A. Rabano - Academia.edu (original) (raw)

Papers by A. Rabano

Alzheimer's & Dementia, 2015

Journal of …, 2004

The glucose transporter isoform-2 (GLUT-2) and glucokinase are considered to be components of a g... more The glucose transporter isoform-2 (GLUT-2) and glucokinase are considered to be components of a glucose sensor system controlling several key processes, and hence may modulate feeding behaviour. We have found GLUT-2 and glucokinase mRNAs in several brain regions, including the ventromedial and arcuate nuclei of the hypothalamus. GLUT-2, glucokinase and glucokinase regulatory protein mRNAs and proteins were present in these areas as determined by biochemical approaches. In addition, glucose-phosphorylating activity with a high apparent K m for glucose that displayed no product inhibition by glucose-6-phosphate was observed. Increased glycaemia after meals may be recognized by specific hypothalamic neurones due to the high K m of GLUT-2 and glucokinase. This enzyme is considered to be the true glucose sensor because it catalyses the rate-limiting step of glucose catabolism its activity being regulated by interaction with glucokinase regulatory protein, that functions as a metabolic sensor.

Glia, 2010

A continuous normal function of olfactory ensheathing glia (OEG) is to promote axonal regeneratio... more A continuous normal function of olfactory ensheathing glia (OEG) is to promote axonal regeneration from the olfactory neuroepithelium to the brain, and their neuroregenerative potential in other CNS sites such as the injured spinal cord has been studied for over a decade. However, human OEG are difficult to obtain in large amounts directly from tissues, and the derived primary cultures have a limited duplication capacity. Thus, although auto-transplantation may be an obvious option for initial proof-of-concept trials, alternatives must be explored to obtain large quantities of homogeneous, pre-characterized OEG for wide-scale therapeutic use. We have cultured primary human OEG derived from olfactory bulbs (OB) obtained by necropsy and successfully extended the replicative lifespan of these cells using lentivectors encoding Bmi-1 and TERT transgenes flanked by loxP sites. In contrast to the primary cells which could only be expanded for a limited number of passages (approximately 12)...

Translational psychiatry, 2016

Different neurodegenerative disorders often show similar lesions, such as the presence of amyloid... more Different neurodegenerative disorders often show similar lesions, such as the presence of amyloid plaques, TAU-neurotangles and synuclein inclusions. The genetically inherited forms are rare, so we wondered whether shared epigenetic aberrations, such as those affecting DNA methylation, might also exist. The studied samples were gray matter samples from the prefrontal cortex of control and neurodegenerative disease-associated cases. We performed the DNA methylation analyses of Alzheimer's disease, dementia with Lewy bodies, Parkinson's disease and Alzheimer-like neurodegenerative profile associated with Down's syndrome samples. The DNA methylation landscapes obtained show that neurodegenerative diseases share similar aberrant CpG methylation shifts targeting a defined gene set. Our findings suggest that neurodegenerative disorders might have similar pathogenetic mechanisms that subsequently evolve into different clinical entities. The identified aberrant DNA methylation c...

American Journal of Hypertension, 1998

Obesity is a metabolic disorder in which multiple clinical and biochemical alterations coexist. H... more Obesity is a metabolic disorder in which multiple clinical and biochemical alterations coexist. However, the progression of these alterations in relation to weight gain has not been investigated in detail. Therefore, we studied the evolution of insulin resistance and associated risk factors in a model of experimental obesity in dogs. We also studied whether chronic exposure to these pathogenic factors could induce cardiac and vascular alterations. Twenty male age- and body weight-matched beagle dogs were divided into four groups (n = 5), according to diet and pharmacologic therapy received, and followed for 2 years. Control animals were maintained with a regular diet, while the 15 remaining animals were fed a high-fat diet. The Obese group of dogs received no therapy, whereas the Capto group received 25 mg/12 h captopril, and the Prava+Capto was treated with 10 mg/24 h pravastatin plus the same dose of captopril throughout the study. Periodical determinations of clinical and biochemical parameters were made, and the degree of insulin resistance was also estimated. After the 2-year follow-up, the dogs were killed and vascular thickening in the aorta and the coronary arteries was evaluated. In addition, cardiac hypertrophy was estimated by heart weight and free-wall left ventricular width. Chronic pravastatin plus captopril treatment, together with decreasing weight gain rate, ameliorated the progression of insulin resistance and associated risk factors (hyperinsulinemia, hypercholesterolemia) related to this severe model. In addition, this combined therapy showed cardioprotective action, as cardiac and vascular hypertrophy observed in the Obese group was prevented. These positive results seems to emerge from the synergistic effects of both drugs, as captopril as monotherapy induced only a slight benefit on these parameters.

Alzheimer's & Dementia, 2014

Alzheimer's & Dementia, 2014

ABSTRACT Background: Alzheimer's disease (AD) is the main cause of dementia in developed ... more ABSTRACT Background: Alzheimer's disease (AD) is the main cause of dementia in developed countries and it is estimated that either alone or in combination with cerebral vascular pathology represents over 75%of the etiology of dementias. However, the absence of a consensus system for the neuropathological evaluation of vascular pathology limits classification of cases with mixed pathology and comparability between laboratories. In order to address this issue, we have applied a recently developed system for the assessment of vascular pathology (VPS), together with the classification system of the National Institute on Aging - Alzheimer's Association(NIA) for Alzheimer's type changes in a series of 50 patients with advanced dementia. Methods: Postmortem neuropathological data were obtained from 50 brains donated to the Tissue Bank of the CIEN Foundation.All subjects were older than 70 years(age = 84.88 ± 6.13, 70% female, 71% with high school studies), had a diagnosis of m oderate or severe dementia, and had been institutionalized at the Alzheimer Center of Reina Sofía Foundation, with regular clinical and cognitive evaluations, before brain donation. Results: The combined use of the NIA and VPS staging allowed a classification of cases into 3 groups:58%Alzheimer's predominant (AP), 12%, vascular predominant (VP) and 28% mixed pathology (MP). Significant differences were observed in the SMMSE and verbal fluency between the vascular predominant and both other groups of patients. Conclusions: The combination of scales measuring vascular and Alzheimer's type pathology in postmortem neuropathological evaluation of patients with moderate to advanced dementia allows a classification of cases according to the predominant pathology. This classification reveals significant differences between groups in premortem cognitive outcomes of patients.

PLoS ONE, 2008

Immunohistochemical staining of tissues is a powerful tool used to delineate the presence or abse... more Immunohistochemical staining of tissues is a powerful tool used to delineate the presence or absence of an antigen. During the last 30 years, antigen visualization in human brain tissue has been significantly limited by the masking effect of fixatives. In the present study, we have used a new method for antigen retrieval in formalin-fixed human brain tissue and examined the effectiveness of this protocol to reveal masked antigens in tissues with both short and long formalin fixation times. This new method, which is based on the use of citraconic acid, has not been previously utilized in brain tissue although it has been employed in various other tissues such as tonsil, ovary, skin, lymph node, stomach, breast, colon, lung and thymus. Thus, we reported here a novel method to carry out immunohistochemical studies in free-floating human brain sections. Since fixation of brain tissue specimens in formaldehyde is a commonly method used in brain banks, this new antigen retrieval method could facilitate immunohistochemical studies of brains with prolonged formalin fixation times.

Neuroscience Letters, 2011

Investigate how the subventricular proliferation and organisation is modified in a patient with F... more Investigate how the subventricular proliferation and organisation is modified in a patient with FTLD-ALS. We studied the subventricular zone (SVZ) of a patient with FTLD-ALS immunohistochemical and histologically. We found an increase of Ki-67 positive cells and neuroblast in the subventricular zone, suggesting an activation of proliferating activity in response to FTD-ALS. This proliferation can act as a compensatory mechanism for rapid neuronal death and its modulation could provide a new therapeutic pathway in ALS. These results suggest a modification of neurogenesis in FTD-ALS.

Movement Disorders, 2002

Steele-Richardson-Olszewski syndrome (SROS) is a neurodegenerative disorder of unknown aetiology,... more Steele-Richardson-Olszewski syndrome (SROS) is a neurodegenerative disorder of unknown aetiology, most frequently sporadic. Familial cases of SROS have been described. An intronic polymorphism of the tau gene is associated with sporadic SROS and mutations of the tau gene are present in atypical cases of SROS. The role of tau has been excluded in other families with pathology proven SROS, suggesting that this syndrome may have multiple causes. An 82-year-old patient, father of 3 children with autosomal recessive juvenile parkinsonism due to combined heterozygous mutations of the parkin gene, developed clinical features of SROS 2 years before death. The diagnosis was confirmed by pathology. He carried the C212Y mutation of the parkin gene and was homozygous for the A0 polymorphism and for the H1 haplotype. The role of parkin in the processing of tau is discussed.

Journal of Neurology, Neurosurgery & Psychiatry, 2012

... User Name. Password. Remember me. Forgot your sign in details? Email Alert Signup. BMJ Career... more ... User Name. Password. Remember me. Forgot your sign in details? Email Alert Signup. BMJ Careers - Latest Neurology and Neurosurgery jobs. Latest neurology and neurosurgeryjobs. Show me all Neurology jobs >>. Online ISSN 1468-330X. ...

Journal of Neurology, Neurosurgery & Psychiatry, 2011

Journal of Neurology, 2010

Journal of Molecular Neuroscience, 2006

Journal of Medical Genetics, 2013

Seipin/BSCL2 mutations can cause type 2 congenital generalised lipodystrophy (BSCL) or dominant m... more Seipin/BSCL2 mutations can cause type 2 congenital generalised lipodystrophy (BSCL) or dominant motor neurone diseases. Type 2 BSCL is frequently associated with some degree of intellectual impairment, but not to fatal neurodegeneration. In order to unveil the aetiology and pathogenetic mechanisms of a new neurodegenerative syndrome associated with a novel BSCL2 mutation, six children, four of them showing the BSCL features, were studied. Mutational and splicing analyses of BSCL2 were performed. The brain of two of these children was examined postmortem. Relative expression of BSCL2 transcripts was analysed by real-time reverse transcription-polymerase chain reaction (RT-PCR) in different tissues of the index case and controls. Overexpressed mutated seipin in HeLa cells was analysed by immunofluorescence and western blotting. Two patients carried a novel homozygous c.985C>T mutation, which appeared in the other four patients in compound heterozygosity. Splicing analysis showed that the c.985C>T mutation causes an aberrant splicing site leading to skipping of exon 7. Expression of exon 7-skipping transcripts was very high with respect to that of the non-skipped transcripts in all the analysed tissues of the index case. Neuropathological studies showed severe neurone loss, astrogliosis and intranuclear ubiquitin(+) aggregates in neurones from multiple cortical regions and in the caudate nucleus. Our results suggest that exon 7 skipping in the BSCL2 gene due to the c.985C>T mutation is responsible for a novel early onset, fatal neurodegenerative syndrome involving cerebral cortex and basal ganglia.

Human Molecular Genetics, 2012

Although a-synuclein (a-SYN) aggregation is a hallmark of sporadic and familial Parkinson's disea... more Although a-synuclein (a-SYN) aggregation is a hallmark of sporadic and familial Parkinson's disease (PD), it is not known how it contributes to early events of PD pathogenesis such as oxidative and inflammatory stress. Here, we addressed this question in a new animal model based on stereotaxic delivery of an adeno-associated viral vector (rAAV) for expression of human a-SYN in the ventral midbrain of mice lacking the transcription factor Nrf2 (Nrf2 2/2). Two months after surgery, Nrf2 2/2 mice exhibited exacerbated degeneration of nigral dopaminergic neurons and increased dystrophic dendrites, reminiscent of Lewy neurites, which correlated with impaired proteasome gene expression and activity. Dopaminergic neuron loss was associated with an increase in neuroinflammation and gliosis that were intensified in Nrf2 2/2 mice. In response to exogenously added a-SYN, Nrf2 2/ 2 microglia failed to activate the expression of two antiinflammatory genes, heme oxygenase-1 (HO-1) and nicotinamide adenine dinucleotide phosphate quinone oxidorreductase-1 (NQO1). This impaired Nrf2 response correlated with a shift in the microglial activation profile, towards increased production of proinflammatory markers, IL-6, IL-1b and iNOS and reduced phagocytic capacity of fluorescent beads, and lower messenger RNA levels for TAM receptors Axl and Mer. Postmortem brain tissue samples from patients in early-to middle-stage progression of PD showed increased HO-1 expression in astrocytes and microglia, suggesting an attempt of the diseased brain to compensate these hallmarks of PD through activation of the Nrf2 pathway. This study demonstrates that a-SYN and Nrf2 deficiency cooperate on protein aggregation, neuroinflammation and neuronal death and provides a bifactorial animal model to study early-stage PD.

European Journal of Neurology, 2004

In this report, we present the clinical and pathological details of a kindred of four individuals... more In this report, we present the clinical and pathological details of a kindred of four individuals with a novel missense mutation (V272A) of the presenilin 1 gene (PSEN1) that experienced a subcortical dementia. The age of onset of symptoms ranged 26-36year old, with an age at death of 36-46 years. Initial symptom was a marked mood disorder, with prominent parkinsonism in one case. The neuropsychological study, as well as the neuroimaging and PET in the proband were concordant with a subcortical dementia. The cerebral pathology showed in this patient, aside from the classical lesions of Alzheimer disease, Lewy bodies in cortex and substantia nigra, and widespread subcortical neuritic lesions. This clinical pattern and pathology expands the clinical spectrum of familial Alzheimer's disease and compel to include mutations of PSEN1 gene in the genetic study of subcortical dementia.

Brain, 2005

We describe the clinical phenotype and pathology of a new autosomal dominant late-onset familial ... more We describe the clinical phenotype and pathology of a new autosomal dominant late-onset familial form of Alzheimer's disease in four extensive kindred originated in a genetically isolated population. Twelve affected and 16 unaffected members of these kindred were examined clinically, and a brain post-mortem study was carried out in one case. The preliminary genetic assessment included complex segregation analysis, evaluation of the power to detect linkage, and exclusion of candidate genes. Dementia has been recorded for six generations in ancestors of examined cases. Review of death certificates allowed linking of all subjects in four extensive pedigrees. Affected individuals examined had progressive memory loss with onset between 57 and 74 years of age, along with seizures, myoclonus and parkinsonism in advanced stages. The brain of the case examined postmortem showed widespread neocortical neuritic plaques and neurofibrillary tangles (stage VI of Braak), amyloid angiopathy, and Lewy bodies restricted to limbic areas. Sequencing exons 16 and 17 of amyloid precursor protein, and exons 4-12 of presenilin 1 and presenilin 2 genes did not disclose any mutations. Genotyping with markers D21S265, D14S71, D14S77, D1S2850 and D1S479 located 1-3 cM from the previously reported genes further excluded linkage to these genes. Seven out of 12 cases were apolipoprotein E (APOE) «3/3, although the presence of an APOE «4 allele was associated with an increased risk of dementia (odd ratio 6.17; 95% confidence interval: 1.15-33.15), but not to an earlier age of onset. Complex segregation analysis showed that the best model fitting the data was that of a major gene (dominant) with a gene frequency close to 3% in this population. Simulation analysis predicted an average logarithm of odds (LOD) of 2.2 at u = 0.05. These four families, which seem to be part of a common extended pedigree originated by a founder arriving in this region in the 18th century, represent an autosomal dominant late-onset familial Alzheimer's disease not linked to previously known genetic loci. The simulation analysis suggests that it will be feasible to locate a novel responsible gene in these kindred.

Brain, 2013

The central nervous system has a pattern of gene expression that is closely regulated with respec... more The central nervous system has a pattern of gene expression that is closely regulated with respect to functional and anatomical regions. DNA methylation is a major regulator of transcriptional activity, and aberrations in the distribution of this epigenetic mark may be involved in many neurological disorders, such as Alzheimer's disease. Herein, we have analysed 12 distinct mouse brain regions according to their CpG 5'-end gene methylation patterns and observed their unique epigenetic landscapes. The DNA methylomes obtained from the cerebral cortex were used to identify aberrant DNA methylation changes that occurred in two mouse models of Alzheimer's disease. We were able to translate these findings to patients with Alzheimer's disease, identifying DNA methylation-associated silencing of three targets genes: thromboxane A2 receptor (TBXA2R), sorbin and SH3 domain containing 3 (SORBS3) and spectrin beta 4 (SPTBN4). These hypermethylation targets indicate that the cyclic AMP response element-binding protein (CREB) activation pathway and the axon initial segment could contribute to the disease.

Alzheimer's & Dementia, 2015

Journal of …, 2004

The glucose transporter isoform-2 (GLUT-2) and glucokinase are considered to be components of a g... more The glucose transporter isoform-2 (GLUT-2) and glucokinase are considered to be components of a glucose sensor system controlling several key processes, and hence may modulate feeding behaviour. We have found GLUT-2 and glucokinase mRNAs in several brain regions, including the ventromedial and arcuate nuclei of the hypothalamus. GLUT-2, glucokinase and glucokinase regulatory protein mRNAs and proteins were present in these areas as determined by biochemical approaches. In addition, glucose-phosphorylating activity with a high apparent K m for glucose that displayed no product inhibition by glucose-6-phosphate was observed. Increased glycaemia after meals may be recognized by specific hypothalamic neurones due to the high K m of GLUT-2 and glucokinase. This enzyme is considered to be the true glucose sensor because it catalyses the rate-limiting step of glucose catabolism its activity being regulated by interaction with glucokinase regulatory protein, that functions as a metabolic sensor.

Glia, 2010

A continuous normal function of olfactory ensheathing glia (OEG) is to promote axonal regeneratio... more A continuous normal function of olfactory ensheathing glia (OEG) is to promote axonal regeneration from the olfactory neuroepithelium to the brain, and their neuroregenerative potential in other CNS sites such as the injured spinal cord has been studied for over a decade. However, human OEG are difficult to obtain in large amounts directly from tissues, and the derived primary cultures have a limited duplication capacity. Thus, although auto-transplantation may be an obvious option for initial proof-of-concept trials, alternatives must be explored to obtain large quantities of homogeneous, pre-characterized OEG for wide-scale therapeutic use. We have cultured primary human OEG derived from olfactory bulbs (OB) obtained by necropsy and successfully extended the replicative lifespan of these cells using lentivectors encoding Bmi-1 and TERT transgenes flanked by loxP sites. In contrast to the primary cells which could only be expanded for a limited number of passages (approximately 12)...

Translational psychiatry, 2016

Different neurodegenerative disorders often show similar lesions, such as the presence of amyloid... more Different neurodegenerative disorders often show similar lesions, such as the presence of amyloid plaques, TAU-neurotangles and synuclein inclusions. The genetically inherited forms are rare, so we wondered whether shared epigenetic aberrations, such as those affecting DNA methylation, might also exist. The studied samples were gray matter samples from the prefrontal cortex of control and neurodegenerative disease-associated cases. We performed the DNA methylation analyses of Alzheimer's disease, dementia with Lewy bodies, Parkinson's disease and Alzheimer-like neurodegenerative profile associated with Down's syndrome samples. The DNA methylation landscapes obtained show that neurodegenerative diseases share similar aberrant CpG methylation shifts targeting a defined gene set. Our findings suggest that neurodegenerative disorders might have similar pathogenetic mechanisms that subsequently evolve into different clinical entities. The identified aberrant DNA methylation c...

American Journal of Hypertension, 1998

Obesity is a metabolic disorder in which multiple clinical and biochemical alterations coexist. H... more Obesity is a metabolic disorder in which multiple clinical and biochemical alterations coexist. However, the progression of these alterations in relation to weight gain has not been investigated in detail. Therefore, we studied the evolution of insulin resistance and associated risk factors in a model of experimental obesity in dogs. We also studied whether chronic exposure to these pathogenic factors could induce cardiac and vascular alterations. Twenty male age- and body weight-matched beagle dogs were divided into four groups (n = 5), according to diet and pharmacologic therapy received, and followed for 2 years. Control animals were maintained with a regular diet, while the 15 remaining animals were fed a high-fat diet. The Obese group of dogs received no therapy, whereas the Capto group received 25 mg/12 h captopril, and the Prava+Capto was treated with 10 mg/24 h pravastatin plus the same dose of captopril throughout the study. Periodical determinations of clinical and biochemical parameters were made, and the degree of insulin resistance was also estimated. After the 2-year follow-up, the dogs were killed and vascular thickening in the aorta and the coronary arteries was evaluated. In addition, cardiac hypertrophy was estimated by heart weight and free-wall left ventricular width. Chronic pravastatin plus captopril treatment, together with decreasing weight gain rate, ameliorated the progression of insulin resistance and associated risk factors (hyperinsulinemia, hypercholesterolemia) related to this severe model. In addition, this combined therapy showed cardioprotective action, as cardiac and vascular hypertrophy observed in the Obese group was prevented. These positive results seems to emerge from the synergistic effects of both drugs, as captopril as monotherapy induced only a slight benefit on these parameters.

Alzheimer's & Dementia, 2014

Alzheimer's & Dementia, 2014

ABSTRACT Background: Alzheimer's disease (AD) is the main cause of dementia in developed ... more ABSTRACT Background: Alzheimer's disease (AD) is the main cause of dementia in developed countries and it is estimated that either alone or in combination with cerebral vascular pathology represents over 75%of the etiology of dementias. However, the absence of a consensus system for the neuropathological evaluation of vascular pathology limits classification of cases with mixed pathology and comparability between laboratories. In order to address this issue, we have applied a recently developed system for the assessment of vascular pathology (VPS), together with the classification system of the National Institute on Aging - Alzheimer's Association(NIA) for Alzheimer's type changes in a series of 50 patients with advanced dementia. Methods: Postmortem neuropathological data were obtained from 50 brains donated to the Tissue Bank of the CIEN Foundation.All subjects were older than 70 years(age = 84.88 ± 6.13, 70% female, 71% with high school studies), had a diagnosis of m oderate or severe dementia, and had been institutionalized at the Alzheimer Center of Reina Sofía Foundation, with regular clinical and cognitive evaluations, before brain donation. Results: The combined use of the NIA and VPS staging allowed a classification of cases into 3 groups:58%Alzheimer's predominant (AP), 12%, vascular predominant (VP) and 28% mixed pathology (MP). Significant differences were observed in the SMMSE and verbal fluency between the vascular predominant and both other groups of patients. Conclusions: The combination of scales measuring vascular and Alzheimer's type pathology in postmortem neuropathological evaluation of patients with moderate to advanced dementia allows a classification of cases according to the predominant pathology. This classification reveals significant differences between groups in premortem cognitive outcomes of patients.

PLoS ONE, 2008

Immunohistochemical staining of tissues is a powerful tool used to delineate the presence or abse... more Immunohistochemical staining of tissues is a powerful tool used to delineate the presence or absence of an antigen. During the last 30 years, antigen visualization in human brain tissue has been significantly limited by the masking effect of fixatives. In the present study, we have used a new method for antigen retrieval in formalin-fixed human brain tissue and examined the effectiveness of this protocol to reveal masked antigens in tissues with both short and long formalin fixation times. This new method, which is based on the use of citraconic acid, has not been previously utilized in brain tissue although it has been employed in various other tissues such as tonsil, ovary, skin, lymph node, stomach, breast, colon, lung and thymus. Thus, we reported here a novel method to carry out immunohistochemical studies in free-floating human brain sections. Since fixation of brain tissue specimens in formaldehyde is a commonly method used in brain banks, this new antigen retrieval method could facilitate immunohistochemical studies of brains with prolonged formalin fixation times.

Neuroscience Letters, 2011

Investigate how the subventricular proliferation and organisation is modified in a patient with F... more Investigate how the subventricular proliferation and organisation is modified in a patient with FTLD-ALS. We studied the subventricular zone (SVZ) of a patient with FTLD-ALS immunohistochemical and histologically. We found an increase of Ki-67 positive cells and neuroblast in the subventricular zone, suggesting an activation of proliferating activity in response to FTD-ALS. This proliferation can act as a compensatory mechanism for rapid neuronal death and its modulation could provide a new therapeutic pathway in ALS. These results suggest a modification of neurogenesis in FTD-ALS.

Movement Disorders, 2002

Steele-Richardson-Olszewski syndrome (SROS) is a neurodegenerative disorder of unknown aetiology,... more Steele-Richardson-Olszewski syndrome (SROS) is a neurodegenerative disorder of unknown aetiology, most frequently sporadic. Familial cases of SROS have been described. An intronic polymorphism of the tau gene is associated with sporadic SROS and mutations of the tau gene are present in atypical cases of SROS. The role of tau has been excluded in other families with pathology proven SROS, suggesting that this syndrome may have multiple causes. An 82-year-old patient, father of 3 children with autosomal recessive juvenile parkinsonism due to combined heterozygous mutations of the parkin gene, developed clinical features of SROS 2 years before death. The diagnosis was confirmed by pathology. He carried the C212Y mutation of the parkin gene and was homozygous for the A0 polymorphism and for the H1 haplotype. The role of parkin in the processing of tau is discussed.

Journal of Neurology, Neurosurgery & Psychiatry, 2012

... User Name. Password. Remember me. Forgot your sign in details? Email Alert Signup. BMJ Career... more ... User Name. Password. Remember me. Forgot your sign in details? Email Alert Signup. BMJ Careers - Latest Neurology and Neurosurgery jobs. Latest neurology and neurosurgeryjobs. Show me all Neurology jobs >>. Online ISSN 1468-330X. ...

Journal of Neurology, Neurosurgery & Psychiatry, 2011

Journal of Neurology, 2010

Journal of Molecular Neuroscience, 2006

Journal of Medical Genetics, 2013

Seipin/BSCL2 mutations can cause type 2 congenital generalised lipodystrophy (BSCL) or dominant m... more Seipin/BSCL2 mutations can cause type 2 congenital generalised lipodystrophy (BSCL) or dominant motor neurone diseases. Type 2 BSCL is frequently associated with some degree of intellectual impairment, but not to fatal neurodegeneration. In order to unveil the aetiology and pathogenetic mechanisms of a new neurodegenerative syndrome associated with a novel BSCL2 mutation, six children, four of them showing the BSCL features, were studied. Mutational and splicing analyses of BSCL2 were performed. The brain of two of these children was examined postmortem. Relative expression of BSCL2 transcripts was analysed by real-time reverse transcription-polymerase chain reaction (RT-PCR) in different tissues of the index case and controls. Overexpressed mutated seipin in HeLa cells was analysed by immunofluorescence and western blotting. Two patients carried a novel homozygous c.985C>T mutation, which appeared in the other four patients in compound heterozygosity. Splicing analysis showed that the c.985C>T mutation causes an aberrant splicing site leading to skipping of exon 7. Expression of exon 7-skipping transcripts was very high with respect to that of the non-skipped transcripts in all the analysed tissues of the index case. Neuropathological studies showed severe neurone loss, astrogliosis and intranuclear ubiquitin(+) aggregates in neurones from multiple cortical regions and in the caudate nucleus. Our results suggest that exon 7 skipping in the BSCL2 gene due to the c.985C>T mutation is responsible for a novel early onset, fatal neurodegenerative syndrome involving cerebral cortex and basal ganglia.

Human Molecular Genetics, 2012

Although a-synuclein (a-SYN) aggregation is a hallmark of sporadic and familial Parkinson's disea... more Although a-synuclein (a-SYN) aggregation is a hallmark of sporadic and familial Parkinson's disease (PD), it is not known how it contributes to early events of PD pathogenesis such as oxidative and inflammatory stress. Here, we addressed this question in a new animal model based on stereotaxic delivery of an adeno-associated viral vector (rAAV) for expression of human a-SYN in the ventral midbrain of mice lacking the transcription factor Nrf2 (Nrf2 2/2). Two months after surgery, Nrf2 2/2 mice exhibited exacerbated degeneration of nigral dopaminergic neurons and increased dystrophic dendrites, reminiscent of Lewy neurites, which correlated with impaired proteasome gene expression and activity. Dopaminergic neuron loss was associated with an increase in neuroinflammation and gliosis that were intensified in Nrf2 2/2 mice. In response to exogenously added a-SYN, Nrf2 2/ 2 microglia failed to activate the expression of two antiinflammatory genes, heme oxygenase-1 (HO-1) and nicotinamide adenine dinucleotide phosphate quinone oxidorreductase-1 (NQO1). This impaired Nrf2 response correlated with a shift in the microglial activation profile, towards increased production of proinflammatory markers, IL-6, IL-1b and iNOS and reduced phagocytic capacity of fluorescent beads, and lower messenger RNA levels for TAM receptors Axl and Mer. Postmortem brain tissue samples from patients in early-to middle-stage progression of PD showed increased HO-1 expression in astrocytes and microglia, suggesting an attempt of the diseased brain to compensate these hallmarks of PD through activation of the Nrf2 pathway. This study demonstrates that a-SYN and Nrf2 deficiency cooperate on protein aggregation, neuroinflammation and neuronal death and provides a bifactorial animal model to study early-stage PD.

European Journal of Neurology, 2004

In this report, we present the clinical and pathological details of a kindred of four individuals... more In this report, we present the clinical and pathological details of a kindred of four individuals with a novel missense mutation (V272A) of the presenilin 1 gene (PSEN1) that experienced a subcortical dementia. The age of onset of symptoms ranged 26-36year old, with an age at death of 36-46 years. Initial symptom was a marked mood disorder, with prominent parkinsonism in one case. The neuropsychological study, as well as the neuroimaging and PET in the proband were concordant with a subcortical dementia. The cerebral pathology showed in this patient, aside from the classical lesions of Alzheimer disease, Lewy bodies in cortex and substantia nigra, and widespread subcortical neuritic lesions. This clinical pattern and pathology expands the clinical spectrum of familial Alzheimer's disease and compel to include mutations of PSEN1 gene in the genetic study of subcortical dementia.

Brain, 2005

We describe the clinical phenotype and pathology of a new autosomal dominant late-onset familial ... more We describe the clinical phenotype and pathology of a new autosomal dominant late-onset familial form of Alzheimer's disease in four extensive kindred originated in a genetically isolated population. Twelve affected and 16 unaffected members of these kindred were examined clinically, and a brain post-mortem study was carried out in one case. The preliminary genetic assessment included complex segregation analysis, evaluation of the power to detect linkage, and exclusion of candidate genes. Dementia has been recorded for six generations in ancestors of examined cases. Review of death certificates allowed linking of all subjects in four extensive pedigrees. Affected individuals examined had progressive memory loss with onset between 57 and 74 years of age, along with seizures, myoclonus and parkinsonism in advanced stages. The brain of the case examined postmortem showed widespread neocortical neuritic plaques and neurofibrillary tangles (stage VI of Braak), amyloid angiopathy, and Lewy bodies restricted to limbic areas. Sequencing exons 16 and 17 of amyloid precursor protein, and exons 4-12 of presenilin 1 and presenilin 2 genes did not disclose any mutations. Genotyping with markers D21S265, D14S71, D14S77, D1S2850 and D1S479 located 1-3 cM from the previously reported genes further excluded linkage to these genes. Seven out of 12 cases were apolipoprotein E (APOE) «3/3, although the presence of an APOE «4 allele was associated with an increased risk of dementia (odd ratio 6.17; 95% confidence interval: 1.15-33.15), but not to an earlier age of onset. Complex segregation analysis showed that the best model fitting the data was that of a major gene (dominant) with a gene frequency close to 3% in this population. Simulation analysis predicted an average logarithm of odds (LOD) of 2.2 at u = 0.05. These four families, which seem to be part of a common extended pedigree originated by a founder arriving in this region in the 18th century, represent an autosomal dominant late-onset familial Alzheimer's disease not linked to previously known genetic loci. The simulation analysis suggests that it will be feasible to locate a novel responsible gene in these kindred.

Brain, 2013

The central nervous system has a pattern of gene expression that is closely regulated with respec... more The central nervous system has a pattern of gene expression that is closely regulated with respect to functional and anatomical regions. DNA methylation is a major regulator of transcriptional activity, and aberrations in the distribution of this epigenetic mark may be involved in many neurological disorders, such as Alzheimer's disease. Herein, we have analysed 12 distinct mouse brain regions according to their CpG 5'-end gene methylation patterns and observed their unique epigenetic landscapes. The DNA methylomes obtained from the cerebral cortex were used to identify aberrant DNA methylation changes that occurred in two mouse models of Alzheimer's disease. We were able to translate these findings to patients with Alzheimer's disease, identifying DNA methylation-associated silencing of three targets genes: thromboxane A2 receptor (TBXA2R), sorbin and SH3 domain containing 3 (SORBS3) and spectrin beta 4 (SPTBN4). These hypermethylation targets indicate that the cyclic AMP response element-binding protein (CREB) activation pathway and the axon initial segment could contribute to the disease.