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primary lateral sclerosis AND frontotemporal dementia

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https://www.readbyqxmd.com/read/27776165/distinct-c9orf72-associated-dipeptide-repeat-structures-correlate-with-neuronal-toxicity
#1
Brittany N Flores, Mark E Dulchavsky, Amy Krans, Michael R Sawaya, Henry L Paulson, Peter K Todd, Sami J Barmada, Magdalena I Ivanova
Hexanucleotide repeat expansions in C9orf72 are the most common inherited cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The expansions elicit toxicity in part through repeat-associated non-AUG (RAN) translation of the intronic (GGGGCC)n sequence into dipeptide repeat-containing proteins (DPRs). Little is known, however, about the structural characteristics and aggregation propensities of the dipeptide units comprising DPRs. To address this question, we synthesized dipeptide units corresponding to the three sense-strand RAN translation products, analyzed their structures by circular dichroism, electron microscopy and dye binding assays, and assessed their relative toxicity when applied to primary cortical neurons...
2016: PloS One
https://www.readbyqxmd.com/read/27768524/c9orf72-plays-a-central-role-in-rab-gtpase-dependent-regulation-of-autophagy
#2
Christopher P Webster, Emma F Smith, Andrew J Grierson, Kurt J De Vos
A GGGGCC hexanucleotide repeat expansion in the first intron of the C9orf72 gene is the most common genetic defect associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (C9ALS/FTD). Haploinsufficiency and a resulting loss of C9orf72 protein function has been suggested as a possible pathogenic mechanism in C9ALS/FTD. C9ALS/FTD patients exhibit specific ubiquitin and p62/sequestosome-1 positive but TDP-43 negative inclusions in the cerebellum and hippocampus, indicating possible autophagy deficits in these patients...
October 21, 2016: Small GTPases
https://www.readbyqxmd.com/read/27659605/rna-binding-proteins-implicated-in-neurodegenerative-diseases
#3
Mark R Cookson
Gene expression is regulated at many levels, including after generation of the primary RNA transcript from DNA but before translation into protein. Such post-translational gene regulation occurs via the action of a multitude of RNA binding proteins and include varied actions from splicing to regulation of association with the translational machinery. Primary evidence that such processes might contribute to disease mechanisms in neurodegenerative disorders comes from the observation of mutations in RNA binding proteins, particularly in diseases in the amyotrophic lateral sclerosis-frontotemporal dementia spectrum and in some forms of ataxia and tremor...
September 23, 2016: Wiley Interdisciplinary Reviews. RNA
https://www.readbyqxmd.com/read/27556379/are-astrocytes-executive-cells-within-the-central-nervous-system
#4
Roberto E Sica, Roberto Caccuri, Cecilia Quarracino, Francisco Capani
Experimental evidence suggests that astrocytes play a crucial role in the physiology of the central nervous system (CNS) by modulating synaptic activity and plasticity. Based on what is currently known we postulate that astrocytes are fundamental, along with neurons, for the information processing that takes place within the CNS. On the other hand, experimental findings and human observations signal that some of the primary degenerative diseases of the CNS, like frontotemporal dementia, Parkinson's disease, Alzheimer's dementia, Huntington's dementia, primary cerebellar ataxias and amyotrophic lateral sclerosis, all of which affect the human species exclusively, may be due to astroglial dysfunction...
August 2016: Arquivos de Neuro-psiquiatria
https://www.readbyqxmd.com/read/27543771/survival-in-the-pre-senile-dementia-frontotemporal-lobar-degeneration-with-tdp-43-proteinopathy-effects-of-genetic-demographic-and-neuropathological-variables
#5
R A Armstrong
Factors associated with survival were studied in 84 neuropathologically documented cases of the pre-senile dementia frontotemporal dementia lobar degeneration (FTLD) with transactive response (TAR) DNA-binding protein of 43 kDa (TDP-43) proteinopathy (FTLD-TDP). Kaplan-Meier survival analysis estimated mean survival as 7.9 years (range: 1-19 years, SD = 4.64). Familial and sporadic cases exhibited similar survival, including progranulin (GRN) gene mutation cases. No significant differences in survival were associated with sex, disease onset, Braak disease stage, or disease subtype, but higher survival was associated with lower post-mortem brain weight...
2016: Folia Neuropathologica
https://www.readbyqxmd.com/read/27488596/tdp-43-pathology-and-cognition-in-als-a-prospective-clinicopathologic-correlation-study
#6
Johannes Prudlo, Jochem König, Christina Schuster, Elisabeth Kasper, Andreas Büttner, Stefan Teipel, Manuela Neumann
OBJECTIVE: Although a systematic spread of pathologic TDP-43 expression throughout the CNS in amyotrophic lateral sclerosis (ALS) has been proposed, the relationship between cognition and the extent and neuroanatomic distribution of TDP-43 pathology has not received considerable attention. METHODS: We investigated the association between cognitive functioning and the extent of TDP-43 pathology in postmortem CNS tissue from 18 patients with ALS stratified into 3 groups based on detailed prospective neuropsychological testing (cognitively not impaired, n = 6; cognitively impaired, n = 6; ALS- frontotemporal dementia [FTD], n = 6) and analyzed these cases for clinicopathologic correlations...
September 6, 2016: Neurology
https://www.readbyqxmd.com/read/27450455/pathogenesis-of-amyotrophic-lateral-sclerosis
#7
REVIEW
Sarah Morgan, Richard W Orrell
INTRODUCTION: Amyotrophic lateral sclerosis (ALS) or motor neuron disease is a rapidly progressive neurodegenerative disorder. The primary involvement is of motor neurons in the brain, spinal cord and peripherally. There is secondary weakness of muscles and primary involvement of other brain regions, especially involving cognition. SOURCES OF DATA: Peer-reviewed journal articles and reviews. PubMed.gov AREAS OF AGREEMENT: The pathogenesis of ALS remains largely unknown...
September 2016: British Medical Bulletin
https://www.readbyqxmd.com/read/27334615/the-c9orf72-protein-interacts-with-rab1a-and-the-ulk1-complex-to-regulate-initiation-of-autophagy
#8
Christopher P Webster, Emma F Smith, Claudia S Bauer, Annekathrin Moller, Guillaume M Hautbergue, Laura Ferraiuolo, Monika A Myszczynska, Adrian Higginbottom, Matthew J Walsh, Alexander J Whitworth, Brian K Kaspar, Kathrin Meyer, Pamela J Shaw, Andrew J Grierson, Kurt J De Vos
A GGGGCC hexanucleotide repeat expansion in the C9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia (C9ALS/FTD). C9orf72 encodes two C9orf72 protein isoforms of unclear function. Reduced levels of C9orf72 expression have been reported in C9ALS/FTD patients, and although C9orf72 haploinsufficiency has been proposed to contribute to C9ALS/FTD, its significance is not yet clear. Here, we report that C9orf72 interacts with Rab1a and the Unc-51-like kinase 1 (ULK1) autophagy initiation complex...
August 1, 2016: EMBO Journal
https://www.readbyqxmd.com/read/27144467/the-clinical-spectrum-of-sporadic-and-familial-forms-of-frontotemporal-dementia
#9
REVIEW
Ione O C Woollacott, Jonathan D Rohrer
The term frontotemporal dementia (FTD) describes a clinically, genetically and pathologically diverse group of neurodegenerative disorders. Symptoms of FTD can present in individuals in their 20s through to their 90s, but the mean age at onset is in the sixth decade. The most common presentation is with a change in personality and impaired social conduct (behavioural variant FTD). Less frequently patients present with language problems (primary progressive aphasia). Both of these groups of patients can develop motor features consistent with either motor neuron disease (usually the amyotrophic lateral sclerosis variant) or parkinsonism (most commonly a progressive supranuclear palsy or corticobasal syndrome)...
August 2016: Journal of Neurochemistry
https://www.readbyqxmd.com/read/26903389/the-role-of-apoe-in-the-occurrence-of-frontotemporal-dementia-in-amyotrophic-lateral-sclerosis
#10
Adriano Chiò, Maura Brunetti, Marco Barberis, Barbara Iazzolino, Anna Montuschi, Antonio Ilardi, Stefania Cammarosano, Antonio Canosa, Cristina Moglia, Andrea Calvo
IMPORTANCE: Amyotrophic lateral sclerosis (ALS) is a heterogeneous disease with a wide spectrum of involvement of cognitive functions. The mechanisms of this heterogeneity are still largely unknown, but genetic variants may account for this variability. OBJECTIVE: To assess the influence of the apolipoprotein E (APOE) and C9ORF72 genotypes on cognitive impairment in a population-based series of Italian patients with ALS. DESIGN, SETTING, AND PARTICIPANTS: All 504 patients with ALS living in Piemonte, Italy, diagnosed between January 1, 2009, and December 31, 2013, and identified through the Piemonte and Valle d'Aosta register for ALS, were eligible to participate in the study...
April 2016: JAMA Neurology
https://www.readbyqxmd.com/read/26810719/atypical-parkinsonism-in-c9orf72-expansions-a-case-report-and-systematic-review-of-45-cases-from-the-literature
#11
Carlo Wilke, Jörn K Pomper, Saskia Biskup, Cornelia Puskás, Daniela Berg, Matthis Synofzik
While C9orf72 repeat expansions usually present with frontotemporal dementia (FTD) and/or amyotrophic lateral sclerosis (ALS), an increasing number of reports suggests that the primary phenotype of C9orf72 patients may also include movement disorders. We here provide the first systematic clinical characterisation of C9orf72-associated parkinsonism. We report a C9orf72 expansion carrier presenting with a clinical syndrome of progressive supranuclear palsy (PSP), pronounced mesencephalic atrophy on MRI and PSP-characteristic electrooculography findings...
March 2016: Journal of Neurology
https://www.readbyqxmd.com/read/26789001/profiling-speech-and-pausing-in-amyotrophic-lateral-sclerosis-als-and-frontotemporal-dementia-ftd
#12
COMPARATIVE STUDY
Yana Yunusova, Naida L Graham, Sanjana Shellikeri, Kent Phuong, Madhura Kulkarni, Elizabeth Rochon, David F Tang-Wai, Tiffany W Chow, Sandra E Black, Lorne H Zinman, Jordan R Green
OBJECTIVE: This study examines reading aloud in patients with amyotrophic lateral sclerosis (ALS) and those with frontotemporal dementia (FTD) in order to determine whether differences in patterns of speaking and pausing exist between patients with primary motor vs. primary cognitive-linguistic deficits, and in contrast to healthy controls. DESIGN: 136 participants were included in the study: 33 controls, 85 patients with ALS, and 18 patients with either the behavioural variant of FTD (FTD-BV) or progressive nonfluent aphasia (FTD-PNFA)...
2016: PloS One
https://www.readbyqxmd.com/read/26602023/cognitive-impairment-in-amyotrophic-lateral-sclerosis-clues-from-the-sod1-mouse
#13
REVIEW
Alida Spalloni, Patrizia Longone
Amyotrophic lateral sclerosis (ALS) is now recognized as a multisystem disorder, in which the primary pathology is the degeneration of motor neurons, with cognitive and/or behavioral dysfunctions that constitutes the non-motor manifestations of ALS. The combination of clinical, neuroimaging, and neuropathological data, and detailed genetic studies suggest that ALS and frontotemporal dementia (FTD) might form part of a disease continuum, with pure ALS and pure FTD at the two extremes. Mutations in the superoxide dismutase 1 (SOD1) gene were the first genetic mutations linked to the insurgence of ALS...
January 2016: Neuroscience and Biobehavioral Reviews
https://www.readbyqxmd.com/read/26408000/c9orf72-expression-and-cellular-localization-over-mouse-development
#14
Rachel A K Atkinson, Carmen M Fernandez-Martos, Julie D Atkin, James C Vickers, Anna E King
INTRODUCTION: A majority of familial frontotemporal lobar dementia and amyotrophic lateral sclerosis cases are associated with a large repeat expansion in a non-coding region of the C9ORF72 gene. Currently, little is known about the normal function and the expression pattern of the C9ORF72 protein. The aims of this study were to characterize the expression pattern and cellular localization of the three reported mouse isoforms of C9orf72, over a developmental time-course in primary cultured cortical neurons and brain tissue from C57BL/6 mice...
2015: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/26344877/the-chchd10-p34s-variant-is-not-associated-with-als-in-a-uk-cohort-of-familial-and-sporadic-patients
#15
Chun Hao Wong, Simon Topp, Athina Soragia Gkazi, Claire Troakes, Jack W Miller, Martina de Majo, Janine Kirby, Pamela J Shaw, Karen E Morrison, Jacqueline de Belleroche, Caroline A Vance, Ammar Al-Chalabi, Safa Al-Sarraj, Christopher E Shaw, Bradley N Smith
Mutations in CHCHD10 have recently been reported as a cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. To address the genetic contribution of CHCHD10 to ALS, we have screened a cohort of 425 UK ALS ± frontotemporal dementia patients and 576 local controls in all coding exons of CHCHD10 by Sanger sequencing. We identified a previously reported p.P34S variant that is also present in neurologically healthy controls (p = 0.58). Our results suggest that CHCHD10 is not a primary cause of ALS in UK cases...
October 2015: Neurobiology of Aging
https://www.readbyqxmd.com/read/26308899/ggggcc-repeat-expansion-in-c9orf72-compromises-nucleocytoplasmic-transport
#16
Brian D Freibaum, Yubing Lu, Rodrigo Lopez-Gonzalez, Nam Chul Kim, Sandra Almeida, Kyung-Ha Lee, Nisha Badders, Marc Valentine, Bruce L Miller, Philip C Wong, Leonard Petrucelli, Hong Joo Kim, Fen-Biao Gao, J Paul Taylor
The GGGGCC (G4C2) repeat expansion in a noncoding region of C9orf72 is the most common cause of sporadic and familial forms of amyotrophic lateral sclerosis and frontotemporal dementia. The basis for pathogenesis is unknown. To elucidate the consequences of G4C2 repeat expansion in a tractable genetic system, we generated transgenic fly lines expressing 8, 28 or 58 G4C2-repeat-containing transcripts that do not have a translation start site (AUG) but contain an open-reading frame for green fluorescent protein to detect repeat-associated non-AUG (RAN) translation...
September 3, 2015: Nature
https://www.readbyqxmd.com/read/26270072/neurodegeneration-and-identity
#17
Nina Strohminger, Shaun Nichols
There is a widespread notion, both within the sciences and among the general public, that mental deterioration can rob individuals of their identity. Yet there have been no systematic investigations of what types of cognitive damage lead people to appear to no longer be themselves. We measured perceived identity change in patients with three kinds of neurodegenerative disease: frontotemporal dementia, Alzheimer's disease, and amyotrophic lateral sclerosis. Structural equation models revealed that injury to the moral faculty plays the primary role in identity discontinuity...
September 2015: Psychological Science
https://www.readbyqxmd.com/read/26227992/the-big-bluff-of-amyotrophic-lateral-sclerosis-diagnosis-the-role-of-neurodegenerative-disease-mimics
#18
REVIEW
Ilaria Bicchi, Carla Emiliani, Angelo Vescovi, Sabata Martino
Neurodegenerative diseases include a significant number of pathologies affecting the nervous system. Generally, the primary cause of each disease is specific; however, recently, it was shown that they may be correlated at molecular level. This aspect, together with the exhibition of similar symptoms, renders the diagnosis of these disorders difficult. Amyotrophic lateral sclerosis is one of these pathologies. Herein, we report several cases of amyotrophic lateral sclerosis misdiagnosed as a consequence of features that are common to several neurodegenerative diseases, such as Parkinson's, Huntington's and Alzheimer's disease, spinal muscular atrophy, progressive bulbar palsy, spastic paraplegia and frontotemporal dementia, and mostly with the lysosomal storage disorder GM2 gangliosidosis...
2015: Neuro-degenerative Diseases
https://www.readbyqxmd.com/read/26223148/motor-function-and-behaviour-across-the-als-ftd-spectrum
#19
D De Silva, S Hsieh, J Caga, F V C Leslie, M C Kiernan, J R Hodges, E Mioshi, J R Burrell
BACKGROUND: Behavioural/functional disturbances, characteristic of frontotemporal dementia (FTD), are also a feature of amyotrophic lateral sclerosis (ALS) and patients with combined ALS and FTD (FTD-ALS). AIM OF THE STUDY: To investigate the progression of behavioural disturbances in ALS and FTD using the FTD functional rating scale (FTDFRS). METHODS: Patients with ALS, FTD-ALS and FTD were recruited from specialist clinics. Baseline assessments included the FTDFRS and the ALS functional rating scale-revised (ALSFRS-R)...
May 2016: Acta Neurologica Scandinavica
https://www.readbyqxmd.com/read/26221742/the-ubiquitin-proteasome-system-as-a-potential-therapeutic-target-for-treatment-of-neurodegenerative-diseases
#20
REVIEW
Alena Opattova, Martin Cente, Michal Novak, Peter Filipcik
Impairment of "protein quality control" in neurons is associated with etiopathogenesis of neurodegenerative diseases. The worn-out products of cell metabolism should be safely eliminated via the proteasome, autophago-lysosome and exocytosis. Insufficient activity of these degradation mechanisms within neurons leads to the accumulation of toxic protein oligomers, which represent a starting material for development of neurodegenerative proteinopathy. The spectrum of CNS linked proteinopathies is particularly broad and includes Alzheimer's disease (AD), Parkinson's disease (PD), Lewy body dementia, Pick disease, Frontotemporal dementia, Huntington disease, Amyotrophic lateral sclerosis and many others...
October 2015: General Physiology and Biophysics
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