Fast versus slow disease progression in amyotrophic lateral sclerosis–clinical and genetic factors at the edges of the survival spectrum

Witzel, Simon; Wagner, Matias; Zhao, Chen; Kandler, Katharina; Graf, Elisabeth; Berutti, Riccardo; Oexle, Konrad; Brenner, Dávid; Winkelmann, Juliane; Ludolph, Albert C.

doi:10.1016/j.neurobiolaging.2022.07.005

Cited by 7 publications

(2 citation statements)

References 41 publications

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“…2B ) between brain tissues from different individuals suggests that heterogeneity in ALS may extend to TDP-43-related splicing changes. It is likely that the heterogeneity in DEU/cryptic exon expression in tissue is underpinned by the same factors, such as regional TDP-43 aggregate load (84) and genetic causes/ modifiers (85, 86), that drive clinical heterogeneity of ALS.…”

Section: Discussionmentioning

confidence: 99%

A panel of TDP-43-regulated splicing events verify loss of TDP-43 function in amyotrophic lateral sclerosis brain tissue

Cao

Ryan

et al. 2023

Preprint

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TDP-43 dysfunction is a molecular hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). A major hypothesis of TDP-43 dysfunction in disease is the loss of normal nuclear function, resulting in impaired RNA regulation and the emergence of cryptic exons. Cryptic exons and exon changes are emerging as promising markers of lost TDP-43 function in addition to revealing biological pathways involved in neurodegeneration in ALS/FTD. Here, we investigated TDP-43 loss of function by depleting TARDBP from human post-mortem brain pericytes and identifying differential exon usage events with RNA-sequencing analysis. Differential exon usage events validated by qPCR were compiled into a panel with other well-established TDP-43 loss-of-function exon markers and then tested in ALS and control motor cortex tissue. We find that profiles of TDP-43-related cryptic exons and changed exon usage discriminate ALS brain tissue from controls, and propose that splicing panels may have predictive value for therapeutic intervention.

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Section: Discussionmentioning

confidence: 99%

A panel of TDP-43-regulated splicing events verify loss of TDP-43 function in amyotrophic lateral sclerosis brain tissue

Cao

Ryan

et al. 2023

Preprint

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“…During the course of ALS, all voluntary muscles are eventually affected, including the respiratory muscles, and the disease is usually fatal within 2-5 years of symptom onset. There is a relatively small subgroup of patients that demonstrate slower disease progression, surviving even beyond 10 years (Witzel et al 2022). Recently, the possibility was suggested that disease course becomes slower over time (Czaplinski et al 2006).…”

Section: Introduction 11 Als Disease Featuresmentioning

confidence: 99%

DALSO: domain ALS ontology

Podsiadły-Marczykowska,

Andersen,

Gromicho

et al. 2024

Preprint

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Amyotrophic lateral sclerosis (ALS) is an incurable, rapidly progressive neurodegenerative disease. During the course of ALS, virtually all skeletal muscles are gradually affected, including the respiratory muscles, and the disease is usually fatal within 2–5 years of symptom onset. Unequivocal and conclusive tests for ALS do not exist, its disease etiology is still unknown, and therapeutic options are limited. This paper presents the ALS domain ontology (DALSO), model containing formalized, semantic descriptions of a wide range of modeled disease related notions such as patient demographics, clinical findings and history, disease clinical features and diagnostic classifications, risk factors, genetics and pathophysiological mechanisms of motor neuron degeneration. The DALSO’s aim and information scope, design assumption, structure and implementation details are also described. DALSO covers the broad range of significant biomedical concepts ranging from clinical to molecular feature of the modeled disease, it represents a comprehensive, structured knowledge source for the ALS disease domain. To the best of authors’ knowledge, the DALSO is the first attempt to develop a formal, computational model representing knowledge of this fatal motor neuron disease. It provides the means for integrating and annotating clinical and research data, not only at the generic domain knowledge level, but also at the level of individual patient case studies. The DALSO is expressed in OWL2 language, contains 910 classes, is consistent and free of logical errors. Its syntactic correctness was validated by the Fact++ reasoner.

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Unveiling the SOD1-mediated ALS phenotype: insights from a comprehensive meta-analysis

Domi,

Schito,

Sferruzza

et al. 2023

J Neurol

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Fast versus slow disease progression in amyotrophic lateral sclerosis–clinical and genetic factors at the edges of the survival spectrum

Cited by 7 publications

References 41 publications

A panel of TDP-43-regulated splicing events verify loss of TDP-43 function in amyotrophic lateral sclerosis brain tissue

A panel of TDP-43-regulated splicing events verify loss of TDP-43 function in amyotrophic lateral sclerosis brain tissue

DALSO: domain ALS ontology

Unveiling the SOD1-mediated ALS phenotype: insights from a comprehensive meta-analysis

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