Immunogenetics of Parkinson's disease: Translational studies from rodents to humans

Parkinson's disease (PD) is a complex neurodegenerative disease, characterized by a progressive loss
of dopaminergic neurons (DN) in the substantia nigra (SN) that innervate the striatum (ST) and pathological
accumulation of alpha-synuclein (αsyn) protein in aggregates called Lewy bodies (LB) and Lewy neurites
(LN). As a complex disease, PD presents a genetically heterogeneous origin. Mutations in single genes
account for 5-10% of all the cases. The remaining 90-95% of the cases present a complex and
multifactorial etiology, where there is an interplay between genetic and environmental factors that can
synergize to initiate the selective degeneration of DN in the SN and the development of PD pathology. In
this thesis, we aimed to contribute to the understating of the genetic architecture of PD, and its implications
in the DN loss and inflammatory aspects of the disease. We first explored differences in dopaminergic
susceptibility in two mouse strains that have a partial loss of Engrailed 1 (en1), a gene important for
dopaminergic neuronal development and survival. Using linkage analysis, we identified 23 loci determining
dopaminergic susceptibility. The next part of the thesis was focus on immune mechanisms in PD, for that
we used a congenic rat strain to study whether allelic variants of Mhc2ta, could affect α-syn-induced
pathology and dopaminergic neurodegeneration. Our results identified Mhc2ta as a facilitator and
aggravator of PD-like αsyn pathology. The last part of this thesis, was focused on determining the
frequency of known pathogenic variants causing PD, in a Swedish multi-center sample collection. Out of
7 studied pathogenic variants, we identified the LRRK2 p.G2019S mutation and SNCA duplication to be
present at a low frequency among Swedish patients, supporting the notion of the very complex genetic
architecture of PD, and suggesting other factors underlying PD risk in this population. Overall, the results
gathered in this thesis have given insight into the complex genetics underlying disease risk and identifying
MHC2TA as a potential modulator of the immune response in PD.