Brain region-specific microglial phenotypes and responses in Parkinson’s disease

Parkinson's disease (PD) is a progressive neurodegenerative disorder that affects 1-2% of the population over 65 years. While PD has traditionally been regarded as a more or less isolated disorder of the nigrostriatal dopaminergic system, recent studies indicate that this is an oversimplification; in addition to the classic motor deficits, also non-motor symptoms are prominent, that include autonomic dysfunction, sensory and cognitive impairments, neuropsychiatric changes and sleep disturbances. These non-motor symptoms greatly impact the quality of life and are associated with extra-nigral changes, that comprise alpha-synuclein pathology as well as microglial activation throughout the brain.
The involvement of microglia and alpha-synuclein had been studied in relation to the dopaminergic cell loss in the substantia nigra and the motor symptoms. So far, however, little attention was paid to such changes in extra-nigral regions, involved in non-motor symptoms. Microglia further form a diverse cell group with specific phenotypes, that can exert either beneficial or detrimental effects, depending on their location and context. Hence, the overall aim of this thesis was to study microglia in brain regions that are differently affected during PD, and to study whether or not such differences relate to the alpha-synuclein neuropathology.
We show that microglia respond to the alpha-synuclein neuropathology in a highly brain-region specific manner, a response that is particularly prominent during the early stages of PD. More insight into the mechanisms driving these microglial responses will contribute to a better understanding of the etiology of, and possible ways to prevent, PD-related pathology and symptomatology.