Parkinson's disease (PD) is a neurodegenerative disorder characterized by motor dysfunction and several non-motor symptoms. Recently, the spotlight has been on neuroinflammation as a critical player in this degenerative process in PD. This has led to the hypothesis that the function of glial cells, such as astrocytes and microglia, might play a pivotal role in the degeneration of nigrostriatal neurons in PD. In this symposium, I would like to introduce two specific areas of our research that focus on the relationship between astrocytes and PD:
1. The Role of Astrocyte Proliferation in Levodopa-induced Dyskinesia
L-dopa remains the gold standard therapy for PD. However, its short half-life means that as the nigrostriatal dopaminergic neuronal loss due to progression of PD, its therapeutic effects become inconsistent. Such fluctuations in blood levels of L-dopa can cause complications such as L-dopa-induced dyskinesia. We revealed that ODI, one of the parameters of advanced diffusion MRI-NODDI, was increased in the striatum, indicating abnormal microstructures of striatal cells. To analyze the pathological mechanism of this increase in ODI, we employed a rat dyskinesia model that was analyzed by immunohistology and 9.4T MRI imaging. We found a positive correlation between GFAP-positive astrocytes and ODI values. These findings indicate the importance of astrocytes in the context of L-dopa treatment.
2. Astrocyte Dysfunction in Familial Parkinson's Disease
While most PD are sporadic, approximately 5% have clear genetic underpinnings. PARK2, the most common autosomal recessive familial PD, is linked to mutations in the parkin gene. In contrast, PARK8, the most prevalent autosomal dominant variant, arises from mutations in the LRRK2 gene. Intriguingly, neither of these forms shows signs of astrogliosis in the substantia nigra. This observation underlines the potential significance of astrocyte dysfunction in the pathogenesis of these familial forms.
In summary, the dynamic interaction between astrocytes and the broader pathology of PD presents an exciting frontier for research and potentially novel therapeutic avenues.