Papers by Manuel Menendez
Journal of Molecular Neuroscience, 2014
The deregulation of several microRNAs (miRNAs) has been associated with neurodegenerative process... more The deregulation of several microRNAs (miRNAs) has been associated with neurodegenerative processes, including Parkinson's disease (PD). Our aim was to characterize the level of miRNAs in the substantia nigra (SN) of PD patients and healthy donors. This is an important issue to characterize new putative markers and therapeutic targets for PD. RNA was extracted from the SN of postmortem PD (n=8) and healthy (n=4) subjects, and the level of 733 human miRNAs was assayed with TaqMan low-density arrays (TLDAs). Overall, there was a miRNA downregulation in the SN of patients. The mean level of 11 miRNAs was significantly different (p<0.05) between patients and controls, with 10 downregulated among the patients. MiR-198, -135b, -485-5p, and -548d were the best candidates and were quantified with individual TaqMan assays in the 12 samples. MiR-135b showed the most significant difference between patients and healthy donors. The bioinformatic analysis suggested that this miRNA could bind to genes implicated in several neurodegenerative pathways.
Neuroscience Letters, 2014
h i g h l i g h t s • We determined the association of rs356165-rs11931074 and PD-risk in a Spani... more h i g h l i g h t s • We determined the association of rs356165-rs11931074 and PD-risk in a Spanish cohort. • We measured the RNA levels of the four SNCA isoforms in postmortem brain tissues. • We did not find a correlation of genotype with isoforms level. • We found a tendency of higher levels of the three short SNCA isoforms in the SN of PD brains.
Journal of Neurology, 2013
Journal of Molecular Neuroscience, 2011
Mutations in the beta-amyloid precursor protein gene (APP) have been found in familial early-onse... more Mutations in the beta-amyloid precursor protein gene (APP) have been found in familial early-onset Alzheímer's disease (AD). DNA variants at several genes have been linked to the risk of developing the most common late-onset form of AD (LOAD). A few studies analyzed the contribution of APP variants to LOAD, with negative or conflicting results. We determined the variation in the 18 APP exons and flanking intronic sequences in a total of 350 LOAD patients from Spain. A total of 13 nucleotide changes were found and 6 were new and not found among 340 healthy controls, including the only missense change (D243N). The in silico analysis suggested that none of them would have an effect on pre-mRNA splicing or protein folding (D243N). Patients and controls were also genotyped for three APP promoter polymorphisms, and none of them was significantly associated with LOAD. We concluded that APP variants would not contribute to the risk of developing LOAD in our population.
Journal of Molecular Neuroscience, 2011
Alpha-synuclein gene (SNCA) polymorphisms have been associated with the common sporadic form of P... more Alpha-synuclein gene (SNCA) polymorphisms have been associated with the common sporadic form of Parkinson's disease (PD). We searched for DNA variants at the SNCA 3′ UTR through single strand conformation analysis and direct sequencing in a cohort of Spanish PD patients and controls. We have genotyped the rs356165 SNCA 3′ UTR polymorphism in a total of 1,135 PD patients and 772 healthy controls from two Spanish cohorts (Asturias and Navarre). We identified six SNCA 3′ UTR variants. Single nucleotide polymorphism (SNP) rs356165 was significantly associated with PD risk in the Spanish cohort (p=0.0001; odd ratio= 1.37, 95%CI=1.19-1.58). This SNP was also significantly associated with early age at onset of PD. Our work highlights rs356165 as an important determinant of the risk of developing PD and early age at onset and encourages future research to identify a functional effect on SNCA expression.
Journal of Human Genetics, 2014
Mutations in the leucine-rich repeat kinase 2 gene (LRRK2) are the most common genetic determinan... more Mutations in the leucine-rich repeat kinase 2 gene (LRRK2) are the most common genetic determinants of familial and sporadic Parkinson's disease (PD). Most of the mutational screenings analyzed the exon-coding sequence. Our aim was to determine whether LRRK2 3 0 untranslated region (UTR) variants were associated with the risk of developing PD in a large cohort of patients (n ¼ 743) and controls (n ¼ 523) from Spain. We identified a total of 12 3 0 UTR variants (two new). Single-nucleotide polymorphism (SNP) rs66737902 C allele was overrepresented in patients (P ¼ 0.005; odds ratio ¼ 1.47). This SNP was in linkage disequilibrium with the p.R1441G mutation, but the association remained significant among mutation-negative cases. We found a significant lower level of the LRRK2 transcript in the Substantia nigra (SN) of PD postmortem donors (n ¼ 9) who were rs66737902 C carriers (P ¼ 0.01). This SNP was predicted to affect a binding site for miR-138-2-3p. We showed that this microRNA was expressed in all the SN samples. In conclusion, we found a significant association between SNP rs66737902 and the risk of developing PD. This effect on PD risk could be explained by differences in LRRK2 transcript levels between the two alleles.
Journal of Clinical Pathology, 1997
Aims-To study the homozygous deletion and methylation status of the 5' CpG island of the p16 and ... more Aims-To study the homozygous deletion and methylation status of the 5' CpG island of the p16 and p15 genes (9p2l) in a set of primary advanced head and neck squamous cell carcinomas (SCC) and to test whether inactivation of these genes by these mechanisms contributes to head and neck SCC development. Methods-DNA was extracted from fresh tumours. Homozygous deletion was determined by the polymerase chain reaction (PCR) followed by hybridisation with the corresponding probe, radioactively labelled by the random priiing method. Methylation status ofthe CpG island ofthe 5' region of these genes was assessed by digestion with the appropiate restriction enzymes followed by PCR and subsequent hybridisation with the corresponding probe. The presence of point mutations was determined by PCR-SSCP (single strand conformation polymorphism). Results-The p16 and p15 genes were homozygously deleted in 20% and 10% of the tumours, respectively. No point mutations were found at p16 and p15. The 5' CpG island at the p16 gene was methylated in 20% of the cases. Conclusions-The tumour suppressor gene p16 is inactivated through homozygous deletion or methylation in a significant proportion of cases of head and neck SCC.
American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 2010
MicroRNAs are small RNA sequences that negatively regulate gene expression by binding to the 3´ u... more MicroRNAs are small RNA sequences that negatively regulate gene expression by binding to the 3´ untranslated regions of mRNAs. MiR-133b has been implicated in Parkinson´s Disease (PD) by a mechanism that involves the regulation of the transcription factor PITX3. The variation in these genes could contribute to the risk of developing PD. We searched for DNA variants in miR-133 and PITX3 genes in PD patients and healthy controls from Spain. We found common DNA variants in the three miR-133 genes. Genotyping of a first set of patients (n=777) and controls (n=650) showed a higher frequency of homozygous for a miR-133b variant (-90 del A
Alzheimer's & Dementia, 2012
Alzheimer's & Dementia, 2013
Alzheimer's & Dementia, 2006
Neuroscience Letters, 2014
Mutations in the alpha-synuclein (SNCA) gene cause autosomal dominant Parkinson&a... more Mutations in the alpha-synuclein (SNCA) gene cause autosomal dominant Parkinson's disease (PD). Common SNCA polymorphisms have been associated with the risk of developing PD. Abnormal expression and post-translational modification of SNCA has been found in PD-brains. In addition to a full length transcript (SNCA-140) there are three short isoforms (SNCA-98, -112, and -126) that could be prone to aggregation. The association between SNCA polymorphisms and PD could be explained through an increased expression of these alternative transcripts. Our aim was to measure the different SNCA transcripts in the substantia nigra (SN), cerebellum (CB), and occipital cortex (OC) from PD-patients (n=9) and healthy subjects (n=6). In addition, we determined whether two SNCA polymorphisms (SNPs rs356165 and rs11931074) were related to differences in transcript isoform expression. PD brain tissues showed higher levels of the three short transcripts in the SN, but only SNCA-112 and SNCA-98 were significantly increased in the CB of patients vs. controls (p=0.02, p=0.03). The genotyping of a large cohort of PD-patients and controls showed that haplotype rs356165-A+rs11931074-G had a protective effect (OR=0.71; CI=0.59-0.83), while the G-T haplotype increased the risk for PD (OR=1.44; CI=1.06-1.96). We did not find significant differences for the SNCA levels between the haplotypes. In conclusion, we found statistically significant higher levels of the SNCA-112 and SNCA-98 transcripts in the CB of PD brains, and a trend toward higher levels of the short transcript isoforms in the SN of PD brains.
Journal of Human Genetics, 2014
Mutations in the leucine-rich repeat kinase 2 gene (LRRK2) are the most common genetic determinan... more Mutations in the leucine-rich repeat kinase 2 gene (LRRK2) are the most common genetic determinants of familial and sporadic Parkinson's disease (PD). Most of the mutational screenings analyzed the exon-coding sequence. Our aim was to determine whether LRRK2 3' untranslated region (UTR) variants were associated with the risk of developing PD in a large cohort of patients (n=743) and controls (n=523) from Spain. We identified a total of 12 3'UTR variants (two new). Single-nucleotide polymorphism (SNP) rs66737902 C allele was overrepresented in patients (P=0.005; odds ratio=1.47). This SNP was in linkage disequilibrium with the p.R1441G mutation, but the association remained significant among mutation-negative cases. We found a significant lower level of the LRRK2 transcript in the Substantia nigra (SN) of PD postmortem donors (n=9) who were rs66737902 C carriers (P=0.01). This SNP was predicted to affect a binding site for miR-138-2-3p. We showed that this microRNA was expressed in all the SN samples. In conclusion, we found a significant association between SNP rs66737902 and the risk of developing PD. This effect on PD risk could be explained by differences in LRRK2 transcript levels between the two alleles.
International Archives of Medicine, 2014
The ventral tegmental area is strongly associated with the reward system. Dopamine is released in... more The ventral tegmental area is strongly associated with the reward system. Dopamine is released in areas such as the nucleus accumbens and prefrontal cortex as a result of rewarding experiences such as food, sex, and neutral stimuli that become associated with them. Electrical stimulation of the ventral tegmental area or its output pathways can itself serve as a potent reward. Different drugs that increase dopamine levels are intrinsically rewarding. Although the dopaminergic system represent the cornerstone of the reward system, other neurotransmitters such as endogenous opioids, glutamate, γ-Aminobutyric acid, acetylcholine, serotonin, adenosine, endocannabinoids, orexins, galanin and histamine all affect this mesolimbic dopaminergic system. Consequently, genetic variations of neurotransmission are thought influence reward processing that in turn may affect distinctive social behavior and susceptibility to addiction. Here, we discuss current evidence on the orquestic regulation of different neurotranmitters on reward-seeking behavior and its potential effect on drug addiction.
International archives of medicine, 2014
This systematic review aims to provide information about the implications of the movement-related... more This systematic review aims to provide information about the implications of the movement-related cortical potential (MRCP) in acute and chronic responses to the counter resistance training. The structuring of the methods of this study followed the proposals of the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses). It was performed an electronically search in Pubmed/Medline and ISI Web of Knowledge data bases, from 1987 to 2013, besides the manual search in the selected references. The following terms were used: Bereitschaftspotential, MRCP, strength and force. The logical operator "AND" was used to combine descriptors and terms used to search publications. At the end, 11 studies attended all the eligibility criteria and the results demonstrated that the behavior of MRCP is altered because of different factors such as: force level, rate of force development, fatigue induced by exercise, and the specific phase of muscular action, leading to an incr...
Neuropsychologia, 2009
In order to explore the possible contribution of the motor system to the representation of verbs,... more In order to explore the possible contribution of the motor system to the representation of verbs, we studied the relative preservation of the capacity of Parkinson disease patients to name matched sets of object and action pictures. The performance of this group of participants was compared with that of a group of healthy seniors, and a group of Alzheimer disease patients. Generalized linear mixed-effects analyses showed that, whereas the two control groups had similar accuracy scores in response to objects and actions, Parkinson disease patients presented a significant impairment in their capacity to name actions compared to objects. The results of this study support the idea that verb representations are grounded in neural networks to which brain areas involved in motor control contribute.
Dementia and Geriatric Cognitive Disorders, 2009
The search for early cognitive markers of Alzheimer's dis... more The search for early cognitive markers of Alzheimer's disease (AD) has focused on episodic memory and spatiotemporal orientation. However, recent research suggests that semantic memory is also impaired in the preclinical stages of AD. Age- and education-matched groups of participants with AD, mild cognitive impairment, and subjective memory complaints and healthy controls were assessed with 16 cognitive tests encompassing attention, orientation, episodic and semantic memory, and language tasks. The battery correctly distinguished AD patients from healthy seniors in 92% of the cases. Three semantic memory-based tasks turned out to be particularly powerful for this purpose. Our results suggest that semantic memory tasks should be included in the battery of tests for the evaluation of cognitively impaired patients.
Uploads
Papers by Manuel Menendez