A soluble truncated tau species related to cognitive dysfunction and caspase-2 is elevated in the brain of Huntington's disease patients

Peng Liu, Benjamin R. Smith, Eric S. Huang, Abhishek Mahesh, Jean Paul G. Vonsattel, Ashley J. Petersen, Rocio Gomez-Pastor, Karen H. Ashe

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

Huntington's disease (HD) is a progressive neurodegenerative disease. Involuntary movements, cognitive impairment and psychiatric disturbance are the major clinical manifestations, and gradual atrophy and selective neuronal loss in the striatum and cerebral cortex are the pathologic hallmarks. HD is caused by expanded CAG trinucleotide repeats at the N-terminus of IT15 that encodes the huntingtin (HTT) protein, though the molecular mechanisms through which the mutant HTT (mHTT) exerts toxic effects remain obscure. Members of the caspase family, including caspase-2 (Casp2), play an important role in HD pathogenesis. Genetic ablation of Casp2 ameliorates cognitive and motor deficits of HD mice, though the molecular targets of Casp2 are still unclear. It is well established that the microtubule-associated protein tau potentiates cognitive dysfunction in a variety of neurodegenerative disorders, including HD. Our recent study indicates that Casp2-catalyzed tau cleavage at aspartate 314 (tau 2N4R isoform numbering system) mediates synaptotoxicity, cognitive deficits and neurodegeneration in cellular and mouse models of frontotemporal dementia; further, levels of Δtau314, the soluble, N-terminal cleavage product, are elevated in individuals with mild cognitive impairment and Alzheimer's disease, compared with cognitively normal individuals. Here, we identified the presence of Δtau314 proteins in the striatum (caudate nucleus) and prefrontal cortex (Brodmann's area 8/9) of human subjects, and showed that in both structures, levels of Casp2 and Δtau314 proteins correlate well, and both proteins are higher in HD patients than non-HD individuals. Our findings advance our understanding of the contribution of Casp2-mediated Δtau314 production to HD pathogenesis.

Original languageEnglish (US)
Number of pages1
JournalActa Neuropathologica Communications
Volume7
Issue number1
DOIs
StatePublished - Jul 30 2019

Keywords

  • Caspase-2
  • Caudate nucleus
  • Frontal cortex
  • Huntingtin
  • Huntington’s disease
  • Immunoprecipitation
  • Microtubule-associated protein tau
  • Striatum
  • Truncation
  • Western blotting

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