Abstract
Huntington's disease is a neurodegenerative disorder caused by an abnormal CAG repeat expansion within exon 1 of the huntingtin gene HTT. While several genetic modifiers, distinct from the Huntington's disease locus itself, have been identified as being linked to the clinical expression and progression of Huntington's disease, the exact molecular mechanisms driving its pathogenic cascade and clinical features, especially the dementia, are not fully understood. Recently the microtubule associated protein tau, MAPT, which is associated with several neurodegenerative disorders, has been implicated in Huntington's disease. We explored this association in more detail at the neuropathological, genetic and clinical level. We first investigated tau pathology by looking for the presence of hyperphosphorylated tau aggregates, co-localization of tau with mutant HTT and its oligomeric intermediates in post-mortem brain samples from patients with Huntington's disease (n = 16) compared to cases with a known tauopathy and healthy controls. Next, we undertook a genotype-phenotype analysis of a large cohort of patients with Huntington's disease (n = 960) with a particular focus on cognitive decline. We report not only on the tau pathology in the Huntington's disease brain but also the association between genetic variation in tau gene and the clinical expression and progression of the disease. We found extensive pathological inclusions containing abnormally phosphorylated tau protein that co-localized in some instances with mutant HTT. We confirmed this related to the disease process rather than age, by showing it is also present in two patients with young-onset Huntington's disease (26 and 40 years old at death). In addition we demonstrate that tau oligomers (suggested to be the most likely neurotoxic tau entity) are present in the Huntington's disease brains. Finally we highlight the clinical significance of this pathology by demonstrating that the MAPT haplotypes affect the rate of cognitive decline in a large cohort of patients with Huntington's disease. Our findings therefore highlight a novel important role of tau in the pathogenic process and clinical expression of Huntington's disease, which in turn opens up new therapeutic avenues for this incurable condition.
Highlights
Huntington’s disease is an autosomal dominant neurodegenerative disorder characterized by motor, psychiatric and cognitive deficits
The insular cortex contained the greatest density of hyperphosphorylated tau aggregates, which were distributed throughout all the cellular layers with the nucleus accumbens and inferior/anterior putamen being the site of greatest tau pathology in the striatum
The specificity of the AT8 staining was confirmed in known tauopathy cases (Supplementary Fig. 2)
Summary
Huntington’s disease is an autosomal dominant neurodegenerative disorder characterized by motor, psychiatric and cognitive deficits. Several studies have identified a large set of possible genes (Zuccato et al, 2010), distinct from the Huntington’s disease locus itself, that could modify the disease manifestation and progression but their relevance remains unclear. As such there is a need to find other genes and/or genetic variants, which will provide novel clues to the complex pathogenesis of Huntington’s disease. One such candidate is the microtubule-associated protein tau (MAPT) gene
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