Accumulation of the parkin-interacting substrate (PARIS; ZNF746), due to inactivation of parkin, contributes to Parkinson’s disease (PD) through repression of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α; PPARGC1A) activity. Here, we identify farnesol as an inhibitor of PARIS. Farnesol promoted the farnesylation of PARIS, preventing its repression of PGC-1α via decreasing PARIS occupancy on the PPARGC1A promoter. Farnesol prevented dopaminergic neuronal loss and behavioral deficits via farnesylation of PARIS in PARIS transgenic mice, ventral midbrain transduction of AAV-PARIS, adult conditional parkin KO mice, and the α-synuclein preformed fibril model of sporadic PD. PARIS farnesylation is decreased in the substantia nigra of patients with PD, suggesting that reduced farnesylation of PARIS may play a role in PD. Thus, farnesol may be beneficial in the treatment of PD by enhancing the farnesylation of PARIS and restoring PGC-1α activity.

Background/Aims: Previous studies indicate that patients with the parkinsonian subtype of multiple system atrophy (MSA-P) experience cognitive impairment. This study aimed to identify the existence of cognitive impairments and the different topographic patterns of morphological changes in MSA-P by means of imaging analysis, and also whether these morphological changes could be associated with cognitive dysfunctions in MSA-P. Methods: We recruited 15 nondemented probable MSA-P patients and 32 normal controls (NC) for neuropsychological testing and MRI. We analyzed morphological changes using cortical thickness analysis, voxel-based morphometry (VBM) and cerebellar volumetry. Multiple linear regression analysis was performed to evaluate the correlation of each cognitive score with the mean thickness of significant cortical-thinning clusters, mean gray-matter density of VBM clusters and cerebellar volume. Results: The scores on the Digit Span Test, the Seoul Verbal Learning Test (immediate and delayed), the phonemic Controlled Oral Word Association Test and the Stroop color test were significantly lower in the MSA-P group than in the NC group. We found two clusters exhibiting significant cortical thinning in the right paracentral lobule and parahippocampal gyrus. VBM analysis revealed significant gray-matter atrophy in the MSA-P group in the bilateral basal ganglia, cerebellum and temporal and frontal cortical areas. Multiple linear regression analysis demonstrated that cognitive dysfunction correlated significantly with thinning in the neocortex, cerebellum and striatum. Conclusions: Our data demonstrate that cortical and cerebellar atrophy and striatal degeneration are associated with cognitive impairment in patients with MSA-P.

Kim JS, et al. J Clin Neurol. 2013 Oct;9(4):274-279. http://dx.doi.org/10.3988/jcn.2013.9.4.274