ABSTRACT
The peroxisome-proliferator-activated receptor gamma coactivator 1 α (PGC1α) has been implicated in the pathogenesis of several neurodegenerative disorders, including Huntington's disease (HD). Recent data demonstrating white matter abnormalities in PGC1α knock-out (KO) mice prompted us to examine the role of PGC1α in CNS myelination and its relevance to HD pathogenesis. We found deficient postnatal myelination in the striatum of PGC1α KO mice, accompanied by a decrease in myelin basic protein (MBP). In addition, brain cholesterol, its precursors, and the rate-limiting enzymes for cholesterol synthesis, HMG CoA synthase (HMGCS1) and HMG CoA reductase (HMGCR), were also reduced in PGC1α KO mice. Moreover, knockdown of PGC1α in oligodendrocytes by lentiviral shRNA led to a decrease in MBP, HMGCS1, and Hmgcr mRNAs. Chromatin immunoprecipitations revealed the recruitment of PGC1α to MBP promoter in mouse brain, and PGC1α over-expression increased MBP and SREBP-2 promoter activity, suggesting that PGC1α regulates MBP and cholesterol synthesis at the transcriptional level. Importantly, expression of mutant huntingtin (Htt) in primary oligodendrocytes resulted in decreased expression of PGC1α and its targets HmgcS1, Hmgcr, and MBP. Decreased expression of MBP and deficient myelination were found postnatally and in adult R6/2 mouse model of HD. Diffusion tensor imaging detected white matter abnormalities in the corpus callosum of R6/2 mice, and electron microscopy revealed thinner myelin sheaths and increased myelin periodicity in BACHD [bacterial artificial chromosome (BAC)-mediated transgenic model for Huntington's disease] mice expressing full-length mutant Htt. Together, these data suggest that PGC1α plays a role in postnatal myelination and that deficient PGC1α activity in oligodendrocytes may contribute to abnormal myelination in HD.
Subject(s)
Demyelinating Diseases/metabolism , Huntington Disease/metabolism , Myelin Sheath/metabolism , Oligodendroglia/metabolism , Transcription Factors/metabolism , Analysis of Variance , Animals , Blotting, Western , Brain/metabolism , Brain/pathology , Chromatin Immunoprecipitation , Demyelinating Diseases/genetics , Demyelinating Diseases/pathology , Diffusion Tensor Imaging , Disease Models, Animal , Huntington Disease/genetics , Huntington Disease/pathology , Hydroxymethylglutaryl CoA Reductases/genetics , Hydroxymethylglutaryl CoA Reductases/metabolism , Hydroxymethylglutaryl-CoA Synthase/genetics , Hydroxymethylglutaryl-CoA Synthase/metabolism , Immunohistochemistry , Mice , Mice, Knockout , Myelin Basic Protein/genetics , Myelin Basic Protein/metabolism , Myelin Sheath/pathology , Oligodendroglia/pathology , Reverse Transcriptase Polymerase Chain Reaction , Transcription Factors/geneticsABSTRACT
We aimed in this study to assess the clinical usefulness of fractional anisotropy (FA) maps in the evaluation of lacunar infarctions in striatum, internal capsule and thalamus. We retrospectively reviewed 28 patients (18 men, 10 women; mean age 63 years) who had acute lacunar infarction in striatum, internal capsule and thalamus on diffusion weighted MR imaging (DWI). Fractional anisotropy (FA) maps were generated in addition to conventional T2 weighted images (T2WI) and trace maps of DWI. Two radiologists reviewed the location of infarcts in combination with and without FA maps. Exact location of infarction was determined by FA maps, i.e. on the white band of internal capsule or outside the internal capsule. Accuracy and inter-observer agreement on determination of the location of infarction was evaluated. Accuracy of infarct localization by T2WI-DWI only was varied from 72 to 91% according to the observers. Inter-observer agreement value was moderate (Kappa=0.446), when images were interpreted by T2WI-DWI only. Clinical manifestation of each lesions were varied, but sensory motor stroke was mainly observed in thalamic lesion (50%), while pure motor hemiparesis was predominant in the case of infarct involving internal capsule, corona radiata (91%) and basal ganglia (83%). The FA map is useful in the evaluation of lacunar lesions in striatum, internal capsule and thalamus. Clinical presentation varies according to the exact location of lacunar infarctions, and more accurate diagnosis can be made by FA maps as well as conventional T2-weighted image and DWI.
