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1.
Hum Genet ; 138(11-12): 1409-1417, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31748968

RESUMO

Pelizaeus-Merzbacher-like disease (PMLD) is an autosomal recessive hypomyelinating leukodystrophy, which is clinically and radiologically similar to X-linked Pelizaeus-Merzbacher disease (PMD). PMLD is characterized by early-onset nystagmus, delayed development (motor delay, speech delay and dysarthria), dystonia, hypotonia typically evolving into spasticity, ataxia, seizures, optic atrophy, and diffuse leukodystrophy on magnetic resonance imaging (MRI). We identified a 12-year-old Caucasian/Hispanic male with the classical clinical characteristics of PMLD with lack of myelination of the subcortical white matter, and absence of the splenium of corpus callosum. Exome sequencing in the trio revealed novel compound heterozygous pathogenic mutations in SNAP29 (p.Leu119AlafsX15, c.354DupG and p.0?, c.2T > C). Quantitative analysis of the patient's blood cells through RNA sequencing identified a significant decrease in SNAP29 mRNA expression, while western blot analysis on fibroblast cells revealed a lack of protein expression compared to parental and control cells. Mutations in SNAP29 have previously been associated with cerebral dysgenesis, neuropathy, ichthyosis, and keratoderma (CEDNIK) syndrome. Typical skin features described in CEDNIK syndrome, such as generalized ichthyosis and keratoderma, were absent in our patient. Moreover, the early onset nystagmus and leukodystrophy were consistent with a PMLD diagnosis. These findings suggest that loss of SNAP29 function, which was previously associated with CEDNIK syndrome, is also associated with PMLD. Overall, our study expands the genetic spectrum of PMLD.

2.
Nat Med ; 25(11): 1680-1683, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31686034

RESUMO

We identified a PSEN1 (presenilin 1) mutation carrier from the world's largest autosomal dominant Alzheimer's disease kindred, who did not develop mild cognitive impairment until her seventies, three decades after the expected age of clinical onset. The individual had two copies of the APOE3 Christchurch (R136S) mutation, unusually high brain amyloid levels and limited tau and neurodegenerative measurements. Our findings have implications for the role of APOE in the pathogenesis, treatment and prevention of Alzheimer's disease.

3.
Hum Mutat ; 2019 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-31660686

RESUMO

We report a likely pathogenic splice-altering AP4S1 intronic variant in two sisters with progressive spastic paraplegia, global developmental delay, shy character, and foot deformities. Sequencing was completed on whole-blood messenger RNA (mRNA) and analyzed for gene expression outliers after exome sequencing analysis failed to identify a causative variant. AP4S1 was identified as an outlier and contained a rare homozygous variant located three bases upstream of exon 5 (NC_000014.8(NM_007077.4):c.295-3C>A). Confirmed by additional RNA-seq, reverse-transcription polymerase chain reaction, and Sanger sequencing, this variant corresponded with exon 5, including skipping, altered isoform usage, and loss of expression from the canonical isoform 2 (NM_001128126.3). Previously, loss-of-function variants within AP4S1 were associated with a quadriplegic cerebral palsy-6 phenotype, AP-4 Deficiency Syndrome. In this study, the inclusion of mRNA-seq allowed for the identification of a previously missed splice-altering variant, and thereby expands the mutational spectrum of AP-4 Deficiency Syndrome to include impacts to some tissue-dependent isoforms.

4.
Mol Genet Genomic Med ; : e995, 2019 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-31595699

RESUMO

BACKGROUND: Childhood hearing impairment affects language and cognitive development. Profound congenital sensorineural hearing impairment can be due to an abnormal cochleovestibular nerve (CVN) and cochleovestibular malformations, however, the etiology of these conditions remains unclear. METHODS: We used a trio-based exome sequencing approach to unravel the underlying molecular etiology of a child with a rare nonsyndromic CVN abnormality and cochlear hypoplasia. Clinical and imaging data were also reviewed. RESULTS: We identified a de novo missense variant [p(Asn174Tyr)] in the DNA-binding Homeodomain of SIX1, a gene which previously has been associated with autosomal dominant hearing loss (ADHL) and branchio-oto-renal or Branchio-otic syndrome, a condition not seen in this patient. CONCLUSIONS: SIX1 has an important function in otic vesicle patterning during embryogenesis, and mice show several abnormalities to their inner ear including loss of inner ear innervation. Previous reports on patients with SIX1 variants lack imaging data and nonsyndromic AD cases were reported to have no inner ear malformations. In conclusion, we show that a de novo variant in SIX1 in a patient with sensorineural hearing loss leads to cochleovestibular malformations and abnormalities of the CVN, without any other abnormalities. Without proper interventions, severe to profound hearing loss is devastating to both education and social integration. Choosing the correct intervention can be challenging and a molecular diagnosis may adjust intervention and improve outcomes, especially for rare cases.

5.
J Alzheimers Dis ; 70(3): 691-713, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31256118

RESUMO

We used Illumina Human HT-12 v4 arrays to compare RNA expression of middle temporal gyrus (MTG; BA21) in Alzheimer's disease (AD = 97) and non-demented controls (ND = 98). A total of 938 transcripts were highly differentially expressed (adj p < 0.01; log2 FC ≥ |0.500|, with 411 overexpressed and 527 underexpressed in AD. Our results correlated with expression profiling in neurons from AD and ND obtained by laser capture microscopy in MTG from an independent dataset (log2 FC correlation: r = 0.504; p = 2.2e-16). Additionally, selected effects were validated by qPCR. ANOVA analysis yielded no difference between genders in response to AD, but some gender specific genes were detected (e.g., IL8 and AGRN in males, and HSPH1 and GRM1 in females). Several transcripts were associated with Braak staging (e.g., AEBP1 and DNALI1), antemortem MMSE (e.g., AEBP1 and GFAP), and tangle density (e.g., RNU1G2, and DNALI1). At the pathway level, we detected enrichment of synaptic vesicle processes and GABAergic transmission genes. Finally, applying the Weighted Correlation Network Analysis, we identified four expression modules enriched for neuronal and synaptic genes, mitochondria-associated membrane, chemical stimulus and olfactory receptor and non-coding RNA metabolism genes. Our results represent an extensive description of MTG mRNA profiling in a large sample of AD and ND. These data provide a list of genes associated with AD, and correlated to neurofibrillary tangles density. In addition, these data emphasize the importance of mitochondrial membranes and transcripts related to olfactory receptors in AD.

6.
Brain Res ; 1719: 217-224, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31176712

RESUMO

We explored RNA expression changes in the middle temporal gyrus (MTG) of Alzheimer's Disease patients (AD) by RNA sequencing the whole transcriptome of 8 AD and 8 Non-Demented (ND) controls. We used three additional expression datasets from related brain regions to validate the findings. The results highlighted the upregulation of AEBP1 and downregulation of NRN1 in AD, as well as their association with Braak staging and neurofibrillary tangles density. Furthermore, more than 400 protein-coding RNAs enriched for "Clathrin-mediated endocytosis" were validated in independent datasets from the same brain region. Finally, using in silico prediction analysis we found a signature of 52 non-protein coding RNAs that perturb key pathways involved in GABAergic transmission and peptide chain elongation. The association of AEBP1 in our data confirmed other published work examining gene expression in the hippocampus of AD patients. NRN1 is involved in neurite outgrowth, and in previous studies it has been shown to reverse synaptic defects and cognitive function impairment in Tg2576 mice. Finally, our results on non-protein coding RNAs suggest a role of these transcripts in altering synaptic and amyloid-ß associated pathways.

7.
Elife ; 82019 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-31210642

RESUMO

In humans, a first-degree family history of dementia (FH) is a well-documented risk factor for Alzheimer's disease (AD); however, the influence of FH on cognition across the lifespan is poorly understood. To address this issue, we developed an internet-based paired-associates learning (PAL) task and tested 59,571 participants between the ages of 18-85. FH was associated with lower PAL performance in both sexes under 65 years old. Modifiers of this effect of FH on PAL performance included age, sex, education, and diabetes. The Apolipoprotein E ε4 allele was also associated with lower PAL scores in FH positive individuals. Here we show, FH is associated with reduced PAL performance four decades before the typical onset of AD; additionally, several heritable and non-heritable modifiers of this effect were identified.

9.
Epigenetics ; 14(3): 310-323, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30806146

RESUMO

Individual differences in cognitive function are due to a combination of heritable and non-heritable factors. A large body of evidence from clinical, cognitive, and pharmacological neuroscience implicates dopaminergic gene variants as modulators of cognitive functions. Neuroepigenetic studies demonstrate environmental factors also influence complex phenotypes by affecting gene expression regulation. To evaluate the mechanism of environmental influence on cognitive abilities, we examined if epigenetic regulation of dopaminergic genes plays a role in cognition. Using a DNA methylation profiling microarray, we used a monozygotic (MZ) twin difference design to evaluate if co-twin differences in methylation of CpG sites near six dopaminergic genes predicted differences in response inhibition and memory performance. Studying MZ twins allows us to assess if environmentally driven differences in methylation affect differences in phenotype while controlling for the influence of genotype and shared family environment. Response inhibition was assessed with the flanker task and short-term and working memory were assessed with digit span recall. We found MZ co-twin differences in DRD4 gene methylation predicted differences in short-term memory. MZ differences in COMT, DBH, DAT1, DRD1, and DRD2 gene methylation predicted differences in response inhibition. Taken together, findings suggest methylation status of dopaminergic genes may influence cognitive functions in a dissociable manner. Our results highlight the importance of the epigenome and environment, over and above the influence of genotype, in supporting complex cognitive functions.

10.
Neuron ; 101(3): 399-411.e5, 2019 02 06.
Artigo em Inglês | MEDLINE | ID: mdl-30595332

RESUMO

An individual's genetic makeup plays a large role in determining susceptibility to Alzheimer's disease (AD) but has largely been ignored in preclinical studies. To test the hypothesis that incorporating genetic diversity into mouse models of AD would improve translational potential, we combined a well-established mouse model of AD with a genetically diverse reference panel to generate mice that harbor identical high-risk human mutations but differ across the remainder of their genome. We first show that genetic variation profoundly modifies the impact of human AD mutations on both cognitive and pathological phenotypes. We then validate this complex AD model by demonstrating high degrees of genetic, transcriptomic, and phenotypic overlap with human AD. Overall, work here both introduces a novel AD mouse population as an innovative and reproducible resource for the study of mechanisms underlying AD and provides evidence that preclinical models incorporating genetic diversity may better translate to human disease.


Assuntos
Doença de Alzheimer/genética , Modelos Animais de Doenças , Medicina de Precisão/métodos , Pesquisa Médica Translacional/normas , Doença de Alzheimer/patologia , Animais , Feminino , Genótipo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Medicina de Precisão/normas , Especificidade da Espécie , Pesquisa Médica Translacional/métodos
11.
Mol Psychiatry ; 2019 Jan 08.
Artigo em Inglês | MEDLINE | ID: mdl-30622336

RESUMO

The lack of effective treatments for Alzheimer's disease (AD) is alarming, considering the number of people currently affected by this disorder and the projected increase over the next few decades. Elevated homocysteine (Hcy) levels double the risk of developing AD. Choline, a primary dietary source of methyl groups, converts Hcy to methionine and reduces age-dependent cognitive decline. Here, we tested the transgenerational benefits of maternal choline supplementation (ChS; 5.0 g/kg choline chloride) in two generations (Gen) of APP/PS1 mice. We first exposed 2.5-month-old mice to the ChS diet and allowed them to breed with each other to generate Gen-1 mice. Gen-1 mice were exposed to the ChS diet only during gestation and lactation; once weaned at postnatal day 21, Gen-1 mice were then kept on the control diet for the remainder of their life. We also bred a subset of Gen-1 mice to each other and obtained Gen-2 mice; these mice were never exposed to ChS. We found that ChS reduced Aß load and microglia activation, and improved cognitive deficits in old Gen-1 and Gen-2 APP/PS1 mice. Mechanistically, these changes were linked to a reduction in brain Hcy levels in both generations. Further, RNA-Seq data from APP/PS1 hippocampal tissue revealed that ChS significantly changed the expression of 27 genes. These genes were enriched for inflammation, histone modifications, and neuronal death functional classes. Our results are the first to demonstrate a transgenerational benefit of ChS and suggest that modifying the maternal diet with additional choline reduces AD pathology across multiple generations.

12.
Int J Neuropsychopharmacol ; 22(3): 186-193, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30576541

RESUMO

BACKGROUND: Schizophrenia is a severe psychiatric disorder with a complex pathophysiology. Given its prevalence, high risk of mortality, early onset, and high levels of disability, researchers have attempted to develop early detection strategies for facilitating timely pharmacological and/or nonpharmacological interventions. Here, we performed a meta-analysis of publicly available gene expression datasets in peripheral tissues in schizophrenia and healthy controls to detect consistent patterns of illness-associated gene expression. We also tested whether our earlier finding of a downregulation of NPTX2 expression in the brain of schizophrenia patients replicated in peripheral tissues. METHODS: We conducted a systematic search in the Gene Expression Omnibus repository (https://www.ncbi.nlm.nih.gov/gds/) and identified 3 datasets matching our inclusion criteria: GSE62333, GSE18312, and GSE27383. After quality controls, the total sample size was: schizophrenia (n = 71) and healthy controls (n = 57) (schizophrenia range: n = 12-40; healthy controls range: n = 8-29). RESULTS: The results of the meta-analysis conducted with the GeneMeta package revealed 2 genes with a false discovery rate < 0.05: atlastin GTPase 3 (ATL3) (upregulated) and arachidonate 15-lipoxygenase, type B (ALOX15B) (downregulated). The result for ATL3 was confirmed using the weighted Z test method, whereas we found a suggestive signal for ALOX15B (false discovery rate < 0.10). CONCLUSIONS: These data point to alterations of peripheral expression of ATL3 in schizophrenia, but did not confirm the significant association signal found for NPTX2 in postmortem brain samples. These findings await replication in newly recruited schizophrenia samples as well as complementary analysis of their encoded peptides in blood.

13.
Front Syst Neurosci ; 12: 53, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30443206

RESUMO

Immediate-early genes (IEGs) are rapidly and transiently induced following excitatory neuronal activity including maximal electroconvulsive shock treatment (ECT). The rapid RNA response can be blocked by the sodium channel antagonist tetrodotoxin (TTX), without blocking seizures, indicating a role for electrical stimulation in electroconvulsive shock-induced mRNA responses. In behaving animals, Arc mRNA is selectively transcribed following patterned neuronal activity and rapidly trafficked to dendrites where it preferentially accumulates at active synapses for local translation. Here we examined whether there is a relationship between the current intensities that elicit seizures and the threshold for Arc mRNA transcription in the rat hippocampus and perirhinal cortex (PRC). Animals received ECT of varying current intensities (0, 20, 40 65, 77 and 85 mA) and were sacrificed 5 min later. While significantly more CA1, CA3 and perirhinal pyramidal cells expressed Arc at the lowest stimulus intensity compared to granule cells, there was an abrupt threshold transition that occurred in all four regions at 77 mA. This precise threshold for Arc expression in all temporal lobe neurons examined may involve regulation of the calcium-dependent mechanisms that are upstream to activity-dependent IEG transcription.

14.
PLoS Genet ; 14(9): e1007589, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30188888

RESUMO

Canine malignant melanoma, a significant cause of mortality in domestic dogs, is a powerful comparative model for human melanoma, but little is known about its genetic etiology. We mapped the genomic landscape of canine melanoma through multi-platform analysis of 37 tumors (31 mucosal, 3 acral, 2 cutaneous, and 1 uveal) and 17 matching constitutional samples including long- and short-insert whole genome sequencing, RNA sequencing, array comparative genomic hybridization, single nucleotide polymorphism array, and targeted Sanger sequencing analyses. We identified novel predominantly truncating mutations in the putative tumor suppressor gene PTPRJ in 19% of cases. No BRAF mutations were detected, but activating RAS mutations (24% of cases) occurred in conserved hotspots in all cutaneous and acral and 13% of mucosal subtypes. MDM2 amplifications (24%) and TP53 mutations (19%) were mutually exclusive. Additional low-frequency recurrent alterations were observed amidst low point mutation rates, an absence of ultraviolet light mutational signatures, and an abundance of copy number and structural alterations. Mutations that modulate cell proliferation and cell cycle control were common and highlight therapeutic axes such as MEK and MDM2 inhibition. This mutational landscape resembles that seen in BRAF wild-type and sun-shielded human melanoma subtypes. Overall, these data inform biological comparisons between canine and human melanoma while suggesting actionable targets in both species.

15.
Brain ; 141(9): 2721-2739, 2018 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-30137212

RESUMO

Our hypothesis is that changes in gene and protein expression are crucial to the development of late-onset Alzheimer’s disease. Previously we examined how DNA alleles control downstream expression of RNA transcripts and how those relationships are changed in late-onset Alzheimer’s disease. We have now examined how proteins are incorporated into networks in two separate series and evaluated our outputs in two different cell lines. Our pipeline included the following steps: (i) predicting expression quantitative trait loci; (ii) determining differential expression; (iii) analysing networks of transcript and peptide relationships; and (iv) validating effects in two separate cell lines. We performed all our analysis in two separate brain series to validate effects. Our two series included 345 samples in the first set (177 controls, 168 cases; age range 65–105; 58% female; KRONOSII cohort) and 409 samples in the replicate set (153 controls, 141 cases, 115 mild cognitive impairment; age range 66–107; 63% female; RUSH cohort). Our top target is heat shock protein family A member 2 (HSPA2), which was identified as a key driver in our two datasets. HSPA2 was validated in two cell lines, with overexpression driving further elevation of amyloid-β40 and amyloid-β42 levels in APP mutant cells, as well as significant elevation of microtubule associated protein tau and phosphorylated-tau in a modified neuroglioma line. This work further demonstrates that studying changes in gene and protein expression is crucial to understanding late onset disease and further nominates HSPA2 as a specific key regulator of late-onset Alzheimer’s disease processes.10.1093/brain/awy215_video1awy215media15824729224001.

16.
Semin Pediatr Neurol ; 26: 28-32, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29961512

RESUMO

Epileptic encephalopathies are childhood brain disorders characterized by a variety of severe epilepsy syndromes that differ by the age of onset and seizure type. Until recently, the cause of many epileptic encephalopathies was unknown. Whole exome or whole genome sequencing has led to the identification of several causal genes in individuals with epileptic encephalopathy, and the list of genes has now expanded greatly. Genetic testing with epilepsy gene panels is now done quite early in the evaluation of children with epilepsy, following brain imaging, electroencephalogram, and metabolic profile. Early infantile epileptic encephalopathy (EIEE1; OMIM #308350) is the earliest of these age-dependent encephalopathies, manifesting as tonic spasms, myoclonic seizures, or partial seizures, with severely abnormal electroencephalogram, often showing a suppression-burst pattern. In this case study, we describe a 33-month-old female child with severe, neonatal onset epileptic encephalopathy. An infantile epilepsy gene panel test revealed 2 novel heterozygous variants in the MECP2 gene; a 70-bp deletion resulting in a frameshift and truncation (p.Lys377ProfsX9) thought to be pathogenic, and a 6-bp in-frame deletion (p.His371_372del), designated as a variant of unknown significance. Based on this test result, the diagnosis of atypical Rett syndrome (RTT) was made. Family-based targeted testing and segregation analysis, however, raised questions about the pathogenicity of these specific MECP2 variants. Whole exome sequencing was performed in this family trio, leading to the discovery of a rare, de novo, missense mutation in GNAO1 (p. Leu284Ser). De novo, heterozygous mutations in GNAO1 have been reported to cause early infantile epileptic encephalopathy-17 (EIEE17; OMIM 615473). The child's severe phenotype, the family history and segregation analysis of variants and prior reports of GNAO1-linked disease allowed us to conclude that the GNAO1 mutation, and not the MECP2 variants, was the cause of this child's neurological disease. With the increased use of genetic panels and whole exome sequencing, we will be confronted with lists of gene variants suspected to be pathogenic or of unknown significance. It is important to integrate clinical information, genetic testing that includes family members and correlates this with the published clinical and scientific literature, to help one arrive at the correct genetic diagnosis.


Assuntos
Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/genética , Síndrome de Rett/diagnóstico , Síndrome de Rett/genética , Espasmos Infantis/diagnóstico , Espasmos Infantis/genética , Pré-Escolar , Diagnóstico Diferencial , Erros de Diagnóstico , Feminino , Humanos , Proteína 2 de Ligação a Metil-CpG/genética , Fenótipo
17.
Science ; 360(6395)2018 06 22.
Artigo em Inglês | MEDLINE | ID: mdl-29930110

RESUMO

Disorders of the brain can exhibit considerable epidemiological comorbidity and often share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from 1,191,588 individuals. Psychiatric disorders share common variant risk, whereas neurological disorders appear more distinct from one another and from the psychiatric disorders. We also identified significant sharing between disorders and a number of brain phenotypes, including cognitive measures. Further, we conducted simulations to explore how statistical power, diagnostic misclassification, and phenotypic heterogeneity affect genetic correlations. These results highlight the importance of common genetic variation as a risk factor for brain disorders and the value of heritability-based methods in understanding their etiology.


Assuntos
Encefalopatias/genética , Transtornos Mentais/genética , Encefalopatias/classificação , Encefalopatias/diagnóstico , Variação Genética , Estudo de Associação Genômica Ampla , Humanos , Transtornos Mentais/classificação , Transtornos Mentais/diagnóstico , Fenótipo , Característica Quantitativa Herdável , Fatores de Risco
18.
Hum Genet ; 137(6-7): 459-470, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29955957

RESUMO

Congenital inner ear malformations affecting both the osseous and membranous labyrinth can have a devastating impact on hearing and language development. With the exception of an enlarged vestibular aqueduct, non-syndromic inner ear malformations are rare, and their underlying molecular biology has thus far remained understudied. To identify molecular factors that might be important in the developing inner ear, we adopted a family-based trio exome sequencing approach in young unrelated subjects with severe inner ear malformations. We identified two previously unreported de novo loss-of-function variants in GREB1L [c.4368G>T;p.(Glu1410fs) and c.982C>T;p.(Arg328*)] in two affected subjects with absent cochleae and eighth cranial nerve malformations. The cochlear aplasia in these affected subjects suggests that a developmental arrest or problem at a very early stage of inner ear development exists, e.g., during the otic pit formation. Craniofacial Greb1l RNA expression peaks in mice during this time frame (E8.5). It also peaks in the developing inner ear during E13-E16, after which it decreases in adulthood. The crucial function of Greb1l in craniofacial development is also evidenced in knockout mice, which develop severe craniofacial abnormalities. In addition, we show that Greb1l-/- zebrafish exhibit a loss of abnormal sensory epithelia innervation. An important role for Greb1l in sensory epithelia innervation development is supported by the eighth cranial nerve deficiencies seen in both affected subjects. In conclusion, we demonstrate that GREB1L is a key player in early inner ear and eighth cranial nerve development. Abnormalities in cochleovestibular anatomy can provide challenges for cochlear implantation. Combining a molecular diagnosis with imaging techniques might aid the development of individually tailored therapeutic interventions in the future.

19.
Front Aging Neurosci ; 10: 155, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29896098

RESUMO

Introduction: SuperAgers are adults age 80+ with episodic memory performance that is at least as good as that of average middle-aged adults. Understanding the biological determinants of SuperAging may have relevance to preventing age-related cognitive decline and dementia. This study aimed to identify associations between genetic variations and the SuperAging phenotype using Whole Exome Sequencing (WES). Methods: Sequence Kernel Association Combined (SKAT-C) test was conducted at the gene level including both rare and common variants in 56 SuperAgers and 22 cognitively-average controls from the Alzheimer's disease Neuroimaging Initiative (ADNI). Results: The SuperAging phenotype was associated with variants in the Mitogen-Activated Protein Kinase Kinase 3 (MAP2K3) gene. Three single nucleotide polymorphisms (SNPs) contributed to the significance (rs2363221 [intron 1], rs2230435 [exon 5], rs736103 [intron 7]). Conclusions: MAP2K3 resides in a biological pathway linked to memory. It is in a signaling cascade associated with beta-amyloid mediated apoptosis and has enriched expression in microglia. This preliminary work suggests MAP2K3 may represent a novel therapeutic target for age-related memory decline and perhaps Alzheimer's disease (AD).

20.
PLoS One ; 13(6): e0198256, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29870545

RESUMO

Enzastaurin is a Protein Kinase C-ß selective inhibitor that was developed to treat cancers. Protein Kinase C-ß is an important enzyme for a variety of neuronal functions; in particular, previous rodent studies have reported deficits in spatial and fear-conditioned learning and memory with lower levels of Protein Kinase C-ß. Due to Enzastaurin's mechanism of action, the present study investigated the consequences of Enzastaurin exposure on learning and memory in 12-month-old Fischer-344 male rats. Rats were treated daily with subcutaneous injections of either vehicle or Enzastaurin, and behaviorally tested using the spatial reference memory Morris Water Maze. Rats treated with Enzastaurin exhibited decreased overnight retention and poorer performance on the latter testing day, indicating a mild, but significant, memory impairment. There were no differences during the probe trial indicating that all animals were able to spatially localize the platform to the proper quadrant by the end of testing. RNA isolated from the hippocampus was analyzed using Next Generation Sequencing (Illumina). No statistically significant transcriptional differences were noted. Our findings suggest that acute Enzastaurin treatment can impair hippocampal-based learning and memory performance, with no effects on transcription in the hippocampus. We propose that care should be taken in future clinical trials that utilize Protein Kinase C-ß inhibitors, to monitor for possible cognitive effects, future research should examine if these effects are fully reversible.

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