Andrés Villegas

A Gain-of-Function Mutation in TRPA1 Causes Familial Episodic Pain Syndrome

Summary Human monogenic pain syndromes have provided important insights into the molecular mechanisms that underlie normal and pathological pain states. We describe an autosomal-dominant familial episodic pain syndrome characterized by episodes of debilitating upper body pain, triggered by fasting and physical stress. Linkage and haplotype analysis mapped this phenotype to a 25 cM region on chromosome 8q12–8q13. Candidate gene sequencing identified a point mutation (N855S) in the S4 transmembrane segment of TRPA1, a key sensor for environmental irritants. The mutant channel showed a normal pharmacological profile but altered biophysical properties, with a 5-fold increase in inward current on activation at normal resting potentials. Quantitative sensory testing demonstrated normal baseline sensory thresholds but an enhanced secondary hyperalgesia to punctate stimuli on treatment with mustard oil. TRPA1 antagonists inhibit the mutant channel, promising a useful therapy for this disorder. Our findings provide evidence that variation in the TRPA1 gene can alter pain perception in humans. Video Abstract

Apolipoprotein Eε4 modifies Alzheimer's disease onset in an E280A PS1 kindred

We previously have identified a large kindred from Colombia in which Alzheimers disease (AD) is caused by the E280A presenilin 1 (PS1) mutation. The objective of this study was to examine whether environmental and genetic factors are responsible for variation in the phenotypic expression of the E280A PS1 mutation. We genotyped coding and promoter polymorphisms of the APOE gene in carriers of the E280A PS1 mutation. Kaplan–Meier product‐limit and Cox proportional hazard models were used in the statistical analyses. DNA was available from 114 carriers of the E280A PS1 mutation, including 52 subjects with AD. APOE ε4 allele carriers were more likely to develop AD at an earlier age than subjects without the ε4 allele (hazard ratio, 2.07; 95% confidence interval, 1.07–3.99; p = 0.030). Subjects with low education were more likely to develop AD later than those with higher education (hazard ratio, 0.476; 95% confidence interval, 0.26–0.87). Low educational level was associated with rural residence (p < 0.001). Promoter APOE variants did not influence either the onset or the duration of the disease. This study is the first to our knowledge to demonstrate that genetic and environmental factors influence age of onset in a kindred with a familial AD mutation. Ann Neurol 2003

Syntax, action verbs, action semantics, and object semantics in Parkinson's disease: Dissociability, progression, and executive influences

Several studies have recently shown that basal ganglia (BG) deterioration leads to distinctive impairments in the domains of syntax, action verbs, and action semantics. In particular, such disruptions have been repeatedly observed in Parkinsons disease (PD) patients. However, it remains unclear whether these deficits are language-specific and whether they are equally dissociable from other reported disturbances -viz., processing of object semantics. To address these issues, we administered linguistic, semantic, and executive function (EFs) tasks to two groups of non-demented PD patients, with and without mild cognitive impairment (PD-MCI and PD-nMCI, respectively). We compared these two groups with each other and with matched samples of healthy controls. Our results showed that PD patients exhibited linguistic and semantic deficits even in the absence of MCI. However, not all domains were equally related to EFs and MCI across samples. Whereas EFs predicted disturbances of syntax and object semantics in both PD-nMCI and PD-MCI, they had no impact on action-verb and action-semantic impairments in either group. Critically, patients showed disruptions of action-verb production and action semantics in the absence of MCI and without any executive influence, suggesting a sui generis deficit present since early stages of the disease. These findings indicate that varied language domains are differentially related to the BG, contradicting popular approaches to neurolinguistics.

Deposition of hyperphosphorylated tau in cerebellum of PS1 E280A Alzheimer's disease.

Early‐onset familial Alzheimers disease (AD) caused by presenilin‐1 mutation E280A (PS1‐E280A) presents wide clinical and neuropathological variabilities. We characterized clinically and neuropathologically PS1‐E280A focusing in cerebellar involvement and compared it with early‐onset sporadic Alzheimers disease (EOSAD). Twelve E280A brains and 12 matched EOSAD brains were analyzed for beta‐amyloid and hyperphosphorylated tau (pTau) morphology, beta‐amyloid subspecies 1–40, 1–42 levels, pTau levels, and expression of stress kinases in frontal cortex and cerebellum. The data were correlated to clinical and genetic findings. We observed higher beta‐amyloid load, beta‐amyloid 1–42 and pTau concentrations in frontal cortex of PS1‐E280A compared with EOSAD. High beta‐amyloid load was found in the cerebellum of PS1‐E280A and EOSAD patients. In PS1‐E280A, beta‐amyloid localized to the molecular and Purkinje cell layers, whereas EOSAD showed them in Purkinje and granular cell layers. Surprisingly, 11 out of 12 PS1‐E280A patients showed deposition of pTau in the cerebellum. Also, seven out of 12 PS1‐E280A patients presented cerebellar ataxia. We conclude that deposition of beta‐amyloid in the cerebellum is prominent in early‐onset AD irrespective of genetic or sporadic origin. The presence of pTau in cerebellum in PS1‐E280A underscores the relevance of cerebellar involvement in AD and might be correlated to clinical phenotype.

Familial Alzheimer’s disease–associated presenilin-1 alters cerebellar activity and calcium homeostasis

Familial Alzheimers disease (FAD) is characterized by autosomal dominant heritability and early disease onset. Mutations in the gene encoding presenilin-1 (PS1) are found in approximately 80% of cases of FAD, with some of these patients presenting cerebellar damage with amyloid plaques and ataxia with unclear pathophysiology. A Colombian kindred carrying the PS1-E280A mutation is the largest known cohort of PS1-FAD patients. Here, we investigated PS1-E280A-associated cerebellar dysfunction and found that it occurs early in PS1-E208A carriers, while cerebellar signs are highly prevalent in patients with dementia. Postmortem analysis of cerebella of PS1-E280A carrier revealed greater Purkinje cell (PC) loss and more abnormal mitochondria compared with controls. In PS1-E280A tissue, ER/mitochondria tethering was impaired, Ca2+ channels IP3Rs and CACNA1A were downregulated, and Ca2+-dependent mitochondrial transport proteins MIRO1 and KIF5C were reduced. Accordingly, expression of PS1-E280A in a neuronal cell line altered ER/mitochondria tethering and transport compared with that in cells expressing wild-type PS1. In a murine model of PS1-FAD, animals exhibited mild ataxia and reduced PC simple spike activity prior to cerebellar β-amyloid deposition. Our data suggest that impaired calcium homeostasis and mitochondrial dysfunction in PS1-FAD PCs reduces their activity and contributes to motor coordination deficits prior to Aβ aggregation and dementia. We propose that PS1-E280A affects both Ca2+ homeostasis and Aβ precursor processing, leading to FAD and neurodegeneration.

Language Deficits as a Preclinical Window into Parkinson’s Disease: Evidence from Asymptomatic Parkin and Dardarin Mutation Carriers

OBJECTIVES The worldwide spread of Parkinsons disease (PD) calls for sensitive and specific measures enabling its early (or, ideally, preclinical) detection. Here, we use language measures revealing deficits in PD to explore whether similar disturbances are present in asymptomatic individuals at risk for the disease. METHODS We administered executive, semantic, verb-production, and syntactic tasks to sporadic PD patients, genetic PD patients with PARK2 (parkin) or LRRK2 (dardarin) mutation, asymptomatic first-degree relatives of the latter with similar mutations, and socio-demographically matched controls. Moreover, to detect sui generis language disturbances, we ran analysis of covariance tests using executive functions as covariate. RESULTS The two clinical groups showed impairments in all measures, most of which survived covariation with executive functions. However, the key finding concerned asymptomatic mutation carriers. While these subjects showed intact executive, semantic, and action-verb production skills, they evinced deficits in a syntactic test with minimal working memory load. CONCLUSIONS We propose that this sui generis disturbance may constitute a prodromal sign anticipating eventual development of PD. Moreover, our results suggest that mutations on specific genes (PARK2 and LRRK2) compromising basal ganglia functioning may be subtly related to language-processing mechanisms. (JINS, 2017, 23, 150-158).

Tracking the Cognitive, Social, and Neuroanatomical Profile in Early Neurodegeneration: Type III Cockayne Syndrome

Cockayne syndrome (CS) is an autosomal recessive disease associated with premature aging, progressive multiorgan degeneration, and nervous system abnormalities including cerebral and cerebellar atrophy, brain calcifications, and white matter abnormalities. Although several clinical descriptions of CS patients have reported developmental delay and cognitive impairment with relative preservation of social skills, no previous studies have carried out a comprehensive neuropsychological and social cognition assessment. Furthermore, no previous research in individuals with CS has examined the relationship between brain atrophy and performance on neuropsychological and social cognition tests. This study describes the case of an atypical late-onset type III CS patient who exceeds the mean life expectancy of individuals with this pathology. The patient and a group of healthy controls underwent a comprehensive assessment that included multiple neuropsychological and social cognition (emotion recognition, theory of mind, and empathy) tasks. In addition, we compared the pattern of atrophy in the patient to controls and to its concordance with ERCC8 gene expression in a healthy brain. The results showed memory, language, and executive deficits that contrast with the relative preservation of social cognition skills. The cognitive profile of the patient was consistent with his pattern of global cerebral and cerebellar loss of gray matter volume (frontal structures, bilateral cerebellum, basal ganglia, temporal lobe, and occipito-temporal/occipito-parietal regions), which in turn was anatomically consistent with the ERCC8 gene expression level in a healthy donor’s brain. The study of exceptional cases, such as the one described here, is fundamental to elucidating the processes that affect the brain in premature aging diseases, and such studies provide an important source of information for understanding the problems associated with normal and pathological aging.

A Mutation in DAOA Modifies the Age of Onset in PSEN1 E280A Alzheimer's Disease

We previously reported age of onset (AOO) modifier genes in the worlds largest pedigree segregating early-onset Alzheimers disease (AD), caused by the p.Glu280Ala (E280A) mutation in the PSEN1 gene. Here we report the results of a targeted analysis of functional exonic variants in those AOO modifier genes in sixty individuals with PSEN1 E280A AD who were whole-exome genotyped for ~250,000 variants. Standard quality control, filtering, and annotation for functional variants were applied, and common functional variants located in those previously reported as AOO modifier loci were selected. Multiloci linear mixed-effects models were used to test the association between these variants and AOO. An exonic missense mutation in the G72 (DAOA) gene (rs2391191, P = 1.94 × 10−4, P FDR = 9.34 × 10−3) was found to modify AOO in PSEN1 E280A AD. Nominal associations of missense mutations in the CLUAP1 (rs9790, P = 7.63 × 10−3, P FDR = 0.1832) and EXOC2 (rs17136239, P = 0.0325, P FDR = 0.391) genes were also found. Previous studies have linked polymorphisms in the DAOA gene with the occurrence of neuropsychiatric symptoms such as depression, apathy, aggression, delusions, hallucinations, and psychosis in AD. Our findings strongly suggest that this new conspicuous functional AOO modifier within the G72 (DAOA) gene could be pivotal for understanding the genetic basis of AD.

p120-catenin is necessary for neuroprotection induced by CDK5 silencing in models of Alzheimer's disease.

Cyclin‐dependent kinase 5 (CDK5) plays important roles in synaptic function. Its unregulated over‐activation has been, however, associated with neurodegeneration in Alzheimers disease. Our previous studies revealed that CDK5 silencing ameliorates tauopathy and spatial memory impairment in the 3xTgAD mouse model. However, how CDK5 targeting affects synaptic adhesion proteins, such as those involved in the cadherin/catenin system, during learning and memory processes is not completely understood. In this study, we detected reduced expression of p120 catenin (p120 ctn), N‐cadherin, and β‐catenin in the brain of human Alzheimers disease patients, in addition to a reduced PSD95 and GluN2B protein levels in a 3xTgAD mouse model. Such decrease in synaptic proteins was recovered by CDK5 silencing in mice leading to a better learning and memory performance. Additionally, CDK5 inhibition or knockout increased p120 ctn levels. Moreover, in a glutamate‐induced excitotoxicity model, CDK5 silencing‐induced neuroprotection depended on p120 ctn. Together, those findings suggest that p120 ctn plays an important role in the neuronal dysfunction of Alzheimers disease models and contributes to CDK5 silencing‐induced neuroprotection and improvement of memory function.

Mutations modifying sporadic Alzheimer's disease age of onset

The identification of mutations modifying the age of onset (AOO) in Alzheimers disease (AD) is crucial for understanding the natural history of AD and, therefore, for early interventions. Patients with sporadic AD (sAD) from a genetic isolate in the extremes of the AOO distribution were whole‐exome genotyped. Single‐ and multi‐locus linear mixed‐effects models were used to identify functional variants modifying AOO. A posteriori enrichment and bioinformatic analyses were applied to evaluate the non‐random clustering of the associate variants to physiopathological pathways involved in AD. We identified more than 20 pathogenic, genome‐wide statistically significant mutations of major modifier effect on the AOO. These variants are harbored in genes implicated in neuron apoptosis, neurogenesis, inflammatory processes linked to AD, oligodendrocyte differentiation, and memory processes. This set of new genes harboring these mutations could be of importance for prediction, follow‐up and eventually as therapeutical targets of AD.