共查询到20条相似文献,搜索用时 15 毫秒
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Zhengrui Xi Ming Zhang Amalia C. Bruni Raffaele G. Maletta Rosanna Colao Pietro Fratta James M. Polke Mary G. Sweeney Ese Mudanohwo Benedetta Nacmias Sandro Sorbi Maria Carmela Tartaglia Innocenzo Rainero Elisa Rubino Lorenzo Pinessi Daniela Galimberti Ezequiel I. Surace Philip McGoldrick Paul McKeever Danielle Moreno Christine Sato Yan Liang Julia Keith Lorne Zinman Janice Robertson Ekaterina Rogaeva 《Acta neuropathologica》2015,129(5):715-727
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Brettschneider J Van Deerlin VM Robinson JL Kwong L Lee EB Ali YO Safren N Monteiro MJ Toledo JB Elman L McCluskey L Irwin DJ Grossman M Molina-Porcel L Lee VM Trojanowski JQ 《Acta neuropathologica》2012,123(6):825-839
C9ORF72-hexanucleotide repeat expansions and ubiquilin-2 (UBQLN2) mutations are recently identified genetic markers in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). We investigate the relationship between C9ORF72 expansions and the clinical phenotype and neuropathology of ALS and FTLD. Genetic analysis and immunohistochemistry (IHC) were performed on autopsy-confirmed ALS (N = 75), FTLD-TDP (N = 30), AD (N = 14), and controls (N = 11). IHC for neurodegenerative disease pathology consisted of C9ORF72, UBQLN, p62, and TDP-43. A C9ORF72 expansion was identified in 19.4 % of ALS and 31 % of FTLD-TDP cases. ALS cases with C9ORF72 expansions frequently showed a bulbar onset of disease (57 %) and more rapid disease progression to death compared to non-expansion cases. Staining with C9ORF72 antibodies did not yield specific pathology. UBQLN pathology showed a highly distinct pattern in ALS and FTLD-TDP cases with the C9ORF72 expansion, with UBQLN-positive cytoplasmic inclusions in the cerebellar granular layer and extensive UBQLN-positive aggregates and dystrophic neurites in the hippocampal molecular layer and CA regions. These UBQLN pathologies were sufficiently unique to allow correct prediction of cases that were later confirmed to have C9ORF72 expansions by genetic analysis. UBQLN pathology partially co-localized with p62, and to a minor extent with TDP-43 positive dystrophic neurites and spinal cord skein-like inclusions. Our data indicate a pathophysiological link between C9ORF72 expansions and UBQLN proteins in ALS and FTLD-TDP that is associated with a highly characteristic pattern of UBQLN pathology. Our study indicates that this pathology is associated with alterations in clinical phenotype, and suggests that the presence of C9ORF72 repeat expansions may indicate a worse prognosis in ALS. 相似文献
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Stephanie May Daniel Hornburg Martin H. Schludi Thomas Arzberger Kristin Rentzsch Benjamin M. Schwenk Friedrich A. Grässer Kohji Mori Elisabeth Kremmer Julia Banzhaf-Strathmann Matthias Mann Felix Meissner Dieter Edbauer 《Acta neuropathologica》2014,128(4):485-503
Hexanucleotide repeat expansion in C9orf72 is the most common pathogenic mutation in patients with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Despite the lack of an ATG start codon, the repeat expansion is translated in all reading frames into dipeptide repeat (DPR) proteins, which form insoluble, ubiquitinated, p62-positive aggregates that are most abundant in the cerebral cortex and cerebellum. To specifically analyze DPR toxicity and aggregation, we expressed DPR proteins from synthetic genes containing a start codon but lacking extensive GGGGCC repeats. Poly-Gly-Ala (GA) formed p62-positive cytoplasmic aggregates, inhibited dendritic arborization and induced apoptosis in primary neurons. Quantitative mass spectrometry analysis to identify poly-GA co-aggregating proteins revealed a significant enrichment of proteins of the ubiquitin–proteasome system. Among the other interacting proteins, we identified the transport factor Unc119, which has been previously linked to neuromuscular and axonal function, as a poly-GA co-aggregating protein. Strikingly, the levels of soluble Unc119 are strongly reduced upon poly-GA expression in neurons, suggesting a loss of function mechanism. Similar to poly-GA expression, Unc119 knockdown inhibits dendritic branching and causes neurotoxicity. Unc119 overexpression partially rescues poly-GA toxicity suggesting that poly-GA expression causes Unc119 loss of function. In C9orf72 patients, Unc119 is detectable in 9.5 % of GA inclusions in the frontal cortex, but only in 1.6 % of GA inclusions in the cerebellum, an area largely spared of neurodegeneration. A fraction of neurons with Unc119 inclusions shows loss of cytosolic staining. Poly-GA-induced Unc119 loss of function may thereby contribute to selective vulnerability of neurons with DPR protein inclusions in the pathogenesis of C9orf72 FTLD/ALS. 相似文献
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Frontotemporal lobar dementia (FTLD) is the most common cause of dementia in patients younger than 60 years of age, and causes
progressive neurodegeneration of the frontal and temporal lobes usually accompanied by devastating changes in language or
behavior in affected individuals. Mutations in the progranulin (GRN) gene account for a significant fraction of familial FTLD, and in the vast majority of cases, these mutations lead to reduced
expression of progranulin via nonsense-mediated mRNA decay. Progranulin is a secreted glycoprotein that regulates a diverse
range of cellular functions including cell proliferation, cell migration, and inflammation. Recent fundamental discoveries
about progranulin biology, including the findings that sortilin and tumor necrosis factor receptor (TNFR) are high affinity
progranulin receptors, are beginning to shed light on the mechanism(s) by which progranulin deficiency causes FTLD. This review
will explore how alterations in basic cellular functions due to PGRN deficiency, both intrinsic and extrinsic to neurons,
might lead to the development of FTLD. 相似文献
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R. M. Liscic L. T. Grinberg J. Zidar M. A. Gitcho N. J. Cairns 《European journal of neurology》2008,15(8):772-780
Major discoveries have been made in the recent past in the genetics, biochemistry and neuropathology of frontotemporal lobar degeneration (FTLD). TAR DNA-binding protein 43 (TDP-43), encoded by the TARDBP gene, has been identified as the major pathological protein of FTLD with ubiquitin-immunoreactive (ub-ir) inclusions (FTLD-U) with or without amyotrophic lateral sclerosis (ALS) and sporadic ALS. Recently, mutations in the TARDBP gene in familial and sporadic ALS have been reported which demonstrate that abnormal TDP-43 alone is sufficient to cause neurodegeneration. Several familial cases of FTLD-U, however, are now known to have mutations in the progranulin ( GRN ) gene, but granulin is not a component of the TDP-43- and ub-ir inclusions. Further, TDP-43 is found to be a component of the inclusions of an increasing number of neurodegenerative diseases. Other FTLD-U entities with TDP-43 proteinopathy include: FTLD-U with valosin-containing protein ( VCP ) gene mutation and FTLD with ALS linked to chromosome 9p. In contrast, chromosome 3-linked dementia, FTLD-U with chromatin modifying protein 2B ( CHMP2B ) mutation, has ub-ir, TDP-43-negative inclusions. In summary, recent discoveries have generated new insights into the pathogenesis of a spectrum of disorders called TDP-43 proteinopathies including: FTLD-U, FTLD-U with ALS, ALS, and a broadening spectrum of other disorders. It is anticipated that these discoveries and a revised nosology of FTLD will contribute toward an accurate diagnosis, and facilitate the development of new diagnostic tests and therapeutics. 相似文献
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Mandrioli Jessica Zucchi Elisabetta Martinelli Ilaria Van der Most Laura Gianferrari Giulia Moglia Cristina Manera Umberto Solero Luca Vasta Rosario Canosa Antonio Grassano Maurizio Brunetti Maura Mazzini Letizia De Marchi Fabiola Simonini Cecilia Fini Nicola Tupler Rossella Vinceti Marco Chiò Adriano Calvo Andrea 《Journal of neurology》2023,270(2):877-890
Journal of Neurology - To unveil clinical features, comorbidities, disease progression and prognostic factors in a population-based cohort of ALS patients carrying C9ORF72 expansion... 相似文献
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Murray ME DeJesus-Hernandez M Rutherford NJ Baker M Duara R Graff-Radford NR Wszolek ZK Ferman TJ Josephs KA Boylan KB Rademakers R Dickson DW 《Acta neuropathologica》2011,122(6):673-690
Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are part of a disease spectrum associated with TDP-43 pathology. Strong evidence supporting this is the existence of kindreds with family members affected by FTD, ALS or mixed features of FTD and ALS, referred to as FTD-MND. Some of these families have linkage to chromosome 9, with hexanucleotide expansion mutation in a noncoding region of C9ORF72. Discovery of the mutation defines c9FTD/ALS. Prior to discovery of mutations in C9ORF72, it was assumed that TDP-43 pathology in c9FTD/ALS was uniform. In this study, we examined the neuropathology and clinical features of 20 cases of c9FTD/ALS from a brain bank for neurodegenerative disorders. Included are six patients clinically diagnosed with ALS, eight FTD, one FTD-MND and four Alzheimer-type dementia. Clinical information was unavailable for one patient. Pathologically, the cases all had TDP-43 pathology, but there were three major pathologic groups: ALS, FTLD-MND and FTLD-TDP. The ALS cases were morphologically similar to typical sporadic ALS with almost no extramotor TDP-43 pathology; all had oligodendroglial cytoplasmic inclusions. The FTLD-MND showed predominantly Mackenzie Type 3 TDP-43 pathology, and all had ALS-like pathology in motor neurons, but more extensive extramotor pathology, with oligodendroglial cytoplasmic inclusions and infrequent hippocampal sclerosis. The FTLD-TDP cases had several features similar to FTLD-TDP due to mutations in the gene for progranulin, including Mackenzie Type 1 TDP-43 pathology with neuronal intranuclear inclusions and hippocampal sclerosis. FTLD-TDP patients were older and some were thought to have Alzheimer-type dementia. In addition to the FTD and ALS clinical presentations, the present study shows that c9FTD/ALS can have other presentations, possibly related to age of onset and the presence of hippocampal sclerosis. Moreover, there is pathologic heterogeneity not only between ALS and FTLD, but also within the FTLD group. Further studies are needed to address the molecular mechanism of clinical and pathological heterogeneity of c9FTD/ALS due to mutations in C9ORF72. 相似文献
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Savica R Adeli A Vemuri P Knopman DS Dejesus-Hernandez M Rademakers R Fields JA Whitwell J Jack CR Lowe V Petersen RC Boeve BF 《Archives of neurology》2012,69(9):1164-1169
BACKGROUND The hexanucleotide repeat in the chromosome 9 open reading frame 72 (C9ORF72) gene was recently discovered as the underlying genetic cause of many families with frontotemporal dementia (FTD) and/or amyotrophic lateral sclerosis (ALS) linked to chromosome 9 (c9FTD/ALS). We report the clinical, neuropsychologic, and neuroimaging findings of a family with the C9ORF72 mutation and clinical diagnoses bridging the FTD, parkinsonism, and ALS spectrum. OBJECTIVE To characterize the antemortem characteristics of a family with c9FTD/ALS associated with the GGGGCC repeat expansion in C9ORF72. DESIGN Clinical series. SETTING Tertiary care academic medical center. PATIENTS The members of a family affected by the mutation with features of FTD and/or ALS. MAIN OUTCOME MEASURES Clinical, neuropsychologic, and neuroimaging assessments. RESULTS All 3 examined subjects had the hexanucleotide expansion detected in C9ORF72. All had personality/behavioral changes early in the course of the disease. One case had levodopa-unresponsive parkinsonism, and 1 had ALS. Magnetic resonance imaging showed symmetric bilateral frontal, temporal, insular, and cingulate atrophy. CONCLUSIONS This report highlights the clinical and neuroimaging characteristics of a family with c9FTD/ALS. Further studies are needed to better understand the phenotypical variability and the cliniconeuroimaging-neuropathologic correlations. 相似文献
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Ross Jay P. Leblond Claire S. Laurent Sandra B. Spiegelman Dan Dionne-Laporte Alexandre Camu William Dupré Nicolas Dion Patrick A. Rouleau Guy A. 《Neurogenetics》2020,21(3):227-242
neurogenetics - “Oligogenic inheritance” is used to describe cases where more than one rare pathogenic variant is observed in the same individual. While multiple variants can alter... 相似文献