Genetics Dissertation Seminar

A Role for ΔFOSB in the Regulation of Parkin in Brain Regions Containing Differentially Susceptible Dopaminergic Neurons

Joseph Patterson

October 12, 2016; 1:00 PM- 2:00 PM; 3280 BPS


The hallmark pathologies of Parkinson disease (PD) are the formation of Lewy bodies and the progressive loss of nigrostriatal dopamine (NSDA) neurons. In mice, the NSDA neurons are preferentially damaged through exposure to the neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Another population of DA neurons that are initially damaged by MPTP, but are able to recover are the tuberoinfundibular DA (TIDA) neurons. Parkin is a product of the PARK2 gene, which is linked to autosomal recessive or juvenile PD, and has been shown to correlate with the ability of the TIDA neurons to recover. Parkin has multiple functions in neurons and is predicted to protect against the neurotoxic effects of MPTP. Potential transcription factors of parkin were identified using TFSEARCH, PROMO, and Patch 1.0. From these candidates, only FosB and ΔFosB have expression patterns that mirror parkin .

Examination of the temporal expression and cellular localization of FosB and ΔFosB after acute neurotoxicant administration were examined. Regions containing the cell bodies of the TIDA (arcuate nucleus; ARC) and NSDA (substantia nigra; SN) neurons were dissected and processed for Western blot analysis. The results reveal that expression of FosB and ΔFosB correlates with parkin, increasing in the ARC and not in the SN. Furthermore, total FosB protein was localized to nuclei of NSDA and TIDA neurons, and expression of each FosB and ΔFosB examined in cytoplasmic and nuclear fractions derived from the ARC and SN. Though the number of DA neurons expressing total FosB does not change, ΔFosB does increase in the nuclear fraction from the ARC.

Additionally, AAV-mediated expression vectors were used to increase ΔFosB in the NSDA and TIDA neurons, in both cases, parkin increased about 2-fold. In addition to ΔFosB, the dominant negative protein ΔJunD, which lacks a DNA binding domain and predominantly dimerizes with the FosBs and inhibits their ability to act as transcription factors was injected into the ARC. The AAV-ΔJunD virus was able to block the increase of parkin after MPTP in the TIDA neurons. Taken together, the results support the role of FosB and ΔFosB as transcription factors of parkin, since they are predicted to bind the Park2 promoter, their expression correlates with the differential expression of parkin, increases prior to parkin, are present in nuclei of TIDA neurons, ΔFosB is sufficient to drive parkin expression, and ΔJunD blocks the increase of parkin in the ARC in response to MPTP.

Committee Members:

Dr. Keith Lookingland (Mentor)
Dr. Christian Chan
Dr. Monique Floer
Dr. John Goudreau