Previous studies showed that PGC1α KO mice display white matter lesions in CNS (Lin et al. 2004
) and that PGCα levels dramatically increase during peak myelination (Cowell et al., 2007
). In this study, we attempted to directly examine if PGC1α plays a role in postnatal myelination. We found decreased MBP, cholesterol biosynthesis and deficient myelination during the postnatal period in PGC1α KO mice. These findings were extended to primary oligodendrocytes where PGCα expression was up-regulated in parallel with expression of MBP upon differentiation of oligodendrocytes. Moreover, down-regulation of endogenous PGCα in oligodendrocytes resulted in decreased expression of MBP and the key cholesterol synthesis enzymes HMGCS1 and HMGCR. Our finding that PGCα activates MBP promoter in cultured cells and gets recruited to MBP promoter in vivo
, further suggests that PGCα regulates MBP gene expression. Similarly, PGCα can activate the SRE containing promoter, suggesting that PGCα regulates cholesterol synthesis by directly or indirectly regulating the SRE binding protein, SREBP. PGC-1 coactivators have been previously reported to interact with nuclear receptors such as retinoid X receptor (RXR) and liver X receptor (LXR), and non-nuclear receptor transcription factors involved in the regulation of cellular cholesterol metabolism (Oberkofler et al., 2003
; Finck and Kelly, 2006
). While the detailed mechanism remains to be elucidated, our results support the notion that PGCα regulates MBP expression and cholesterol metabolism in oligodendrocytes at the transcriptional level.
Defective cholesterol biosynthesis results in deficient myelination (Saher et al., 2005
; Verheijen et al., 2009
); however, it is not clear how the production of cholesterol and other myelin components such as MBP is coordinated. In Schwann cells, the peripheral counterpart of OLs, the major myelin protein P0 requires cholesterol for exiting the ER and for peripheral myelin compaction (Saher et al., 2009
). Similarly, decreased MBP gene expression was previously reported as a result of deficient cholesterol synthesis (Saher et al., 2005
). Intriguingly, another recent study showed that MBP can also activate SREBP signaling by modifying the SRE-mediated gene expression suggesting that MBP may directly participate in the regulation of cholesterol synthesis genes (Chatterjee et al., 2009
). Although these studies suggest that the relationship between MBP and cholesterol synthesis is complex, our data that PGC1α regulates expression of both MBP and cholesterol synthesis genes suggested a coordinated regulation. It will be therefore of interest to further examine the molecular mechanism of PGC1α-mediated regulation of these key myelin components.
Reduced cholesterol biosynthesis and brain cholesterol levels have been reported in several HD mouse models, together with reduced brain cholesterol turnover in mice and humans (Valenza and Cattaneo, 2006
; Valenza et al., 2007
; Leoni et al., 2008
; Valenza et al., 2010
). In addition, several recent reports have implicated dysfunction of PGCα in the pathogenesis of HD (Cui et al., 2006
; Weydt et al., 2006
; Chaturvedi et al., 2009
; Weydt et al., 2009
; Chaturvedi et al., 2010
; McConoughey et al., 2010
; Rona-Voros and Weydt, 2010
; Hathorn et al., 2011
). While these studies suggest that PGCα dysfunction in HD primarily affects neurons and muscle cells, our findings indicate that inhibition of PGCα in oligodendrocytes by mutant Htt also contributes to the disease pathogenesis in HD. This conclusion is supported by our finding of abnormal myelination in mouse models of HD.
Structural MRI measurements of gray and white matter volumes, and cortical thickness, have shown widespread areas of atrophy in subjects with prodromal HD (Paulsen et al., 2008
; Tabrizi et al., 2009
; Nopoulos et al., 2010
). In HD patients there are also signs of myelin abnormalities such as increased number of oligodendrocytes (Myers et al., 1991
; Gomez-Tortosa et al., 2001
) and increased ferritin iron level (myelin breakdown product) (Bartzokis et al., 2007
). An increased density of oligodendrocytes is observed in the head of the caudate nucleus for the lower grades (0 and 1) in postmortem HD brain, possibly suggesting a compensatory increase due to deficient myelination in early stages of HD (Myers et al, 1991
). However, it remains unclear whether these white matter changes represent the initial event in HD neuropathology or occur as a result of neuronal damage. Recent MRI studies highlighted the possibility that white matter changes might not be due to simply the loss of cortical gray matter neurons (Stoffers et al., 2010
). In support of this hypothesis, we were able to detect deficient myelination during the early postnatal period in R6/2 and BACHD mouse models of HD, suggesting that abnormalities in myelination occur very early in HD pathogenesis. Compared to R6/2 mice, BACHD mouse model expresses the full-length mutant Htt and has a milder phenotype (Gray et al., 2008
). Unsurprisingly, less striking defects in postnatal myelination were found in these mice. Since no deficits in neuronal function have been reported during the early postnatal period in HD mouse models, these results suggest that oligodendrocytes may be more sensitive to mutant Htt expression than neurons and that perturbations of oligodendrocyte function may be an important early pathogenic event in HD. It remains to be established whether these alterations in myelination observed in HD mice correlate with white matter abnormalities detected in human HD. Our DTI studies in R6/2 mice detect compromised white matter integrity in the corpus callosum where we also observed deficient myelination suggesting that at least in HD mice a positive correlation exists between myelination and white matter abnormalities. These data are also consistent with the recent neuroimaging study that detected compromised white matter integrity of corpus callosum in premanifest HD (Rosas et al., 2006
; Rosas et al., 2010
). Similarly, structural MRI studies in another fragment model of HD (171aa) revealed white mater atrophy that correlate with findings in human HD (Cheng et al., 2011
). Although our data showed that myelin deficiency persists throughout the life of R6/2 mice, it remains to be determined how dysmyelination may contribute to neuronal dysfunction and subsequent neurodegeneration. It will be of interest to employ more sensitive neuroimaging methods to examine whether early white matter atrophy occurs in brain areas devoid of any gray matter pathology or vice versa.
In sum, our data suggest that PGCα plays a role in postnatal myelination by regulating expression of MBP and cholesterol synthesis. In addition, we found deficient myelination in HD mouse models and decreased PGC1α activity in oligodendrocytes expressing mutant huntingtin suggesting that PGC1α may contribute to abnormal myelination in HD. These findings raise a possibility that upregulating PGC1α activity in oligodendrocytes may represent a novel strategy for early therapeutic interventions in HD.