Ubiquitinated TDP-43 in Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis

Abstract

Ubiquitin-positive, tau- and α-synuclein–negative inclusions are hallmarks of frontotemporal lobar degeneration with ubiquitin-positive inclusions and amyotrophic lateral sclerosis. Although the identity of the ubiquitinated protein specific to either disorder was unknown, we showed that TDP-43 is the major disease protein in both disorders. Pathologic TDP-43 was hyper-phosphorylated, ubiquitinated, and cleaved to generate C-terminal fragments and was recovered only from affected central nervous system regions, including hippocampus, neocortex, and spinal cord. TDP-43 represents the common pathologic substrate linking these neurodegenerative disorders.

Keywords

Amyotrophic lateral sclerosisFrontotemporal lobar degenerationUbiquitinNeocortexNeurodegenerationPathologyTARDBPNeuroscienceSpinal cordFrontotemporal dementiaBiologyMedicineDiseaseSOD1GeneticsDementia

MeSH Terms

Amino Acid SequenceAmyotrophic Lateral SclerosisAntibodiesMonoclonalBrain ChemistryCerebral CortexDNA-Binding ProteinsDementiaFluorescent Antibody TechniqueHippocampusHumansImmunoblottingMolecular Sequence DataMotor NeuronsNeuronsPeptide FragmentsPhosphorylationSpinal CordUbiquitin

Affiliated Institutions

Related Publications

Frontotemporal lobar degeneration with motor neuron disease-type inclusions predominates in 76 cases of frontotemporal degeneration

Anne M. Lipton , Charles L. White , Eileen H. Bigio

This report presents the largest series of consecutive, neuropathologically confirmed cases of frontotemporal degeneration (FTD). Prior studies have found dementia lacking disti...

2004 Acta Neuropathologica 190 citations

Histopathological changes underlying frontotemporal lobar degeneration with clinicopathological correlation

Jing Shi , Catherine L. Shaw , Daniel du Plessis +12 more

We have investigated the pathological correlates of dementia in the brains from a consecutive series of 70 patients dying with a clinical diagnosis of frontotemporal lobar degen...

2005 Acta Neuropathologica 139 citations

Clinicopathological correlates in frontotemporal dementia

John R. Hodges , Rhys Davies , John H. Xuereb +5 more

Abstract The term frontotemporal dementia (FTD) encompasses a range of clinical syndromes that are believed not to map reliably onto the spectrum of recognized pathologies. This...

2004 Annals of Neurology 578 citations

Amyotrophic lateral sclerosis: Part 1. Clinical features, pathology, and ethical issues in management

Rup Tandan , Walter G. Bradley

Abstract Amyotrophic lateral sclerosis (ALS) is a progressive degenerative disease of the motor system in adults that occurs in sporadic, familial, and Western Pacific forms. In...

1985 Annals of Neurology 369 citations

Ubiquitin Immunohistochemistry Suggests Classic Motor Neuron Disease, Motor Neuron Disease With Dementia, and Frontotemporal Dementia of the Motor Neuron Disease Type Represent a Clinicopathologic Spectrum

Ian R. Mackenzie , Howard Feldman

One of the characteristic pathologic changes in classic motor neuron disease (MND) is the presence of ubiquitin-immunoreactive (ub-ir) inclusions in the cytoplasm of lower motor...

2005 Journal of Neuropathology & Experimen... 159 citations

Publication Info

Year: 2006
Type: article
Volume: 314
Issue: 5796
Pages: 130-133
Citations: 6366
Access: Closed

External Links

Download PDF (Free) View on DOI.org PubMed Semantic Scholar

Social Impact

Altmetric

Ubiquitinated TDP-43 in Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis

PlumX Metrics

Social media, news, blog, policy document mentions

Citation Metrics

6366

OpenAlex

613

Influential

5615

CrossRef

Cite This

APA Style

                            
                                
                                    Manuela Neumann, 
                                
                                    Deepak M. Sampathu, 
                                
                                    Linda K. Kwong
                                
                                et al.
                            
                            (2006). 
                            Ubiquitinated TDP-43 in Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis. 
                            Science
                            , 314
                            (5796)
                            , 130-133.
                            https://doi.org/10.1126/science.1134108
                        

Identifiers

DOI: 10.1126/science.1134108
PMID: 17023659

Data Quality

Data completeness: 81%