Loss of function of C9orf72 causes motor deficits in a zebrafish model of Amyotrophic Lateral Sclerosis

2013 ◽  
pp. n/a-n/a ◽  
Author(s):  
Sorana Ciura ◽  
Serena Lattante ◽  
Isabelle Le Ber ◽  
Morwena Latouche ◽  
Hervé Tostivint ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Deficits ◽  
Loss Of Function ◽  
Zebrafish Model ◽  
Lateral Sclerosis

scholarly journals The Link between VAPB Loss of Function and Amyotrophic Lateral Sclerosis

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1865
Author(s):  
Nica Borgese ◽  
Nicola Iacomino ◽  
Sara Francesca Colombo ◽  
Francesca Navone
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Adaptor Proteins ◽  
Loss Of Function ◽  
Membrane Contact Sites ◽  
Physiological Processes ◽  
Main Driver ◽  
Single Allele ◽  
Induced Pluripotent ◽  
Lateral Sclerosis

The VAP proteins are integral adaptor proteins of the endoplasmic reticulum (ER) membrane that recruit a myriad of interacting partners to the ER surface. Through these interactions, the VAPs mediate a large number of processes, notably the generation of membrane contact sites between the ER and essentially all other cellular membranes. In 2004, it was discovered that a mutation (p.P56S) in the VAPB paralogue causes a rare form of dominantly inherited familial amyotrophic lateral sclerosis (ALS8). The mutant protein is aggregation-prone, non-functional and unstable, and its expression from a single allele appears to be insufficient to support toxic gain-of-function effects within motor neurons. Instead, loss-of-function of the single wild-type allele is required for pathological effects, and VAPB haploinsufficiency may be the main driver of the disease. In this article, we review the studies on the effects of VAPB deficit in cellular and animal models. Several basic cell physiological processes are affected by downregulation or complete depletion of VAPB, impinging on phosphoinositide homeostasis, Ca2+ signalling, ion transport, neurite extension, and ER stress. In the future, the distinction between the roles of the two VAP paralogues (A and B), as well as studies on motor neurons generated from induced pluripotent stem cells (iPSC) of ALS8 patients will further elucidate the pathogenic basis of p.P56S familial ALS, as well as of other more common forms of the disease.

“My World Has Expanded Even Though I'm Stuck at Home”: Experiences of Individuals With Amyotrophic Lateral Sclerosis Who Use Augmentative and Alternative Communication and Social Media

2015 ◽  
Vol 24 (4) ◽  
pp. 680-695 ◽  
Author(s):  
Jessica Caron ◽  
Janice Light
Keyword(s):  
Social Media ◽  
Amyotrophic Lateral Sclerosis ◽  
Augmentative And Alternative Communication ◽  
Future Research ◽  
Loss Of Function ◽  
Alternative Communication ◽  
Communication Modes ◽  
Communication Needs ◽  
Use Of Social Media ◽  
Lateral Sclerosis

PurposeThis study aimed to expand the current understanding of how persons with amyotrophic lateral sclerosis (pALS) use augmentative and alternative communication and social media to address their communication needs.MethodAn online focus group was used to investigate the experiences of 9 pALS who use augmentative and alternative communication and social media. Questions posed to the group related to (a) current use of social media, (b) advantages of social media, (c) barriers to independent use, (d) supports to independent use, and (e) recommendations for developers, policy makers, and other pALS.ResultsParticipants primarily reported that use of social media was a beneficial tool that provided increased communication opportunities, connections to communication partners, and networks of support. Specific results are discussed with reference to the research as well as implications for practice and recommendations for future research.ConclusionsAs individuals with ALS experience loss of function, some communication modes may no longer be viable. Providing access to different modes of communication, including social media, can allow independence, participation and better quality of life.

scholarly journals Concomitant gain and loss of function pathomechanisms in C9ORF72 amyotrophic lateral sclerosis

2021 ◽  
Vol 4 (4) ◽  
pp. e202000764
Author(s):  
Arun Pal ◽  
Benedikt Kretner ◽  
Masin Abo-Rady ◽  
Hannes Glaβ ◽  
Banaja P Dash ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Loss Of Function ◽  
Dna Double Strand Breaks ◽  
Hexanucleotide Repeat ◽  
Rna Foci ◽  
Repeat Expansions ◽  
Organelle Motility ◽  
Trafficking Defects ◽  
Induced Pluripotent ◽  
Lateral Sclerosis

Intronic hexanucleotide repeat expansions (HREs) in C9ORF72 are the most frequent genetic cause of amyotrophic lateral sclerosis, a devastating, incurable motoneuron (MN) disease. The mechanism by which HREs trigger pathogenesis remains elusive. The discovery of repeat-associated non-ATG (RAN) translation of dipeptide repeat proteins (DPRs) from HREs along with reduced exonic C9ORF72 expression suggests gain of toxic functions (GOFs) through DPRs versus loss of C9ORF72 functions (LOFs). Through multiparametric high-content (HC) live profiling in spinal MNs from induced pluripotent stem cells and comparison to mutant FUS and TDP43, we show that HRE C9ORF72 caused a distinct, later spatiotemporal appearance of mainly proximal axonal organelle motility deficits concomitant to augmented DNA double-strand breaks (DSBs), RNA foci, DPRs, and apoptosis. We show that both GOFs and LOFs were necessary to yield the overall C9ORF72 pathology. Increased RNA foci and DPRs concurred with onset of axon trafficking defects, DSBs, and cell death, although DSB induction itself did not phenocopy C9ORF72 mutants. Interestingly, the majority of LOF-specific DEGs were shared with HRE-mediated GOF DEGs. Finally, C9ORF72 LOF was sufficient—albeit to a smaller extent—to induce premature distal axonal trafficking deficits and increased DSBs.

scholarly journals Frontal Anatomical Correlates of Cognitive and Speech Motor Deficits in Amyotrophic Lateral Sclerosis

2019 ◽  
Vol 2019 ◽  
pp. 1-11 ◽  
Author(s):  
Yana Yunusova ◽  
Jamal Ansari ◽  
Joel Ramirez ◽  
Sanjana Shellikeri ◽  
Greg J. Stanisz ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Frontal Lobe ◽  
Speech Rate ◽  
Neuropsychological Testing ◽  
Partial Least Square ◽  
Least Square ◽  
Speaking Rate ◽  
Motor Deficits ◽  
Brain Changes ◽  
Lateral Sclerosis

The goal of this study was to identify neurostructural frontal lobe correlates of cognitive and speaking rate changes in amyotrophic lateral sclerosis (ALS). 17 patients diagnosed with ALS and 12 matched controls underwent clinical, bulbar, and neuropsychological assessment and structural neuroimaging. Neuropsychological testing was performed via a novel computerized frontal battery (ALS-CFB), based on a validated theoretical model of frontal lobe functions, and focused on testing energization, executive function, emotion processing, theory of mind, and behavioral inhibition via antisaccades. The measure of speaking rate represented bulbar motor changes. Neuroanatomical assessment was performed using volumetric analyses focused on frontal lobe regions, postcentral gyrus, and occipital lobes as controls. Partial least square regressions (PLS) were used to predict behavioral (cognitive and speech rate) outcomes using volumetric measures. The data supported the overall hypothesis that distinct behavioral changes in cognition and speaking rate in ALS were related to specific regional neurostructural brain changes. These changes did not support a notion of a general dysexecutive syndrome in ALS. The observed specificity of behavior-brain changes can begin to provide a framework for subtyping of ALS. The data also support a more integrative framework for clinical assessment of frontal lobe functioning in ALS, which requires both behavioral testing and neuroimaging.

The motor neurone disorders

2011 ◽  
Author(s):  
Pamela Shaw
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Muscular Atrophy ◽  
Motor Neurone ◽  
System Control ◽  
Loss Of Function ◽  
The United Kingdom ◽  
System Degeneration ◽  
Motor Neurones ◽  
Related Group ◽  
Lateral Sclerosis

The motor neurone diseases are a group of disorders in which there is selective loss of function of upper and/or lower motor neurones in the motor cortex, brainstem, and spinal cord resulting in impairment in the nervous system control of voluntary movement. The term ‘motor neurone disease’, often abbreviated to ‘MND’, is used differently in different countries. In the United Kingdom it is used as an umbrella term to cover the related group of neurodegenerative disorders including amyotrophic lateral sclerosis, the commonest variant, as well as progressive muscular atrophy, primary lateral sclerosis, and progressive bulbar palsy. However, in many other countries amyotrophic lateral sclerosis, referred to as ALS, has been adopted as the umbrella term for this group of clinical variants of motor system degeneration. There is a tendency now internationally to use the ALS/MND abbreviation to cover this group of conditions. Careful diagnosis within the motor neurone diseases is essential for advising about prognosis, potential genetic implications, and for identifying those with acquired lower motor neurone syndromes who may benefit for the administration of immunomodulatory therapy.

A novel alternative splicing event rescues the mutant tardbp phenotype in a zebrafish model of TDP-43 related Amyotrophic Lateral Sclerosis (ALS) (P03.180)

Neurology ◽  
2012 ◽  
Vol 78 (Meeting Abstracts 1) ◽  
pp. P03.180-P03.180
Author(s):  
C. Hewamadduma ◽  
A. Grierson ◽  
C. Moens ◽  
L. Pan ◽  
T. Ma ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Alternative Splicing ◽  
Zebrafish Model ◽  
Lateral Sclerosis

scholarly journals Nuclear depletion of RNA binding protein ELAVL3 (HuC) in sporadic and familial amyotrophic lateral sclerosis

2021 ◽  
Author(s):  
Sandra Diaz-Garcia ◽  
Vivian I. Ko ◽  
Sonia Vazquez-Sanchez ◽  
Ruth Chia ◽  
Olubankole Aladesuyi Arogundade ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Rna Binding ◽  
Binding Protein ◽  
Rna Binding Protein ◽  
Loss Of Function ◽  
Cryptic Exon ◽  
Protein Levels ◽  
Sporadic Als ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis is a progressive fatal neurodegenerative disease caused by loss of motor neurons and characterized neuropathologically in almost all cases by nuclear depletion and cytoplasmic aggregation of TDP-43, a nuclear RNA binding protein (RBP). We identified ELAVL3 as one of the most downregulated genes in our transcriptome profiles of laser captured microdissection of motor neurons from sporadic ALS nervous systems and the top dysregulated RBPs. Neuropathological characterizations showed ELAVL3 nuclear depletion in a great percentage of remnant motor neurons, sometimes accompanied by cytoplasmic accumulations. These abnormalities were common in sporadic cases with and without intermediate expansions in ATXN2 and familial cases carrying mutations in C9orf72 and SOD1. Depletion of ELAVL3 occurred at both the RNA and protein levels and a short protein isoform was identified but it is not related to a TDP-43-dependent cryptic exon in intron 3. Strikingly, ELAVL3 abnormalities were more frequent than TDP-43 abnormalities and occurred in motor neurons still with normal nuclear TDP-43 present, but all neurons with abnormal TDP-43 also had abnormal ELAVL3. In a neuron-like cell culture model using SH-SY5Y cells, ELAVL3 mislocalization occurred weeks before TDP-43 abnormalities were seen. We interrogated genetic databases but did not identify association of ELAVL3 genetic structure associated with ALS. Taken together, these findings suggest that ELAVL3 is an important RBP in ALS pathogenesis acquired early and the neuropathological data suggest it is involved by loss of function rather than cytoplasmic toxicity.

277 Disentangling corticobasal syndrome from corticobasal degeneration

2018 ◽  
Vol 89 (10) ◽  
pp. A40.4-A41
Author(s):  
Lamb Ruth ◽  
Rohrer Jonathan ◽  
Lubbe Steven ◽  
Weil Rimona ◽  
Lashley Tammaryn ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Family History ◽  
Primary Progressive Aphasia ◽  
Corticobasal Syndrome ◽  
Loss Of Function ◽  
Progressive Aphasia ◽  
Primary Progressive ◽  
Atypical Parkinsonian Syndrome ◽  
History Of ◽  
Lateral Sclerosis

Mutations in the TANK-binding kinase (TBK1) gene have been shown to cause frontotemporal dementia (FTLD) and amyotrophic lateral sclerosis (ALS). The phenotype is highly variable and has been associated with behavioural variant FTD, primary progressive aphasia and pure amyotrophic lateral sclerosis. We describe the clinical, anatomical and pathological features of a patient with onset of a corticobasal syndrome (CBS)/primary progressive aphasia overlap aged 59. The patient presented with progressive speech difficulties and later developed an asymmetric akinetic-rigid syndrome. Neuroimaging showed asymmetrical frontal atrophy, predominantly affecting the right side. There was a strong family history of neurodegenerative disease with 4/7 siblings developing either dementia or ALS in their 50’s-60’s. Following death at age 71, post mortem examination revealed FTLD TDP-43 type A pathology. Genetic screening did not reveal a mutation in the progranulin, microtubule-associated protein tau or C9orf72 genes. However exome sequencing revealed a novel E703X mutation in the TBK1 gene. Although segregation data was not available, this loss of function mutation is highly likely to be pathogenic. In conclusion, we show that TBK1 can be a cause of an atypical parkinsonian syndrome and screening for TBK1 should be considered in CBS patients with a family history of dementia, ALS or CBS.

scholarly journals Structural basis for mutation-induced destabilization of profilin 1 in ALS

2015 ◽  
Vol 112 (26) ◽  
pp. 7984-7989 ◽  
Author(s):  
Sivakumar Boopathy ◽  
Tania V. Silvas ◽  
Maeve Tischbein ◽  
Silvia Jansen ◽  
Shivender M. Shandilya ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Structural Basis ◽  
Loss Of Function ◽  
Native Conformation ◽  
Fatal Disease ◽  
X Ray ◽  
High Propensity ◽  
Pathological Mechanism ◽  
Lateral Sclerosis

Mutations in profilin 1 (PFN1) are associated with amyotrophic lateral sclerosis (ALS); however, the pathological mechanism of PFN1 in this fatal disease is unknown. We demonstrate that ALS-linked mutations severely destabilize the native conformation of PFN1 in vitro and cause accelerated turnover of the PFN1 protein in cells. This mutation-induced destabilization can account for the high propensity of ALS-linked variants to aggregate and also provides rationale for their reported loss-of-function phenotypes in cell-based assays. The source of this destabilization is illuminated by the X-ray crystal structures of several PFN1 proteins, revealing an expanded cavity near the protein core of the destabilized M114T variant. In contrast, the E117G mutation only modestly perturbs the structure and stability of PFN1, an observation that reconciles the occurrence of this mutation in the control population. These findings suggest that a destabilized form of PFN1 underlies PFN1-mediated ALS pathogenesis.

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