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-β(1) ), a pleiotropic cytokine with an established role in mechanisms of neuroprotection. Asymptomatic HD patients showed a reduction in TGF-β(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-β(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-β(1) in the cerebral cortex, localized in neurons, but not in astrocytes. We examined the pharmacological regulation of TGF-β(1) formation in asymptomatic R6/2 mice, where blood TGF-β(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-β(1) formation in the cerebral cortex and corpus striatum, suggesting that a defect in the regulation of TGF-β(1) production is associated with HD. Accordingly, reduced TGF-β(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-β(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-β(1) levels in the brain may influence the progression of HD.
Battaglia
Giuseppe
G
Neuropharmacology Unit, IRCCS Neuromed, Pozzilli, Italy.
Cannella
Milena
M
Riozzi
Barbara
B
Orobello
Sara
S
Maat-Schieman
Marion L
ML
Aronica
Eleonora
E
Busceti
Carla Letizia
CL
Ciarmiello
Andrea
A
Alberti
Silvia
S
Amico
Enrico
E
Sassone
Jenny
J
Sipione
Simonetta
S
Bruno
Valeria
V
Frati
Luigi
L
Nicoletti
Ferdinando
F
Squitieri
Ferdinando
F
D000328:Adult; D000368:Aged; D000596:Amino Acids / Q000494:pharmacology; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000097:blood / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008875:Middle Aged; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D049268:Positron-Emission Tomography; D011180:Postmortem Changes; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D055815:Young Adult
D000596:Amino Acids; D019086:Bridged Bicyclo Compounds, Heterocyclic; C086055:HTT protein, human; D000071058:Huntingtin Protein; C118218:LY 379268; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D018094:Receptors, Metabotropic Glutamate; D053773:Transforming Growth Factor beta1