De novo synthesis of sphingolipids is defective in experimental models of Huntington's disease

Alba Di Pardo, Abdul Basit, Andrea Armirotti, Enrico Amico, Salvatore Castaldo, Giuseppe Pepe, Federico Marracino, Fabio Buttari, Anna F. Digilio, Vittorio Maglione

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Alterations of lipid metabolism have been frequently associated with Huntington's disease (HD) over the past years. HD is the most common neurodegenerative disorder, with a complex pathogenic profile, typically characterized by progressive striatal and cortical degeneration and associated motor, cognitive and behavioral disturbances. Previous findings from our group support the idea that disturbed sphingolipid metabolism could represent an additional hallmark of the disease. Although such a defect represents a common biological denominator among multiple disease models ranging from cells to humans through mouse models, more efforts are needed to clearly define its clinical significance and the role it may play in the progression of the disease. In this study, we provided the first evidence of a defective de novo biosynthetic pathway of sphingolipids in multiple HD pre-clinical models. qPCR analysis revealed perturbed gene expression of sphingolipid-metabolizing enzymes in both early and late stage of the disease. In particular, reduction in the levels of sptlc1 and cerS1 mRNA in the brain tissues from manifest HD mice resulted in a significant decrease in the content of dihydroSphingosine, dihydroSphingosine-1-phospahte and dihydroCeramide [C18:0] as assessed by mass spectrometry. Moreover, in vitro studies highlighted the relevant role that aberrant sphingolipid metabolism may have in the HD cellular homeostasis. With this study, we consolidate the evidence of disturbed sphingolipid metabolism in HD and demonstrate for the first time that the de novo biosynthesis pathway is also significantly affected in the disease. This finding further supports the hypothesis that perturbed sphingolipid metabolism may represent a crucial factor accounting for the high susceptibility to disease in HD.

Original languageEnglish
Article number698
JournalFrontiers in Neuroscience
Volume11
Issue numberDEC
DOIs
Publication statusPublished - Dec 19 2017

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Sphingolipids
Huntington Disease
Theoretical Models
Corpus Striatum
Disease Susceptibility
Biosynthetic Pathways
Lipid Metabolism
Neurodegenerative Diseases
Disease Progression
Mass Spectrometry
Homeostasis
Gene Expression
Messenger RNA
Brain
Enzymes

Keywords

  • Apoptosis
  • dhCer
  • dhS1P
  • dhSph
  • HD
  • Mass spectrometry
  • Sphingolipid de novo biosynthesis

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

De novo synthesis of sphingolipids is defective in experimental models of Huntington's disease. / Pardo, Alba Di; Basit, Abdul; Armirotti, Andrea; Amico, Enrico; Castaldo, Salvatore; Pepe, Giuseppe; Marracino, Federico; Buttari, Fabio; Digilio, Anna F.; Maglione, Vittorio.

In: Frontiers in Neuroscience, Vol. 11, No. DEC, 698, 19.12.2017.

Research output: Contribution to journalArticle

Pardo, Alba Di ; Basit, Abdul ; Armirotti, Andrea ; Amico, Enrico ; Castaldo, Salvatore ; Pepe, Giuseppe ; Marracino, Federico ; Buttari, Fabio ; Digilio, Anna F. ; Maglione, Vittorio. / De novo synthesis of sphingolipids is defective in experimental models of Huntington's disease. In: Frontiers in Neuroscience. 2017 ; Vol. 11, No. DEC.
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