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A25 Metabolism of sialo-conjugates is defective in pre-clinical models of huntington’s disease
  1. Giuseppe Pepe1,
  2. Enrico Amico1,
  3. Salvatore Castaldo1,
  4. Luca Capocci1,
  5. Thomas J Boltje2,
  6. Alba Di Pardo1,
  7. Vittorio Maglione1
  1. 1Centre for Neurogenetics and Rare Diseases, IRCCS Neuromed, Pozzilli (IS), Italy
  2. 2Institute for Molecules and Materials, Synthetic Organic Chemistry, Radboud University, Nijmegen, The Netherlands

Abstract

Background In the last decade, perturbed metabolism of some sialylated molecules has been described to play an essential role in the pathogenesis of Huntington’s disease (HD). In this context, we have contributed to demonstrate that metabolism of sialic-acid containing glycosphingolipids – gangliosides – is impaired in HD and its modulation results therapeutically effective in HD pre-clinical models.

Interestingly, evidence of altered levels of both sialo-glycoproteins and gangliosides suggests an overall perturbed metabolism of sialo-conjugates in HD.

Aims The aim of this study is to investigate whether the metabolism of sialic acid is globally impaired in HD and to identify it as novel potential therapeutic target.

Methods In vitro experiments were carried out in immortalized mouse striatal-derived knock-in cells expressing endogenous levels of wild-type (STHdh7/7) or mutant huntingtin (STHdh111/111). All in vivo studies were performed in R6/2 HD mice and in age-matched control littermates.

Results Our data demonstrate that expression of a number of enzymes (sialyl-transferases) that are involved in the synthesis of different sialo-conjugates, is significantly impaired in multiple HD pre-clinical models. Preliminary results also indicate that metabolism of sialic acid may be easily modulated in vitro and in vivo and therefore pharmacologically targeted. More studies are in progress to fully clarify the beneficial effects of such modulation.

Conclusion Collectively, our results indicate that the metabolism of sialo-conjugates is globally affected in HD and may represent a ‘druggable’ target for developing novel approach for the treatment of the disease.

  • HD
  • gangliosides
  • sialic acid
  • R6/2

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