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

  title={Ubiquitinated TDP-43 in Frontotemporal Lobar Degeneration and Amyotrophic Lateral Sclerosis},
  author={Manuela Neumann and Deepak M. Sampathu and Linda K. Kwong and Adam C. Truax and Matthew C. Micsenyi and Thomas T. t. Chou and Jennifer Bruce and Theresa Schuck and Murray Grossman and Christopher M. Clark and L. F. McCluskey and Bruce L. Miller and Eliezer Masliah and Ian R A Mackenzie and Howard A. Feldman and Wolfgang Feiden and Hans A. Kretzschmar and John Q. Trojanowski and Virginia M. -Y. Lee},
  pages={130 - 133}
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… 

TDP-43: a novel neurodegenerative proteinopathy

Phosphorylated TDP‐43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis

The aim of this study was to identify the phosphorylation sites and responsible kinases, and to clarify the pathological significance ofosphorylation of TDP‐43.

TMEM106B risk variant is implicated in the pathologic presentation of Alzheimer disease

Clinical, clinical, neuropsychological, and imaging studies suggested that the presence of TDP-43 pathology in AD may be associated with a modified phenotype, and a better understanding of what factors predispose to TSPs in AD is critical and could have important clinical implications.

[TDP-43 proteinopathies: ALS and frontotemporal dementias].

  • J. Prudlo
  • Biology
    Fortschritte der Neurologie-Psychiatrie
  • 2009
It is unclear whether the loss of the TDP-43's nuclear function or the gain of a toxic function outside its nucleus is disease causing, and several TARDBP-mutations have been identified as leading to the autosomal-dominant familial ALS (ALS 10), although no TARDPs have yet to be linked to FTLD.

Molecular Neuropathology of TDP-43 Proteinopathies

  • M. Neumann
  • Biology
    International journal of molecular sciences
  • 2009
This review summarizes the recent advances in understanding on the molecular neuropathology and pathobiology of TDP-43 in FTLD and ALS.

TDP-43 proteinopathy in frontotemporal lobar degeneration and amyotrophic lateral sclerosis: protein misfolding diseases without amyloidosis.

Herein, we review advances in understanding a group of disorders collectively known as TAR-DNA binding protein 43 (TDP-43) proteinopathies since the report that TDP-43 is the major disease protein

Frontotemporal lobar degeneration with ubiquitin-positive, but TDP-43-negative inclusions

Three cases of FTLD with ubiquitin- and p62-positive neuronal cytoplasmic inclusions confirmed the existence of TDP-43-negative FTLD-U and extend the clinical and pathological spectrum of this disorder.

Atypical frontotemporal lobar degeneration with ubiquitin-positive, TDP-43-negative neuronal inclusions.

Six cases of early onset FTD with FTLD-U pathology that was negative for TDP-43 are described, believing that these cases represent a new entity that is clinically and pathologically distinct from all currently recognized subtypes of FTLD.

TDP-43 is a culprit in human neurodegeneration, and not just an innocent bystander

In 2008, several papers have been published in quick succession describing mutations in the TDP-43 gene, showing they can be a primary cause of amyotrophic lateral sclerosis.



Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17

It is demonstrated that in multiple FTD families with significant evidence for linkage to the same region on chromosome 17q21, FTD is caused by mutations in progranulin (PGRN) that are likely to create null alleles and identified mutations in PGRN as a cause of neurodegenerative disease.

A family with tau-negative frontotemporal dementia and neuronal intranuclear inclusions linked to chromosome 17.

Detailed clinical and neuropathological findings in a new large, multigenerational family with autosomal dominant FTD and autopsy proven tau-negative, ub-ir neuronal cytoplasmic and intranuclear inclusions are described that is linked to a 19.06 cM region of chromosome 17q21 containing MAPt.

Null mutations in progranulin cause ubiquitin-positive frontotemporal dementia linked to chromosome 17q21

It is demonstrated that FTDU-17 is caused by mutations in the gene coding for progranulin (PGRN), a growth factor involved in multiple physiological and pathological processes including tumorigenesis, and evidence that P GRN haploinsufficiency leads to neurodegeneration because of reduced PGRN-mediated neuronal survival is provided.

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

The variety of morphologies and the anatomic distribution of ub-ir pathology to be greater than previously documented and the degree of overlap suggests that MND, MND-d, and FTD-MND type represent a spectrum of clinical disease with a common pathologic substrate.

Tau is a candidate gene for chromosome 17 frontotemporal dementia

Three lines of evidence indicate that the Val279Met change is an FTDP‐17 causative mutation, and normal valine is found at this position in all three tau interrepeat sequences and in other microtubule associated protein tau homologues.

Histopathological changes underlying frontotemporal lobar degeneration with clinicopathological correlation

Investigation of the pathological correlates of dementia in the brains of 70 patients dying with a clinical diagnosis of frontotemporal lobar degeneration indicates that ubiquitin pathology is the most common histological form associated with FTLD, but this pathology is not tightly linked with, nor is pathologically diagnostic for, any particular clinical form of the disease, including FTD+MND.

The overlap of amyotrophic lateral sclerosis and frontotemporal dementia

Patients with frontotemporal dementia with no known diagnosis of ALS or family history of ALS were clinically and electrophysiologically assessed for the presence of ALS and two had EMG findings suggestive of denervation in one limb.

Clinicopathological correlates in frontotemporal dementia

The pathological substrate can be predicted in a significant proportion of FTD patients, which has important implications for studies targeting mechanistic treatments.

Association of missense and 5′-splice-site mutations in tau with the inherited dementia FTDP-17

Thirteen families have been described with an autosomal dominantly inherited dementia named frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), historically termed Pick's

Hereditary dysphasic disinhibition dementia A frontotemporal dementia linked to 17 q21‐‐22

Hereditary dysphasic disinhibition dementia with parkinsonism linked to chromosome 17 is an autosomal-dominant frontotemporal dementia with many similarities to Pick's disease and may represent phenotypic variants arising from mutations within a common gene.