Objective/Rationale:
Impaired mitochondrial function and enhanced oxidative stress play a major role in the pathogenesis of Parkinson’s disease (PD). PGC-1alpha is a transcriptional cofactor that supports mitochondrial biogenesis and function and defends against oxidative stress has been implicated in PD. We have recently identified brain-specific PGC-1alpha isoforms that are more abundant in human brain than the reference protein and may play an important role in PD.
Project Description:
Levels of transcripts encoding the reference protein and brain-specific isoforms will be quantified in post-mortem brains of PD patients and controls without neurodegenerative disorders. Brain regions, typically affected or spared by PD, will be analyzed and the cellular distribution of transcripts among brain cell types will be determined by in situ hybridization. Isoform specific antibodies will be raised for immunological staining of the respective proteins. Similar measurements will be made in pre-clinical models using disease induction by toxins or stereotactic overexpression of alpha-synuclein. Finally, specific sequence substitutions in DNA region controlling the expression of brain-specific transcripts will be typed in PD patients and controls to determine possible allelic and/or haplotype differences between patients and controls and effects on PD age of onset.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Several studies strongly suggest that reduced expression of PGC-1alpha plays a role in PD and that overexpression of PGC-1alpha can ameliorate signs and symptoms of PD in pre-clinical models or even protect against the disease. However, sustained expression of very high PGC-1alpha levels obtained by viral overexpression appears to be harmful. However, regulating these new brain-specific isoforms may be key to obtaining physiological levels of PGC-1alpha.
Anticipated Outcome:
Our studies should provide insight into the basic biology of brain-specific PGC-1alpha isoforms and their possible role in PD in comparison to the reference protein. If the brain-specific PGC-1alpha isoforms show stronger associations with PD than the reference protein, they are likely to be potential targets for the treatment of PD.
Final Outcome
Our studies revealed major differences of Pgc-1alpha isoforms between Parkinson’s disease pre-clinical models and control models. Both the reference gene and brain-specific transcripts and their encoded proteins are decreased in PD models, but only the levels of brain-specific transcripts differ among the various brain regions. In post-mortem tissues of humans, the brain-specific transcripts are more abundant than the reference gene transcripts and also show different distributions among brain regions. In contrast to the PD models, human PD was not associated with a general decrease of PGC-1alpha transcript levels. Despite the large inter-individual variability of transcripts and proteins, subtle differences in some specific proteins were noted between PD cases and controls. Initial genetic studies in humans showed promising trends for associations of the chromosomal region containing the gene segments encoding brain-specific proteins and/or controlling the expression of brain-specific PGC-1alpha isoforms. These initial data suggest a role of brain-specific PGC-1alpha isoforms in PD and warrant more detailed studies.
March 2014