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L12 Sulforaphane reduces the level of exogenous mutated huntingtin protein in normal human fibroblasts
  1. Joanna Brokowska**,
  2. Aleksandra Hać**,
  3. Grzegorz Węgrzyn,
  4. Anna Herman-Antosiewicz
  1. Department of Molecular Biology, University of Gdansk, Gdansk, Poland
  2. **this authors contributed equally

Abstract

Accumulation of mutated huntingtin aggregates in cells is the main cause of Huntington’s disease. Autophagy allows for removing protein aggregates and prevents their accumulation in normal cells.

In our study we determined whether sulforaphane (SFN), a natural agent present in cruciferous plants and known inducer of autophagy in cancer cells, is able to modulate the amount of mutated huntingtin in normal human fibroblasts expressing the exogenous mutated protein.

We observed reduction in the exogenous mutant huntingtin level as well as a decrease in the amount of its aggregates in normal human fibroblasts treated with sulforaphane. Simultaneously, we observed autophagy induction. Activation of autophagy by SFN in normal human fibroblasts only marginally affected their viability and was accompanied by an inhibition of a major negative regulator of autophagy, mTORC1. Autophagy induction and mTORC1 inhibition was preceded by activation of AMPK kinase, a known inhibitor of mTORC1 and thus autophagy activator. The autophagy induction by SFN coincided with a block in protein synthesis which might be, together with the induction of autophagy, the molecular mechanism leading to reduction of the mutant huntingtin amount in cells by sulforaphane.

Summarising, these results indicate that sulforaphane might potentially be used in therapy of diseases caused by aggregation of mutated proteins, including Huntington’s disease.

  • sulforaphane
  • autophagy
  • huntingtin degradation

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