title: The role of tau in the pathological process and clinical expression of Huntington's disease.
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.
authors.affiliation: 1 John van Geest Cambridge Centre for Brain Repair, Department of Clinical Neuroscience, University of Cambridge, Cambridge, UK.
authors.forename: Romina
authors.initials: R
authors.lastname: Vuono
authors.affiliation: 1 John van Geest Cambridge Centre for Brain Repair, Department of Clinical Neuroscience, University of Cambridge, Cambridge, UK 2 Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.
authors.forename: Sophie
authors.initials: S
authors.lastname: Winder-Rhodes
authors.affiliation: 3 Reta Lila Weston Institute, UCL Institute of Neurology, London, UK.
authors.forename: Rohan
authors.initials: R
authors.lastname: de Silva
authors.affiliation: 4 Centre de Recherche du CHU de Québec (CHUQ), Axe Neuroscience and Département de Psychiatrie et Neurosciences, Québec, QC, Canada.
authors.forename: Giulia
authors.initials: G
authors.lastname: Cisbani
authors.affiliation: 1 John van Geest Cambridge Centre for Brain Repair, Department of Clinical Neuroscience, University of Cambridge, Cambridge, UK.
authors.forename: Janelle
authors.initials: J
authors.lastname: Drouin-Ouellet
authors.affiliation: 1 John van Geest Cambridge Centre for Brain Repair, Department of Clinical Neuroscience, University of Cambridge, Cambridge, UK.
authors.forename: Maria G
authors.initials: MG
authors.lastname: Spillantini
authors.affiliation: 4 Centre de Recherche du CHU de Québec (CHUQ), Axe Neuroscience and Département de Psychiatrie et Neurosciences, Québec, QC, Canada 5 Université Laval, Québec, QC, Canada.
authors.forename: Francesca
authors.initials: F
authors.lastname: Cicchetti
authors.affiliation: 1 John van Geest Cambridge Centre for Brain Repair, Department of Clinical Neuroscience, University of Cambridge, Cambridge, UK rab46@cam.ac.uk.
authors.forename: Roger A
authors.initials: RA
authors.lastname: Barker
mesh_terms: D000328:Adult; D000368:Aged; D001921:Brain / Q000473:pathology*; D005260:Female; D005455:Fluorescent Antibody Technique; D056726:Genetic Association Studies; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics* / Q000473:pathology*; D015151:Immunoblotting; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016875:tau Proteins / Q000235:genetics*
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; C054369:MAPT protein, human; D009419:Nerve Tissue Proteins; D016875:tau Proteins
keywords: Huntington’s disease; dementia; neurofibrillary tangles; neuropathology; tau