Huntingtin fragmentation and increased caspase 3, 8 and 9 activities in lymphoblasts with heterozygous and homozygous Huntington's disease mutation

Vittorio Maglione, Milena Cannella, Roberto Gradini, Giuliana Cislaghi, Ferdinando Squitieri

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Huntington's disease (HD) is caused by mutated huntingtin (htt), a toxic protein ubiquitously expressed in nervous and non-nervous system tissues. Fragmentation of htt by caspases and further accumulation in cells of protein aggregates contribute to cell dysfunction and death. In the attempt to elucidate whether this mechanism depends on patients' genotype, we analysed the pattern of htt fragmentation, the caspase 3, 8 and 9 activities and their variation in lymphoblasts with heterozygous and homozygous CAG mutation and in controls. Cells homozygous for expanded mutation showed greater amount of mutated fragments than heterozygotes and controls, caspase 3, 8 and 9 activities greater in mutated than control cell lines, after cyanide treatment, the caspase 3 and 8 particularly increased in homozygotes. This data offers a biological explanation to the clinical in-patients evidence of mutation homozygosity associated with more severe phenotype.

Original languageEnglish
Pages (from-to)213-216
Number of pages4
JournalMechanisms of Ageing and Development
Volume127
Issue number2
DOIs
Publication statusPublished - Feb 2006

Fingerprint

Caspase 9
Caspase 8
Huntington Disease
Caspase 3
Mutation
Poisons
Homozygote
Cyanides
Heterozygote
Caspases
Cell Death
Genotype
Cells
Tissue
Phenotype
Cell Line
Proteins
Therapeutics

Keywords

  • Caspase activities
  • Homozygous Huntington disease
  • Huntingtin
  • Huntingtin proteolytic fragmentation

ASJC Scopus subject areas

  • Ageing
  • Biochemistry
  • Developmental Biology
  • Developmental Neuroscience

Cite this

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abstract = "Huntington's disease (HD) is caused by mutated huntingtin (htt), a toxic protein ubiquitously expressed in nervous and non-nervous system tissues. Fragmentation of htt by caspases and further accumulation in cells of protein aggregates contribute to cell dysfunction and death. In the attempt to elucidate whether this mechanism depends on patients' genotype, we analysed the pattern of htt fragmentation, the caspase 3, 8 and 9 activities and their variation in lymphoblasts with heterozygous and homozygous CAG mutation and in controls. Cells homozygous for expanded mutation showed greater amount of mutated fragments than heterozygotes and controls, caspase 3, 8 and 9 activities greater in mutated than control cell lines, after cyanide treatment, the caspase 3 and 8 particularly increased in homozygotes. This data offers a biological explanation to the clinical in-patients evidence of mutation homozygosity associated with more severe phenotype.",
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T1 - Huntingtin fragmentation and increased caspase 3, 8 and 9 activities in lymphoblasts with heterozygous and homozygous Huntington's disease mutation

AU - Maglione, Vittorio

AU - Cannella, Milena

AU - Gradini, Roberto

AU - Cislaghi, Giuliana

AU - Squitieri, Ferdinando

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AB - Huntington's disease (HD) is caused by mutated huntingtin (htt), a toxic protein ubiquitously expressed in nervous and non-nervous system tissues. Fragmentation of htt by caspases and further accumulation in cells of protein aggregates contribute to cell dysfunction and death. In the attempt to elucidate whether this mechanism depends on patients' genotype, we analysed the pattern of htt fragmentation, the caspase 3, 8 and 9 activities and their variation in lymphoblasts with heterozygous and homozygous CAG mutation and in controls. Cells homozygous for expanded mutation showed greater amount of mutated fragments than heterozygotes and controls, caspase 3, 8 and 9 activities greater in mutated than control cell lines, after cyanide treatment, the caspase 3 and 8 particularly increased in homozygotes. This data offers a biological explanation to the clinical in-patients evidence of mutation homozygosity associated with more severe phenotype.

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