopaminergic neuron survival. We were able to find several quantitative trait loci (QTLs) determining susceptibility to this model, and will be able to further investigate these loci to find candidate genes. Finally, we used a congenic rat strain to study whether a specific QTL (Vra1), which had been discovered in previous studies as being protective after nerve injury, could protect rats from dopaminergic neurodegeneration induced by two different PD models: the toxin-induced neurodegenerative model, and the α-syn overexpression model. Our results show that the congenic strain suffers less dopaminergic cell loss in both these models, indicating that Vra1 is protective. We also found higher expression levels of the Gsta4 gene in the congenics, suggesting that one or more polymorphisms within and near this gene are likely regulating susceptibility to neurodegeneration. Overall, the results gathered in this thesis have given us enough information to pursue translational studies investigating PD patient and control cohorts that are part of the biobank at Lund University (Sweden).