By Claire Henchcliffe, MD
Associate Professor of Neurology and Neuroscience, Weill Cornell Medical College
Dr. Henchcliffe reports she is on the speakers bureau and advisory boards for Teva, IMPAX, and ACADIA; and receives grant/research support from Biogen and Kaneka.
SYNOPSIS: Although Huntington’s disease (HD) is due to a triplet repeat expansion in the huntingtin gene, this study demonstrates abnormally phosphorylated tau pathology in HD brain tissue.
SOURCE: Vuono R, et al. The role of tau in the pathological process and clinical expression of Huntington’s disease. Brain 2015;138:1907-1918.
This is a two-part study investigating the importance of the microtubule-associated protein tau (MAPT) in Huntington’s disease (HD). HD is caused by CAG triplet repeat expansions in the huntingtin (HTT) gene, but variability in phenotype in individuals with similar repeat numbers has long suggested the importance of other factors. MAPT, extensively studied in other neurodegenerative diseases such as Alzheimer’s disease (AD), frontotemporal dementia, and progressive supranuclear palsy, has recently been implicated in HD. In the first part of the study, brain tissue from 16 individuals with HD from the Cambridge Brain Bank was compared with tissue from individuals with sporadic tauopathies and with healthy controls. Monoclonal antibody staining of tissue sections revealed abnormal hyperphosphorylated tau aggregates within neurons, with perinuclear, flame-shaped, or globular appearance in HD. The expected abnormal inclusions were observed in disease controls but not healthy controls. In HD, the abnormal tau inclusions were observed in the striatum, particularly putamen and nucleus accumbens, and in the cortex, particularly insular cortex. Moreover, some tau aggregates co-localized with mutant HTT aggregates. Two cases involved young patients (ages 26 years and 40 years at death), thus linking findings to presence of the disease rather than the aging process. Specific antibodies also demonstrated presence of oligomeric inclusions in HD striatum, but not cortex. Furthermore, western blot analysis of proteins isolated from brain tissue revealed an isoform profile overlapping with AD, and analysis of transcript profiles confirmed the recent report of an abnormally increased 4R:3R tau isoform ratio in HD.
In the second part of the study, tau haplotype was studied in individuals with genetically proven HD who participated in the European Huntington Disease Network REGISTRY project. This registry comprises 960 patients with HTT genotyping. Of these, 473 had clinical assessments at least a year apart involving motor, cognitive, and functional measures. Patient ages were from 48.1 (± 12.3) to 49.4 (± 12.9) years, and disease duration was from 5.3 (± 4.0) to 7.3 (± 5.0) years (patient characteristics are reported by MAPT haplotype in this article). HTT CAG repeat lengths were from 43.8 (± 3.1) to 44.9 (± 5.1). The investigators genotyped all 960 cases for MAPT haplotypes H1 (found in 60%) and H2 (found in 40%). A trend was found for decline in cognitive performance associated with the MAPT H2 haplotype that was statistically significant for verbal fluency and attention testing. Higher HTT CAG repeat number also correlated with cognitive decline in the whole group, but this finding was driven by the H2 haplotype carriers.
Commentary
The present study adds significantly to our understanding of HD in particular, but also to neurodegenerative disorders in general. The tau protein is involved in microtubule assembly and stabilization and in axonal transport. Although well-studied in other neurodegenerative disorders, such as AD, only recently has attention been paid to a potential role in HD. As in other disorders, such as AD and Parkinson’s disease, the investigators highlight that multiple mechanisms are at play in the HD pathogenic cascade. Moreover, tau now provides an important link across many disorders. These include the tauopathies, such as AD, Pick’s disease, progressive supranuclear palsy, and corticobasal degeneration. In addition, the role of tau is increasingly recognized in other neurodegenerative disorders, such as Parkinson’s disease in which MAPT has been associated by multiple genome wide association studies. Not only are there genetic associations, but alternative splicing leads to production of 3R and 4R isoforms (named for the numbers of microtubule binding repeat domains in each), and altered ratios of 3R:4R are associated with the tauopathies. This is now established by the present study in HD. Post-translational modification, hyperphosphorylation, adds an additional level of complexity, as does aggregation of the tau protein.
In summary, the authors build on a recent report finding rod-like nuclear deposits of tau in postmortem brain tissue from individuals with HD, and the finding of an increased 4R:3R tau isoform ratio in HD. The investigators provide independent confirmation of abnormal tau aggregates in HD. Moreover, their characterization of tau oligomers in the putamen further strengthens the hypothesis that this is significant in pathogenesis, since oligomeric species are now thought to be most toxic to cells. Finally, using data from hundreds of HD patients in the European Huntington Disease Network REGISTRY, the association of MAPT haplotype with cognitive decline strongly suggests that the pathologic changes described have a clinical significance. This report will undoubtedly stimulate more attention to the role of tau in HD and may ultimately suggest specific interventions that will help our patients.
Although Huntington’s disease is due to a triplet repeat expansion in the huntingtin gene, this study demonstrates abnormally phosphorylated tau pathology in Huntington’s disease brain tissue.
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