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1.
Diabetologia ; 63(1): 149-161, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31720731

RESUMO

AIMS/HYPOTHESIS: The conserved hypoxia inducible factor 1 α (HIF1α) injury-response pro-survival pathway has recently been implicated in early beta cell dysfunction but slow beta cell loss in type 2 diabetes. We hypothesised that the unexplained prolonged prediabetes phase in type 1 diabetes may also be, in part, due to activation of the HIF1α signalling pathway. METHODS: RNA sequencing (RNA-Seq) data from human islets with type 1 diabetes or after cytokine exposure in vitro was evaluated for activation of HIF1α targets. This was corroborated by immunostaining human pancreases from individuals with type 1 diabetes for 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), the key effector of HIF1α-mediated metabolic remodelling, and by western blotting of islets and INS-1 832/13 cells exposed to cytokines implicated in type 1 diabetes. RESULTS: HIF1α signalling is activated (p = 4.5 × 10-9) in islets from individuals with type 1 diabetes, and in human islets exposed in vitro to cytokines implicated in type 1 diabetes (p = 1.1 × 10-14). Expression of PFKFB3 is increased fivefold (p < 0.01) in beta cells in type 1 diabetes and in human and rat islets exposed to cytokines that induced increased lactate production. HIF1α attenuates cytokine-induced cell death in beta cells. CONCLUSIONS/INTERPRETATION: The conserved pro-survival HIF1α-mediated injury-response signalling is activated in beta cells in type 1 diabetes and likely contributes to the relatively slow rate of beta cell loss at the expense of early defective glucose-induced insulin secretion.

2.
Alzheimers Dement ; 2019 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-31784375

RESUMO

INTRODUCTION: The Advancing Research and Treatment in Frontotemporal Lobar Degeneration and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects longitudinal studies were designed to describe the natural history of familial-frontotemporal lobar degeneration due to autosomal dominant mutations. METHODS: We examined cognitive performance, behavioral ratings, and brain volumes from the first time point in 320 MAPT, GRN, and C9orf72 family members, including 102 non-mutation carriers, 103 asymptomatic carriers, 43 mildly/questionably symptomatic carriers, and 72 carriers with dementia. RESULTS: Asymptomatic carriers showed similar scores on all clinical measures compared with noncarriers but reduced frontal and temporal volumes. Those with mild/questionable impairment showed decreased verbal recall, fluency, and Trail Making Test performance and impaired mood and self-monitoring. Dementia was associated with impairment in all measures. All MAPT carriers with dementia showed temporal atrophy, but otherwise, there was no single cognitive test or brain region that was abnormal in all subjects. DISCUSSION: Imaging changes appear to precede clinical changes in familial-frontotemporal lobar degeneration, but specific early clinical and imaging changes vary across individuals.

3.
Neuron ; 2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31623919

RESUMO

Neurodegenerative diseases appear to progress by spreading via brain connections. Here we evaluated this transneuronal degeneration hypothesis by attempting to predict future atrophy in a longitudinal cohort of patients with behavioral variant frontotemporal dementia (bvFTD) and semantic variant primary progressive aphasia (svPPA). We determined patient-specific "epicenters" at baseline, located each patient's epicenters in the healthy functional connectome, and derived two region-wise graph theoretical metrics to predict future atrophy: (1) shortest path length to the epicenter and (2) nodal hazard, the cumulative atrophy of a region's first-degree neighbors. Using these predictors and baseline atrophy, we could accurately predict longitudinal atrophy in most patients. The regions most vulnerable to subsequent atrophy were functionally connected to the epicenter and had intermediate levels of baseline atrophy. These findings provide novel, longitudinal evidence that neurodegeneration progresses along connectional pathways and, further developed, could lead to network-based clinical tools for prognostication and disease monitoring.

4.
Acta Neuropathol Commun ; 7(1): 159, 2019 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-31640778

RESUMO

Tau aggregation is a hallmark feature in a subset of patients with frontotemporal dementia (FTD). Early and selective loss of von Economo neurons (VENs) and fork cells within the frontoinsular (FI) and anterior cingulate cortices (ACC) is observed in patients with sporadic behavioral variant FTD (bvFTD) due to frontotemporal lobar degeneration (FTLD), including FTLD with tau inclusions (FTLD-tau). Recently, we further showed that these specialized neurons show preferential aggregation of TDP-43 in FTLD-TDP. Whether VENs and fork cells are prone to tau accumulation in FTLD-tau remains unclear, and no previous studies of these neurons have focused on patients with pathogenic variants in the gene encoding microtubule-associated protein tau (FTLD-tau/MAPT). Here, we examined regional profiles of tau aggregation and neurodegeneration in 40 brain regions in 8 patients with FTLD-tau/MAPT and 7 with Pick's disease (PiD), a sporadic form of FTLD-tau that often presents with bvFTD. We further qualitatively assessed the cellular patterns of frontoinsular tau aggregation in FTLD-tau/MAPT using antibodies specific for tau hyperphosphorylation, acetylation, or conformational change. ACC and mid-insula were among the regions most affected by neurodegeneration and tau aggregation in FTLD-tau/MAPT and PiD. In these two forms of FTLD-tau, severity of regional neurodegeneration and tau protein aggregation were highly correlated across regions. In FTLD-tau/MAPT, VENs and fork cells showed disproportionate tau protein aggregation in patients with V337 M, A152T, and IVS10 + 16 variants, but not in patients with the P301L variant. As seen in FTLD-TDP, our data suggest that VENs and fork cells represent preferentially vulnerable neuron types in most, but not all of the MAPT variants we studied.

5.
Sci Transl Med ; 11(514)2019 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-31619545

RESUMO

Astrocytes are implicated in neurodegenerative disorders and may contribute to striatal neuron loss or dysfunction in Huntington's disease (HD). Here, we assessed striatal astrocyte gene and protein signatures in two HD mouse models at three stages and compared our results to human HD data at four clinical grades and to mice exhibiting polyglutamine length-dependent pathology. We found disease-model and stage-specific alterations and discovered a core disease-associated astrocyte molecular signature comprising 62 genes that were conserved between mice and humans. Our results show little evidence of neurotoxic A1 astrocytes that have been proposed to be causal for neuronal death in neurodegenerative disorders such as HD. Furthermore, 61 of the 62-core gene expression changes within astrocytes were reversed in a HD mouse model by lowering astrocyte mutant huntingtin protein (mHTT) expression using zinc finger protein (ZFP) transcriptional repressors. Our findings indicate that HD astrocytes progressively lose essential normal functions, some of which can be remedied by lowering mHTT. The data have implications for neurodegenerative disease rescue and repair strategies as well as specific therapeutic relevance for mHTT reduction and contribute to a better understanding of fundamental astrocyte biology and its contributions to disease.

6.
Alzheimers Dement ; 2019 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-31636026

RESUMO

INTRODUCTION: It is important to establish the natural history of familial frontotemporal lobar degeneration (f-FTLD) and provide clinical and biomarker data for planning these studies, particularly in the asymptomatic phase. METHODS: The Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects protocol was designed to enroll and follow at least 300 subjects for more than at least three annual visits who are members of kindreds with a mutation in one of the three most common f-FTLD genes-microtubule-associated protein tau, progranulin, or chromosome 9 open reading frame 72. RESULTS: We present the theoretical considerations of f-FTLD and the aims/objectives of this protocol. We also describe the design and methodology for evaluating and rating subjects, in which detailed clinical and neuropsychological assessments are performed, biofluid samples are collected, and magnetic resonance imaging scans are performed using a standard protocol. DISCUSSION: These data and samples, which are available to interested investigators worldwide, will facilitate planning for upcoming disease-modifying therapeutic trials in f-FTLD.

7.
J Neurosci ; 39(47): 9343-9359, 2019 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-31591156

RESUMO

Subcortical white matter stroke is a common stroke subtype. White matter stroke stimulates adjacent oligodendrocyte progenitor cells (OPCs) to divide and migrate to the lesion, but stroke OPCs have only a limited differentiation into mature oligodendrocytes. To understand the molecular systems that are active in OPC responses in white matter stroke, OPCs were virally labeled and laser-captured in the region of partial damage adjacent to the infarct in male mice. RNAseq indicates two distinct OPC transcriptomes associated with the proliferative and limited-regeneration phases of OPCs after stroke. Molecular pathways related to nuclear receptor activation, ECM turnover, and lipid biosynthesis are activated during proliferative OPC phases after stroke; inflammatory and growth factor signaling is activated in the later stage of limited OPC differentiation. Within ECM proteins, Matrilin-2 is induced early after stroke and then rapidly downregulated. Prediction of upstream regulators of the OPC stroke transcriptome identifies several candidate molecules, including Inhibin A-a negative regulator of Matrilin-2. Inhibin A is induced in reactive astrocytes after stroke, including in humans. In functional assays, Matrilin-2 induces OPC differentiation, and Inhibin A inhibits OPC Matrilin-2 expression and inhibits OPC differentiation. In vivo, Matrilin-2 promotes motor recovery after white matter stroke, and promotes OPC differentiation and ultrastructural evidence of remyelination. These studies show that white matter stroke induces an initial proliferative and reparative response in OPCs, but this is blocked by a local cellular niche where reactive astrocytes secrete Inhibin A, downregulating Matrilin-2 and blocking myelin repair and recovery.SIGNIFICANCE STATEMENT Stroke in the cerebral white matter of the brain is common. The biology of damage and recovery in this stroke subtype are not well defined. These studies use cell-specific RNA sequencing and gain-of-function studies to show that white matter stroke induces a glial signaling niche, present in both humans and mice, between reactive astrocytes and oligodendrocyte progenitor cells. Astrocyte secretion of Inhibin A and downregulation of oligodendrocyte precursor production of Matrilin-2 limit OPC differentiation, tissue repair, and recovery in this disease.

8.
Neurobiol Aging ; 83: 54-62, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31585367

RESUMO

Our aim was to investigate the patterns and trajectories of white matter (WM) diffusion abnormalities in microtubule-associated protein tau (MAPT) mutations carriers. We studied 22 MAPT mutation carriers (12 asymptomatic, 10 symptomatic) and 20 noncarriers from 8 families, who underwent diffusion tensor imaging (DTI) and a subset (10 asymptomatic, 6 symptomatic MAPT mutation carriers, and 10 noncarriers) were followed annually (median = 4 years). Cross-sectional and longitudinal changes in mean diffusivity (MD) and fractional anisotropy were analyzed. Asymptomatic MAPT mutation carriers had higher MD in entorhinal WM, which propagated to the limbic tracts and frontotemporal projections in the symptomatic stage compared with noncarriers. Reduced fractional anisotropy and increased MD in the entorhinal WM were associated with the proximity to estimated and actual age of symptom onset. The annualized change of entorhinal MD on serial DTI was accelerated in MAPT mutation carriers compared with noncarriers. Entorhinal WM diffusion abnormalities precede the symptom onset and track with disease progression in MAPT mutation carriers. Our cross-sectional and longitudinal data showed a potential clinical utility for DTI to track neurodegenerative disease progression for MAPT mutation carriers in clinical trials.

9.
Biol Psychiatry ; 2019 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-31500805

RESUMO

BACKGROUND: 22q11.2 copy number variants are among the most highly penetrant genetic risk variants for developmental neuropsychiatric disorders such as schizophrenia (SCZ) and autism spectrum disorder (ASD). However, the specific mechanisms through which they confer risk remain unclear. METHODS: Using a functional genomics approach, we integrated transcriptomic data from the developing human brain, genome-wide association findings for SCZ and ASD, protein interaction data, and gene expression signatures from SCZ and ASD postmortem cortex to 1) organize genes into the developmental cellular and molecular systems within which they operate, 2) identify neurodevelopmental processes associated with polygenic risk for SCZ and ASD across the allelic frequency spectrum, and 3) elucidate pathways and individual genes through which 22q11.2 copy number variants may confer risk for each disorder. RESULTS: Polygenic risk for SCZ and ASD converged on partially overlapping neurodevelopmental modules involved in synaptic function and transcriptional regulation, with ASD risk variants additionally enriched for modules involved in neuronal differentiation during fetal development. The 22q11.2 locus formed a large protein network during development that disproportionately affected SCZ-associated and ASD-associated neurodevelopmental modules, including loading highly onto synaptic and gene regulatory pathways. SEPT5, PI4KA, and SNAP29 genes are candidate drivers of 22q11.2 synaptic pathology relevant to SCZ and ASD, and DGCR8 and HIRA are candidate drivers of disease-relevant alterations in gene regulation. CONCLUSIONS: This approach offers a powerful framework to identify neurodevelopmental processes affected by diverse risk variants for SCZ and ASD and elucidate mechanisms through which highly penetrant, multigene copy number variants contribute to disease risk.

10.
P R Health Sci J ; 38(3): 144-147, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31536626

RESUMO

With the increasing geopolitical instability and environmental devastation occurring across the globe, human migration is increasing. We report a case that illustrates a migration pattern seen a century ago that is currently in the process of repeating itself. Using information from a neuropathological examination, genetic analyses, and historical sources, we linked a patient with autosomal dominant Alzheimer's disease in Hawai'i with her ancestors in Puerto Rico. In this patient we identified the G206A PSEN1 mutation, previously identified as being linked to a founder effect from Puerto Rico. At the turn of the twentieth century, due to devastating hurricanes in Puerto Rico and the island's new status as a possession of the United States, over 5,000 Puerto Ricans, including the grandparents of our patient, migrated to Hawai'i. This short-term but historic migration has resulted in a significant population of Puerto Ricans in Hawai'i, today. As physicians we sometimes have the opportunity and privilege, through the patients who come to us for help, to be indirect witnesses to such historical events and movements. These occurrences can inform the present and also portend future developments in this rapidly changing world.

11.
Sci Data ; 6(1): 179, 2019 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-31551418

RESUMO

Skeletal muscle is a highly adaptable tissue capable of changes in size, contractility, and metabolism according to functional demands. Atrophy is a decline in mass and strength caused by pathologic loss of myofibrillar proteins, and can result from disuse, aging, or denervation caused by injury or peripheral nerve disorders. We provide a high-quality longitudinal RNA-Seq dataset of skeletal muscle from a cohort of adult C57BL/6J male mice subjected to tibial nerve denervation for 0 (baseline), 1, 3, 7, 14, 30, or 90 days. Using an unbiased genomics approach to identify gene expression changes across the entire longitudinal course of muscle atrophy affords the opportunity to (1) establish acute responses to denervation, (2) detect pathways that mediate rapid loss of muscle mass within the first week after denervation, and (3) capture the molecular phenotype of chronically atrophied muscle at a stage when it is largely resistant to recovery.

12.
Alzheimer Dis Assoc Disord ; 33(4): 327-330, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31513029

RESUMO

OBJECTIVE: A rare variant in TREM2 (p.R47H, rs75932628) has been consistently reported to increase the risk for Alzheimer disease (AD), while mixed evidence has been reported for association of the variant with other neurodegenerative diseases. Here, we investigated the frequency of the R47H variant in a diverse and well-characterized multicenter neurodegenerative disease cohort. METHODS: We examined the frequency of the R47H variant in a diverse neurodegenerative disease cohort, including a total of 3058 patients clinically diagnosed with AD, frontotemporal dementia spectrum syndromes, mild cognitive impairment, progressive supranuclear palsy syndrome, corticobasal syndrome, or amyotrophic lateral sclerosis and 5089 control subjects. RESULTS: We observed a significant association between the R47H variant and AD, while no association was observed with any other neurodegenerative disease included in this study. CONCLUSIONS: Our results support the consensus that the R47H variant is significantly associated with AD. However, we did not find evidence for association of the R47H variant with other neurodegenerative diseases.

13.
Neuron ; 103(6): 1044-1055.e7, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31473062

RESUMO

Sleep is crucial for our survival, and many diseases are linked to long-term poor sleep quality. Before we can use sleep to enhance our health and performance and alleviate diseases associated with poor sleep, a greater understanding of sleep regulation is necessary. We have identified a mutation in the ß1-adrenergic receptor gene in humans who require fewer hours of sleep than most. In vitro, this mutation leads to decreased protein stability and dampened signaling in response to agonist treatment. In vivo, the mice carrying the same mutation demonstrated short sleep behavior. We found that this receptor is highly expressed in the dorsal pons and that these ADRB1+ neurons are active during rapid eye movement (REM) sleep and wakefulness. Activating these neurons can lead to wakefulness, and the activity of these neurons is affected by the mutation. These results highlight the important role of ß1-adrenergic receptors in sleep/wake regulation.

14.
PLoS Genet ; 15(8): e1008295, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31398187

RESUMO

The progressive failure of protein homeostasis is a hallmark of aging and a common feature in neurodegenerative disease. As the enzymes executing the final stages of autophagy, lysosomal proteases are key contributors to the maintenance of protein homeostasis with age. We previously reported that expression of granulin peptides, the cleavage products of the neurodegenerative disease protein progranulin, enhance the accumulation and toxicity of TAR DNA binding protein 43 (TDP-43) in Caenorhabditis elegans (C. elegans). In this study we show that C. elegans granulins are produced in an age- and stress-dependent manner. Granulins localize to the endolysosomal compartment where they impair lysosomal protease expression and activity. Consequently, protein homeostasis is disrupted, promoting the nuclear translocation of the lysosomal transcription factor HLH-30/TFEB, and prompting cells to activate a compensatory transcriptional program. The three C. elegans granulin peptides exhibited distinct but overlapping functional effects in our assays, which may be due to amino acid composition that results in distinct electrostatic and hydrophobicity profiles. Our results support a model in which granulin production modulates a critical transition between the normal, physiological regulation of protease activity and the impairment of lysosomal function that can occur with age and disease.

15.
Alzheimers Dement ; 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31272932

RESUMO

INTRODUCTION: Some models of therapy for neurodegenerative diseases envision starting treatment before symptoms develop. Demonstrating that such treatments are effective requires accurate knowledge of when symptoms would have started without treatment. Familial frontotemporal lobar degeneration offers a unique opportunity to develop predictors of symptom onset. METHODS: We created dementia risk scores in 268 familial frontotemporal lobar degeneration family members by entering covariate-adjusted standardized estimates of brain atrophy into a logistic regression to classify asymptomatic versus demented participants. The score's predictive value was tested in a separate group who were followed up longitudinally (stable vs. converted to dementia) using Cox proportional regressions with dementia risk score as the predictor. RESULTS: Cross-validated logistic regression achieved good separation of asymptomatic versus demented (accuracy = 90%, SE = 0.06). Atrophy scores predicted conversion from asymptomatic or mildly/questionably symptomatic to dementia (HR = 1.51, 95% CI: [1.16,1.98]). DISCUSSION: Individualized quantification of baseline brain atrophy is a promising predictor of progression in asymptomatic familial frontotemporal lobar degeneration mutation carriers.

16.
Mov Disord ; 34(7): 1049-1059, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31059154

RESUMO

BACKGROUND: Progressive supranuclear palsy is a neurodegenerative tauopathy manifesting clinically as a progressive akinetic-rigid syndrome. In this study, we sought to identify genetic variants influencing PSP susceptibility through a genome-wide association analysis of a cohort of well-characterized patients who had participated in the Neuroprotection and Natural History in Parkinson Plus Syndromes and Blood Brain Barrier in Parkinson Plus Syndromes studies. METHODS: We genotyped single-nucleotide polymorphisms in 283 PSP cases from the United Kingdom, Germany, and France and compared these with genotypes from 4472 controls. Copy number variants were identified from genotyping data. RESULTS: We observed associations on chromosome 17 within or close to the MAPT gene and explored the genetic architecture at this locus. We confirmed the previously reported association of rs1768208 in the MOBP gene (P = 3.29 × 10-13 ) and rs1411478 in STX6 (P = 3.45 × 10-10 ). The population-attributable risk from the MAPT, MOBP, and STX6 single-nucleotide polymorphisms was found to be 0.37, 0.26, and 0.08, respectively. In addition, we found 2 instances of copy number variants spanning the MAPT gene in patients with PSP. These copy number variants include tau but few other genes within the chromosome 17 haplotype region, providing additional support for the direct pathogenicity of MAPT in PSP. CONCLUSIONS: Clinicians should also be aware of MAPT duplication as a possible genetic cause of PSP, especially in patients presenting with young age at onset. © 2019 International Parkinson and Movement Disorder Society.

17.
Am J Geriatr Psychiatry ; 27(10): 1046-1056, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31133468

RESUMO

OBJECTIVE: To test the hypothesis that a functional polymorphism of the serotonin transporter gene (serotonin-transporter-linked polymorphic region [5-HTTLPR]), which is thought to be associated with differential environmental sensitivity, moderates the association between low levels of empathic accuracy (i.e., ability to recognize emotions in others) in patients with neurodegenerative disease and caregivers' well-being. METHODS: Participants were 54 patients with neurodegenerative disease and their caregivers. Patients' empathic accuracy was measured using a dynamic tracking task in which they continuously rated the emotions of a character in a film; accuracy was determined by comparing patient ratings with those made by an expert panel. Caregivers provided a saliva sample for genotyping. Caregivers' well-being was measured as a latent construct indicated by validated measures of depression, anxiety, and negative affect. RESULTS: Lower levels of patients' empathic accuracy were associated with lower levels of caregivers' well-being. Importantly, caregivers' 5-HTTLPR genotype moderated this association such that lower empathic accuracy in patients predicted lower well-being for caregivers with the short/short genotype (standardized ß = 0.66), but not for caregivers with the short/long (standardized ß = 0.05) or long/long genotypes (standardized ß = -0.21). CONCLUSION: Consistent with previous findings that the short/short variant of 5-HTTLPR is associated with greater sensitivity to environmental influences, caregivers with the short/short variant manifest lower well-being when caring for a patient with low levels of empathic accuracy than caregivers with the other variants. This finding contributes to the authors' understanding of biological factors associated with individual differences in caregiver vulnerability and resilience.

18.
Alzheimers Dement ; 2019 May 11.
Artigo em Inglês | MEDLINE | ID: mdl-31088775

RESUMO

INTRODUCTION: Identifying clinical measures that track disease in the earliest stages of frontotemporal lobar degeneration (FTLD) is important for clinical trials. Familial FTLD provides a unique paradigm to study early FTLD. Executive dysfunction is a clinically relevant hallmark of FTLD and may be a marker of disease progression. METHODS: Ninety-three mutation carriers with no symptoms or minimal/questionable symptoms (MAPT, n = 31; GRN, n = 28; C9orf72, n = 34; Clinical Dementia Rating scale plus NACC FTLD Module < 1) and 78 noncarriers enrolled through Advancing Research and Treatment in Frontotemporal Lobar Degeneration/Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects studies completed the Executive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research (NIH-EXAMINER) and the UDS neuropsychological battery. Linear mixed-effects models were used to identify group differences in cognition at baseline and longitudinally. We examined associations between cognition, clinical functioning, and magnetic resonance imaging volumes. RESULTS: NIH-EXAMINER scores detected baseline and differences in slopes between carriers and noncarriers, even in carriers with a baseline Clinical Dementia Rating scale plus NACC FTLD Module = 0. NIH-EXAMINER declines were associated with worsening clinical symptoms and brain volume loss. DISCUSSION: The NIH-EXAMINER is sensitive to cognitive changes in presymptomatic familial FTLD and is a promising surrogate endpoint.

19.
J Neurol Neurosurg Psychiatry ; 90(9): 1005-1010, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31079065

RESUMO

OBJECTIVE: To investigate in-vivo cortical gyrification patterns measured by the local gyrification index (lGI) in presymptomatic c9orf72 expansion carriers compared with healthy controls, and investigate relationships between lGI and cortical thickness, an established morphometric measure of neurodegeneration. METHODS: We assessed cortical gyrification and thickness patterns in a cohort of 15 presymptomatic c9orf72 expansion carriers (age 43.7 ± 10.2 years, 9 females) compared with 67 (age 42.4 ± 12.4 years, 36 females) age and sex matched healthy controls using the dedicated Freesurfer pipeline. RESULTS: Compared with controls, presymptomatic carriers showed significantly lower lGI in left frontal and right parieto-occipital regions. Interestingly, those areas with abnormal gyrification in presymptomatic carriers showed no concomitant cortical thickness abnormality. Overall, for both presymptomatic carriers and healthy controls, gyrification and cortical thickness measures were not correlated, suggesting that gyrification captures a feature distinct from cortical thickness. CONCLUSIONS: Presymptomatic c9orf72 expansion carriers show regions of abnormally low gyrification as early as their 30s, decades before expected symptom onset. Cortical gyrification represents a novel grey matter metric distinctive from grey matter thickness or volume and detects differences in presymptomatic carriers at an early age.

20.
Proc Natl Acad Sci U S A ; 116(19): 9628-9633, 2019 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-31019093

RESUMO

GGGGCC (G4C2) repeat expansion in C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). One class of major pathogenic molecules in C9ORF72-ALS/FTD is dipeptide repeat proteins such as poly(GR), whose toxicity has been well documented in cellular and animal models. However, it is not known how poly(GR) toxicity can be alleviated, especially in patient neurons. Using Drosophila as a model system in an unbiased genetic screen, we identified a number of genetic modifiers of poly(GR) toxicity. Surprisingly, partial loss of function of Ku80, an essential DNA repair protein, suppressed poly(GR)-induced retinal degeneration in flies. Ku80 expression was greatly elevated in flies expressing poly(GR) and in C9ORF72 iPSC-derived patient neurons. As a result, the levels of phosphorylated ATM and P53 as well as other downstream proapoptotic proteins such as PUMA, Bax, and cleaved caspase-3 were all significantly increased in C9ORF72 patient neurons. The increase in the levels of Ku80 and some downstream signaling proteins was prevented by CRISPR-Cas9-mediated deletion of expanded G4C2 repeats. More importantly, partial loss of function of Ku80 in these neurons through CRISPR/Cas9-mediated ablation or small RNAs-mediated knockdown suppressed the apoptotic pathway. Thus, partial inhibition of the overactivated Ku80-dependent DNA repair pathway is a promising therapeutic approach in C9ORF72-ALS/FTD.

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