Jordi Pérez-Tur

Cloning of the Gene Containing Mutations that Cause PARK8-Linked Parkinson's Disease

Parkinsons disease (PD; OMIM #168600) is the second most common neurodegenerative disorder in the Western world and presents as a progressive movement disorder. The hallmark pathological features of PD are loss of dopaminergic neurons from the substantia nigra and neuronal intracellular Lewy body inclusions. Parkinsonism is typically sporadic in nature; however, several rare familial forms are linked to genetic loci, and the identification of causal mutations has provided insight into the disease process. PARK8, identified in 2002 by Funayama and colleagues, appears to be a common cause of familial PD. We describe here the cloning of a novel gene that contains missense mutations segregating with PARK8-linked PD in five families from England and Spain. Because of the tremor observed in PD and because a number of the families are of Basque descent, we have named this protein dardarin, derived from the Basque word dardara, meaning tremor.

A mutation in Alzheimer's disease destroying a splice acceptor site in the presenilin-1 gene

A series of mutations has been reported in the presenilin-1 (PS-1) gene which cause early onset Alzheimers disease (AD). The mutations reported to date have encoded missense mutations which alter residues conserved between PS-1 and the presenilin-2 (PS-2) gene. We have recently determined the intron/exon structure of the PS-1 gene and this information has been used to identify a mutation in the splice acceptor site for exon 9 in a family with early onset AD. Amplification of cDNA from lymphoblasts of affected individuals revealed that the effect of the mutation was to cause splicing out of exon 9, however it does not change the open reading frame of the mRNA. The importance of this observation is discussed.

Prevalence of Alzheimer’s disease in very elderly people: A prospective neuropathological study

Background: No previous autopsy-controlled, prospective, and population-based studies are available on the prevalence of AD in very elderly people. Objective: To study the point prevalence of neuropathologically defined AD in a population of people at least 85 years of age, stratified according to their APOE genotype. Methods: A population-based sample of 532 (of a total population of 601) elderly Finnish individuals, aged 85 years or more, were clinically tested for dementia in 1991 (with follow-up studies of the survivors in 1994, 1996, and 1999) and genotyped for APOE. An autopsy involving neuropathologic diagnosis of AD according to modified consensus criteria was performed in 118 of 198 deceased subjects who had been demented on April 1, 1991, and in 62 of 201 nondemented individuals. Results: The prevalence of neuropathologically defined AD was 33%, whereas the prevalence of clinically diagnosed AD was 16%. There was a highly significant (p < 0.001) association between the APOE ε4 allele and AD: Sixty-three percent of APOE ε4 carriers and 20% of noncarriers had neuropathologic AD. The respective figures in subjects aged 90 years or more were 71 and 22%. Conclusions: The prevalence of neuropathologically defined AD is higher than that reported in most previous studies based on clinical diagnosis. The discrepancy between the neuropathologic and clinical diagnoses of AD in very elderly subjects may affect the results of population-based studies. The APOE genotype has a strong effect on the prevalence of neuropathologically defined AD, even after 90 years of age.

Complete analysis of the presenilin 1 gene in early onset Alzheimer's disease

The presenilin 1 gene has recently been identified as the locus on chromosome 14 which is responsible for a large proportion of early onset, autosomal dominantly inherited Alzheimers disease (AD). We have elucidated the intron/exon structure of the gene and designed intronic primers to enable direct sequencing of the entire coding region (10 exons) of the presenilin gene in a large number of families. This strategy has enabled us to find a further two novel mutations in the gene. We discuss the distribution of mutations and the proportions of autosomal dominant AD with a mean age of onset below 60 years caused by mutations in this gene.

Autosomal Dominant Lateral Temporal Epilepsy: Clinical Spectrum, New Epitempin Mutations, and Genetic Heterogeneity in Seven European Families

Summary:  Purpose: To describe the clinical and genetic findings of seven additional pedigrees with autosomal dominant lateral temporal epilepsy (ADLTE).

The novel EPTP repeat defines a superfamily of proteins implicated in epileptic disorders

Recent studies suggest that mutations in the LGI1/Epitempin gene cause autosomal dominant lateral temporal epilepsy. This gene encodes a protein of unknown function, which we postulate is secreted. The LGI1 protein has leucine-rich repeats in the N-terminal sequence and a tandem repeat (which we named EPTP) in its C-terminal region. A redefinition of the C-terminal repeat and the application of sensitive sequence analysis methods enabled us to define a new superfamily of proteins carrying varying numbers of the novel EPTP repeats in combination with various extracellular domains. Genes encoding proteins of this family are located in genomic regions associated with epilepsy and other neurological disorders.

Association between the low density lipoprotein receptor-related protein (LRP) and Alzheimer's disease

Alzheimers disease (AD) is the most common neurodegenerative disorder affecting elderly people. It usually occurs after 65 years old (late-onset AD). The epsilon4 allele of apolipoprotein E (APOE) gene is a risk factor which contributes about 50% of the genetic risk for this form of the disease. The low density lipoprotein receptor-related protein (LRP) is a major receptor for APOE which is found in the senile plaques of AD brains. This makes it a good candidate gene for the disease. There is a polymorphism in the region upstream of the LRP gene that has been associated with AD in an American population. We examined this polymorphism by restriction fragment length polymorphism analysis in a French population with sporadic late-onset AD. In the previous report, a significant increase of the 87 bp allele was found in the AD cases; however, in our population, we observed a significant decrease with this same allele of the LRP gene. The possible reasons for this discrepancy, linkage disequilibrium or statistical anomaly, are discussed.

Genetic association of α2-macroglobulin with Alzheimer's disease in a Finnish elderly population

Recently, two studies have reported an association between the α2‐macroglobulin gene on chromosome 12 and late‐onset Alzheimers disease, whereas others have not been able to replicate these findings. By using a prospective population‐based study, we have investigated the relation between two polymorphisms in this gene with the presence of the disease and also with the extent of pathological changes in the cerebral cortex. The Vantaa 85+ Study includes all 601 persons, at least 85 years of age, who were living in Vantaa, Finland, on April 1, 1991. The neocortical β‐amyloid protein load and the number of neurofibrillary tangles were determined on tissue sections by using methenamine silver staining and a modified Bielschowsky staining, respectively. The A/A genotype in exon 24 of the α2‐macroglobulin gene was associated with neuropathologically defined diagnosis of Alzheimers disease according to the CERAD (Consortium to Establish a Registry for Alzheimers Disease) criteria and with an increase in the neocortical β‐amyloid protein load. The effect of this association was stronger in the apolipoprotein E ε4–negative group. Therefore, genetic variability in the α2‐macroglobulin gene is a risk factor associated with neuropathologically defined Alzheimers disease in our population, as well as with the extent of neocortical β‐amyloid protein deposition.

A novel mutation (K317M) in the MAPT gene causes FTDP and motor neuron disease

Background: Frontotemporal dementia with parkinsonism is often linked to chromosome 17 and is related to mutations in the MAPT gene. In some families the genetic basis is still unknown. The authors report two pedigrees with FTDP-17 harboring a novel mutation (K317M) in exon 11 in the MAPT gene. Methods: The authors identified two apparently unrelated pedigrees with an autosomal dominant neurodegenerative condition. Thirteen patients were examined and eight autopsies were performed. Results: Mean age at onset was 48 years. Mean disease duration was 6 years. Dysarthria often heralded the disease. All cases had parkinsonism and pyramidalism and half of them had amyotrophy. Behavioral or personality changes were not a prominent feature. Cognitive decline appeared late in the evolution. Neuropathologically, a massive degeneration of the substantia nigra without Lewy bodies was a constant finding. A variable degree of frontotemporal atrophy was found. Corticospinal tract degeneration and anterior horn neuron loss were present in six of seven autopsies in which the spinal cord was examined. An extensive deposition of abnormal tau protein in a mixed pattern (neuronal, glial) was observed. Pick’s bodies were not seen. Biochemical analysis of tau revealed two bands of 64 and 68 kDa. Conclusion: Genetic analysis revealed the same novel mutation (K317M) in exon 11 of the MAPT gene in both pedigrees. A common haplotype between members of the two pedigrees suggests that they belong to the same family.

LRRK2 is expressed in areas affected by Parkinson's disease in the adult mouse brain

The leucine‐rich repeat kinase 2 (LRRK2) gene was recently found to have multiple mutations that are causative for autosomal dominant inherited Parkinsons disease (PD). Previously, we used Northern blot analysis to show that this gene was expressed in the cerebellum, cerebral cortex, medulla, spinal cord, occipital pole, frontal lobe, temporal lobe and caudate putamen. However, a more comprehensive map of LRRK2 mRNA localization in the central nervous system is still lacking. In this study we have mapped the distribution of the mRNA encoding for LRRK2 using nonradioactive in situ hybridization. We detected a moderate expression of this PD‐related gene throughout the adult B2B6 mouse brain. A stronger hybridization signal was observed in deep cerebral cortex layers, superficial cingulate cortex layers, the piriform cortex, hippocampal formation, caudate putamen, substantia nigra, the basolateral and basomedial anterior amygdala nuclei, reticular thalamic nucleus and also in the cerebellar granular cell layer. Given that LRRK2 mRNA is highly enriched in motor systems and also is expressed in other systems, we may conclude that mutations in LRRK2 may affect several motor and nonmotor structures that may play an important role in the development of PD.