Study Rationale:
In addition to neurons, astrocytes are the other major cell type that have increased alpha-synuclein in Parkinson’s disease (PD). In fact, more astrocytes have increased alpha-synuclein in affected regions than neurons, and new studies identify this cell type as most changed with both age and environmental factors, two significant risk factors for PD. We have preliminary data showing that different astrocytic reactions to alpha-synuclein occur in different brain regions at the first signs of pathology versus when pathology is fully developed, suggesting that targeting astroglial pathways may need to be astrocyte-subtype and/or stage dependent, the essential questions to be answered in this proposal.
Hypothesis:
We hypothesize that key protein/s involved in astrocyte pathways (i.e., induction factors for A1 inflammatory phenotype, compensatory A2 neuroprotective proteins, PARK-related proteins, and astrocyte specific proteins) will be associated with increased alpha-synuclein in different astrocyte types in the brains of people with PD.
Study Design:
Technical barriers to studying astrocytes in the human brain are due to their regional, functional and dynamic diversity, so we will use extensive tissue arrays of different brain regions from patients at different stages of PD. This will allow the identification of early astrocyte changes in experimentally defined protein pathways by analyzing different astroglia types affected by or spared from alpha-synuclein pathology in the different brain regions that are vulnerable or resistant to the alpha-synuclein pathology at the different stages of PD.
Impact on Diagnosis/Treatment of Parkinson’s Disease:
Human astrocytes are more complex, and some astroglial subtypes are unique, compared to those of other species, making direct proof from post-mortem human brains irreplaceable when seeking targetable astroglial pathways. Experimentally defined astroglial proteins involved in PD may also provide promising peripheral biomarkers for monitoring and diagnosing PD.
Next Steps for Development:
If the types of astrocytes with PD pathology are not human-specific, then perturbation of the pathways identified could be examined in models to establish their impact. We would also examine the biomarker potential of identified proteins in blood extracts and determine if their amounts are specifically changed in PD.