Functional studies of genetic forms of lewy body diseases

Lewy body diseases (LBDs) and other forms of parkinsonism are fatal neurodegenerative disorders that affect millions of people worldwide, and they remain uncurable. Even though a long way remains ahead, the identification and functional study of genetic forms of LBDs has greatly expanded our knowledge on the molecular mechanisms underlying the neurodegenerative process, providing promising targets for therapeutic intervention. The aim of this thesis is to improve our understanding of the pathogenesis of LBDs and related disorders by investigating novel rare genetic forms of LBDs involving the LRP10 and PTPA genes.
In chapter 1, we introduced LBDs and some of the already described genetic factors, including LRP10, and highlighted how these genetic factors can lead to disturbed glial cell function in LBD. In chapters 2-5, we aimed to improve our knowledge on the molecular function of the LRP10 protein, investigate whether LRP10 might have a role in LBD pathogenesis, and study the effect of patient-derived variants on LRP10 protein function. In chapter 6, we identified two bi-allelic missense variants in PTPA, which encodes a major PP2A activator, in two families with early-onset parkinsonism and intellectual disability. Furthermore, we show that these variants present decreased mRNA and protein levels and lead to impaired PP2A activation, and ptpa knock-down in Drosophila neurons induces a levodopa-reversible locomotion impairment. Chapter 7 includes a discussion of our main findings in the context of recent literature, in addition to prospective research directions for areas that are incompletely understood.