Blood level of brain-derived neurotrophic factor mRNA is progressively reduced in rodent models of Huntington's disease: restoration by the neuroprotective compound CEP-1347.
Huntington's disease (HD) is an age-related neurodegenerative disorder that is currently untreatable. A prominent feature of HD pathology is the reduction of the pro-survival neurotrophin Brain-Derived Neurotrophic Factor (BDNF). Both mRNA and protein levels of BDNF are decreased in the brains of several HD rodent models and in human HD patients. We now report for the first time that this molecular event is mirrored in blood from HD rodent models. While protein levels of BDNF are undetectable in mouse blood, mRNA levels are measurable and diminish during HD progression in transgenic mouse (R6/2) and rat models of HD. Among the eight different BDNF transcripts, only BDNF exon III is transcribed in mouse blood and its expression is progressively compromised in R6/2 mice with respect to age-matched wild-types. Assessment of BDNF mRNA in HD rat blood shows a similar result, which is reinforced by evidence that protein levels of the neurotrophin are also significantly reduced at a symptomatic stage. Finally, we demonstrate that acute and chronic treatment of R6/2 mice with CEP-1347, a mixed lineage kinase (MLK) inhibitor with neuroprotective and neurotrophic effects, leads to increased total BDNF mRNA in blood when compared to untreated R6/2 mice. Our results indicate that alterations in BDNF mRNA levels in peripheral blood are a readily accessible measurement of disease progression and drug efficacy in HD rodent models.
Conforti
Paola
P
Department of Pharmacological Sciences and Center for Stem Cell Research, University of Milan, Via Balzaretti 9, 20133 Milano, Italy.
Ramos
Catarina
C
Apostol
Barbara L
BL
Simmons
Danielle A
DA
Nguyen
Huu Phuc
HP
Riess
Olaf
O
Thompson
Leslie Michels
LM
Zuccato
Chiara
C
Cattaneo
Elena
E
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000097:blood / Q000235:genetics; D002227:Carbazoles / Q000378:metabolism* / Q000627:therapeutic use; D004195:Disease Models, Animal; D018450:Disease Progression; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000627:therapeutic use; D005091:Exons; D006801:Humans; D006816:Huntington Disease / Q000097:blood* / Q000188:drug therapy / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D018696:Neuroprotective Agents / Q000378:metabolism* / Q000627:therapeutic use; D012333:RNA, Messenger / Q000097:blood*; D051381:Rats
D019208:Brain-Derived Neurotrophic Factor; D002227:Carbazoles; D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D012333:RNA, Messenger; C106592:3,9-bis((ethylthio)methyl)-K-252a