Transcriptional changes in multiple system atrophy and Parkinson's disease putamen.

Multiple system atrophy (MSA) and sporadic, non-mendelian Parkinson's disease (PD) are progressive neurodegenerative disorders with overlapping clinical symptoms and pathology. The etiology of both disorders is unknown, and complex combinations of multiple susceptibility genes and environmental factors are thought to be involved. Both disorders are characterized by ubiquitous alpha-synuclein aggregates in distinct regions and cell types of the central nervous system. In PD, alpha-synuclein-positive aggregates appear to be largely neuronal while in MSA oligodendroglial inclusions prevail. In PD patients, the alpha-synuclein pathology is thought to evolve in a rather regular pattern, starting in the brainstem and olfactory bulb and extending gradually onto the substantia nigra and ultimately the cerebral cortex while the cerebellum is largely spared. MSA pathology has not been graded in a similar way yet; neuropathological analyses revealed neurodegeneration and gliosis primarily in the brainstem, midbrain and basal ganglia and the cerebellum, while the cortex is largely spared. To identify disease-specific transcriptional patterns in MSA, we chose CNS regions differentially affected in MSA and PD for comparative gene expression profiling: putamen, cerebellum and occipital cortex. Four genes were regulated in both MSA and PD putamen and twelve in MSA and PD cerebellum. Regulated transcripts were validated using real-time quantitative RT-PCR, and immunohistochemistry was performed for the most significantly downregulated transcripts in MSA and PD putamen, GPR86 and RGS14, associated with G protein signaling and transcriptional regulation.