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

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...

Full description

Saved in:

Bibliographic Details
Published in:	Journal of cellular and molecular medicine 2011-03, Vol.15 (3), p.555-571
Main Authors:	Battaglia, Giuseppe, Cannella, Milena, Riozzi, Barbara, Orobello, Sara, Maat‐Schieman, Marion L., Aronica, Eleonora, Busceti, Carla Letizia, Ciarmiello, Andrea, Alberti, Silvia, Amico, Enrico, Sassone, Jenny, Sipione, Simonetta, Bruno, Valeria, Frati, Luigi, Nicoletti, Ferdinando, Squitieri, Ferdinando
Format:	Article
Language:	eng
Subjects:	Adult Aged Amino Acids - pharmacology Animals Astrocytes - drug effects Astrocytes - metabolism Blotting, Western Brain - metabolism Brain - pathology brain cortex Bridged Bicyclo Compounds, Heterocyclic - pharmacology Cells, Cultured Female Humans Huntingtin Protein Huntington Disease - blood Huntington Disease - metabolism Huntington Disease - pathology Huntington’s disease Male Mice Mice, Inbred C57BL Mice, Transgenic Middle Aged Mutation Nerve Tissue Proteins - genetics neurodegeneration neurodysfunction Nuclear Proteins - genetics peripheral markers Positron-Emission Tomography Postmortem Changes Receptors, Metabotropic Glutamate - agonists Reverse Transcriptase Polymerase Chain Reaction Time Factors Transforming Growth Factor beta1 - blood Transforming Growth Factor beta1 - genetics Transforming Growth Factor beta1 - metabolism transforming growth factor‐β Young Adult
Online Access:	Request full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	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.
ISSN:	1582-1838 1582-4934