Early defect of transforming growth factor β1 formation in Huntington's disease

Giuseppe Battaglia, Milena Cannella, Barbara Riozzi, Sara Orobello, Marion L. Maat-Schieman, Eleonora Aronica, Carla Letizia Busceti, Andrea Ciarmiello, Silvia Alberti, Enrico Amico, Jenny Sassone, Simonetta Sipione, Valeria Bruno, Luigi Frati, Ferdinando Nicoletti, Ferdinando Squitieri

Research output: Contribution to journalArticlepeer-review


A defective expression or activity of neurotrophic factors, such as brain- and glial-derived neurotrophic factors, contributes to neuronal damage in Huntington's disease (HD). Here, we focused on transforming growth factor-β (TGF-β1), a pleiotropic cytokine with an established role in mechanisms of neuroprotection. Asymptomatic HD patients showed a reduction in TGF-β1 levels in the peripheral blood, which was related to trinucleotide mutation length and glucose hypometabolism in the caudate nucleus. Immunohistochemical analysis in post-mortem brain tissues showed that TGF-β1 was reduced in cortical neurons of asymptomatic and symptomatic HD patients. Both YAC128 and R6/2 HD mutant mice showed a reduced expression of TGF-β1 in the cerebral cortex, localized in neurons, but not in astrocytes. We examined the pharmacological regulation of TGF-β1 formation in asymptomatic R6/2 mice, where blood TGF-β1 levels were also reduced. In these R6/2 mice, both the mGlu2/3 metabotropic glutamate receptor agonist, LY379268, and riluzole failed to increase TGF-β1 formation in the cerebral cortex and corpus striatum, suggesting that a defect in the regulation of TGF-β1 production is associated with HD. Accordingly, reduced TGF-β1 mRNA and protein levels were found in cultured astrocytes transfected with mutated exon 1 of the human huntingtin gene, and in striatal knock-in cell lines expressing full-length huntingtin with an expanded glutamine repeat. Taken together, our data suggest that serum TGF-β1 levels are potential biomarkers of HD development during the asymptomatic phase of the disease, and raise the possibility that strategies aimed at rescuing TGF-β1 levels in the brain may influence the progression of HD.

Original languageEnglish
Pages (from-to)555-571
Number of pages17
JournalJournal of Cellular and Molecular Medicine
Issue number3
Publication statusPublished - Mar 2011


  • Brain cortex
  • Huntington's disease
  • Neurodegeneration
  • Neurodysfunction
  • Peripheral markers
  • Transforming growth factor-β

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Medicine


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