Our previous report demonstrating that AMPK activation mitigates the pathological phenotypes of
Drosophila Parkin null mutants (Ng et al.
2012) suggests that AMPK and Parkin may be functionally connected. To further investigate the potential relationship between AMPK and Parkin, we examined the expression of Parkin in cortical, striatal, and ventral midbrain regions harvested from normal mouse brain and found that Parkin expression correlates with the levels of pAMPK (Fig.
3b), which is interesting. Correspondingly, the expression of PARIS, a negative regulator of PGC-1α transcription, in the ventral midbrain is reverse that of pAMPK and Parkin (Fig.
3c), which may also explain the observed enhanced PGC-1α level in this region (Fig.
2b). Importantly, when we repeated the analysis with brain regions derived from Parkin null mice (4–6 months old), we recorded a significant and selective decrease in the pAMPK/AMPK ratio in the ventral midbrain region of these mutant mice (Fig.
4a). Alongside this, we also observed an associated significant reduction in the level of PGC-1α in the ventral midbrain region of Parkin-deficient mice relative to their control counterparts (Fig.
4a). Consistent with the report by Shin et al. (
2011), we found that PARIS expression is upregulated in the ventral midbrain of these mutant mice (Fig.
4a). As Parkin and PINK1 functions are intimately interwoven, we also examined the above phenomena in PINK1-deficient mice. We found that PINK1-deficient mice, like their Parkin counterparts, exhibit selective reduction in the pAMPK/AMPK ratio as well as PGC-1α expression in their ventral midbrain region (Fig.
4b). Taken together, our results indicate a selective impairment of the AMPK-PGC-1α axis in Parkin- and PINK1-deficient ventral midbrain neurons.