Juan Manuel García-Martínez

Learn More
Dysregulation of gene expression is one of the mechanisms involved in the pathophysiology of Huntington's disease (HD). Here, we examined whether mutant huntingtin regulates the levels of PH domain leucine-rich repeat protein phosphatase 1 (PHLPP1), a phosphatase that specifically dephosphorylates Akt at Ser473. Our results show decreased PHLPP1 protein(More)
Apoptosis, a cell death mechanism regulated by Bcl-2 family members, has been proposed as one of the mechanisms leading to neuronal loss in Huntington's disease (HD). Here we examined the regulation of Bcl-2 family proteins in three different mouse models of HD with exon 1 mutant huntingtin: the R6/1, the R6/1:BDNF+/-, and the Tet/HD94 in which the(More)
Excitotoxicity has been proposed as one of the mechanisms involved in the specific loss of striatal neurons that occurs in Huntington's disease. Here, we studied the role of calcineurin in the vulnerability of striatal neurons expressing mutant huntingtin to excitotoxicity. To this end, we induced excitotoxicity by adding NMDA to a striatal precursor cell(More)
Glial cell line-derived neurotrophic factor (GDNF) promotes the survival or differentiation of several types of neurons. This study examines GDNF-induced signal transduction and biological effects in cultured striatal neurons. Results show that GDNF addition to striatal cultures transiently increased the protein levels of phosphorylated p42/p44, but did not(More)
The striatum is one of the brain areas most vulnerable to excitotoxicity, a lesion that can be prevented by neurotrophins. In the present study, intrastriatal injection of the N-methyl-d-aspartate receptor (NMDAR) agonist quinolinate (QUIN) was performed in mice heterozygous for neurotrophin-3 (NT3 +/-) or brain-derived neurotrophic factor (BDNF +/-) to(More)
We study the striatal susceptibility to NMDA receptor (NMDAR)-mediated injury of two Huntington's disease (HD) transgenic mice: R6/1 and R6/1:BDNF(+/-). We found that R6/1:BDNF(+/-) mice--which express reduced levels of BDNF--were more resistant than R6/1 mice to intrastriatal injection of quinolinate. This increased resistance is related to a differential(More)
Calcineurin is a serine/threonine phosphatase involved in the regulation of glutamate receptors signaling. Here, we analyzed whether the regulation of calcineurin protein levels and activity modulates the susceptibility of striatal neurons to excitotoxicity in R6/1 and R6/1:BDNF+/- mouse models of Huntington's disease. We show that calcineurin inhibition in(More)
PDK1 activates a group of kinases, including protein kinase B (PKB)/Akt, p70 ribosomal S6 kinase (S6K), and serum and glucocorticoid-induced protein kinase (SGK), that mediate many of the effects of insulin as well as other agonists. PDK1 interacts with phosphoinositides through a pleckstrin homology (PH) domain. To study the role of this interaction, we(More)
BACKGROUND The PI3K-mTOR (phosphoinositide 3-kinase-mammalian target of rapamycin kinase) pathway is activated in the majority of tumours, and there is interest in assessing whether inhibitors of PI3K or mTOR kinase have efficacy in treating cancer. Here, we define the effectiveness of specific mTOR (AZD8055) and PI3K (GDC-0941) inhibitors, currently in(More)
In this study we analyzed whether other members of the Bcl-2 family are regulated in the absence of Bax during the postnatal development of the striatum and cortex and after striatal excitotoxic lesion. Compared with wild-type animals, Bax knockout mice showed region- and time-dependent increases in pro-apoptotic proteins Bak and Bim(EL). Excitotoxicity(More)