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

被引：53

作者：

Battaglia, Giuseppe ^{[2
]}

Cannella, Milena ^{[1
]}

Riozzi, Barbara ^{[2
]}

Orobello, Sara ^{[1
]}

Maat-Schieman, Marion L. ^{[3
]}

Aronica, Eleonora ^{[4
]}

Busceti, Carla Letizia ^{[2
]}

Ciarmiello, Andrea ^{[5
]}

Alberti, Silvia ^{[1
]}

Amico, Enrico ^{[1
]}

Sassone, Jenny ^{[6
]}

Sipione, Simonetta ^{[7
]}

Bruno, Valeria ^{[2
,8
]}

Frati, Luigi ^{[9
]}

Nicoletti, Ferdinando ^{[2
,8
]}

Squitieri, Ferdinando ^{[1
]}

机构：

[1] IRCCS Neuromed, Neurogenet Unit, I-86077 Pozzilli, IS, Italy

[2] IRCCS Neuromed, Neuropharmacol Unit, I-86077 Pozzilli, IS, Italy

[3] Leiden Univ, Med Ctr, Dept Neurol, Leiden, Netherlands

[4] Univ Amsterdam, Acad Med Ctr, Dept Neuropathol, NL-1105 AZ Amsterdam, Netherlands

[5] S Andrea Hosp, Unit Nucl Med, La Spezia, Italy

[6] Univ Milan, IRCCS Ist Auxol Italiano, Dino Ferrari Ctr, Dept Neurol & Lab Neurosci, Milan, Italy

[7] Univ Alberta, Dept Pharmacol, Edmonton, AB, Canada

[8] Univ Roma La Sapienza, Dept Human Physiol & Pharmacol, Rome, Italy

[9] Univ Roma La Sapienza, Dept Expt Med, Rome, Italy

来源：

JOURNAL OF CELLULAR AND MOLECULAR MEDICINE | 2011年 / 15卷 / 03期

关键词：

transforming growth factor-beta; Huntington's disease; brain cortex; peripheral markers; neurodegeneration; neurodysfunction; METABOTROPIC GLUTAMATE RECEPTORS; YAC128 MOUSE MODEL; NEUROTROPHIC FACTOR; TGF-BETA; MUTANT HUNTINGTIN; MICROGLIAL ACTIVATION; ENHANCES EXPRESSION; STRIATAL NEURONS; GENE-EXPRESSION; CEREBRAL-CORTEX;

D O I：

10.1111/j.1582-4934.2010.01011.x

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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-beta (TGF-beta(1)), a pleiotropic cytokine with an established role in mechanisms of neuroprotection. Asymptomatic HD patients showed a reduction in TGF-beta(1) 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-beta(1) 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-beta(1) in the cerebral cortex, localized in neurons, but not in astrocytes. We examined the pharmacological regulation of TGF-beta(1) formation in asymptomatic R6/2 mice, where blood TGF-beta(1) levels were also reduced. In these R6/2 mice, both the mGlu2/3 metabotropic glutamate receptor agonist, LY379268, and riluzole failed to increase TGF-beta(1) formation in the cerebral cortex and corpus striatum, suggesting that a defect in the regulation of TGF-beta(1) production is associated with HD. Accordingly, reduced TGF-beta(1) 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-beta(1) levels are potential biomarkers of HD development during the asymptomatic phase of the disease, and raise the possibility that strategies aimed at rescuing TGF-beta(1) levels in the brain may influence the progression of HD.

引用

页码：555 / 571

页数：17

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