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B24 Huntington’s Disease As A Tauopathy
  1. M Fernández-Nogales1,2,
  2. JR Cabrera1,2,
  3. M Santos-Galindo1,2,
  4. JJM Hoozemans3,
  5. I Ferrer2,4,
  6. AJM Rozemuller3,
  7. F Hernández1,2,
  8. J Avila1,2,
  9. JJ Lucas1,2
  1. 1Center for Molecular Biology “Severo Ochoa” (CBMSO) CSIC/UAM, Madrid 28049, Spain
  2. 2Networking Research Center on Neurodegenerative Diseases (CIBERNED), Instituto de Salud Carlos III, Spain
  3. 3Department of Pathology,VU University Medical Center, Neuroscience Campus Amsterdam, 1007 MB Amsterdam, The Netherlands
  4. 4Institute of Neuropathology, IDIBELL-University Hospital Bellvitge, University of Barcelona, Hospitalet de Llobregat, Barcelona 08908, Spain

Abstract

Tauopathies are a group of neurodegenerative diseases such as Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Pick’s disease (PiD), or frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) that are characterised by altered metabolism and deposition of the microtubule associated protein tau. Alternative splicing of tau exon 10 results in tau isoforms containing either three or four microtubule-binding repeats (3R-tau and 4R-tau). Discovery of silence and intronic mutations leading to increased 4R/3R ratio in FTDP-17 affected families revealed that a disbalance in 4R-tau and 3R-tau in favour of the 4R isoform is sufficient to cause neurodegeneration with personality disturbances, dementia and motor dysfunction.

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder characterised by involuntary movements, psychiatric symptoms and dementia that is caused by an expanded CAG repeat in exon 1 of the Huntingtin (HTT) gene. HD thus belongs to the group of dominant trinucleotide repeat diseases that include many other CAG repeat disorders such as the spinocerebellar ataxias SCA1, SCA2, SCA3, SCA6, SCA7, SCA12, SCA17, dentatorubropallidoluysian atrophy (DRPLA) and spinobulbar muscular atrophy (SBMA) as well as the CUG repeat disorders SCA8 and myotonic dystrophy 1 (DM1). A key element in the pathogenesis of the latter is the binding of splicing factors by the mutant CUG transcript, thus leading to alternative splicing aberrations in multiple genes. Intriguingly, CAG repeats have recently been shown to mimic CUG repeats in the misregulation of alternative splicing. Since it has also been very recently reported that aberrant splicing contributes to the generation of the highly toxic short N-terminal species of HTT, it is conceivable that splicing alterations significantly contribute to HD pathogenesis.

Here we aim to explore whether the neurodegeneration-causing increase in 4R/3R-tau mRNA ratio occurs in HD by performing quantitative RT-PCR from RNA extracted from striatum and cortex of HD and control subjects.

KeyWords
  • Tau
  • MAPT
  • splicing

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