Detection of TDP‐43 oligomers in frontotemporal lobar degeneration–TDP

Kao, Patricia F.; Chen, Yun‐Ru; Liu, Xiaobo; DeCarli, Charles; Seeley, William W.; Jin, Lee‐Way

doi:10.1002/ana.24431

Cited by 26 publications

(32 citation statements)

References 41 publications

(57 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Indeed, more recent evidence demonstrates the presence of toxic TDP-43 oligomers in patients with FTLD and ALS (Fang et al, 2014, Kao et al, 2015). To further demonstrate one of the potential causes of this observed reduced cell viability we wanted to determine the presence of these oligomers in our cell model.…”

Section: Resultsmentioning

confidence: 99%

In vitro prion-like behaviour of TDP-43 in ALS

Smethurst

Newcombe²,

Troakes

et al. 2016

Neurobiology of Disease

Self Cite

115

102

View full text Add to dashboard Cite

Amyotrophic lateral sclerosis (ALS) is the most common form of motor neuron disease (MND), and > 95% of familial and sporadic cases involve the deposition of insoluble aggregated, phosphorylated and cleaved TDP-43 protein. Accumulating clinical and biological evidence now indicates that ALS bears a number of similarities to the prion diseases, with TDP-43 acting as a misfolded ‘prion-like’ protein demonstrating similar underlying pathobiology. Here we systematically address the hypothesis that ALS is a prion-like disorder. First we demonstrate that TDP-43 demonstrates seeded polymerisation in vitro directly from both ALS brain and spinal cord. We next show that the seeding of TDP-43 results in the formation of characteristic insoluble, aggregated, and phosphorylated TDP-43 pathology that directly recapitulates the morphological diversity of TDP-43 inclusions detected in ALS patient CNS tissue. We next demonstrate that this reaction can be serially propagated to produce increasing amounts of phosphorylated TDP-43 pathology, and that aggregates can spread from cell to cell in an analogous fashion to that seen in the prion diseases. Finally, we reproduced our findings in a murine motor neuron-like cell line (NSC-34), where the seeding of TDP-43 induces the formation of TDP-43 oligomers and reduced cell viability. These findings may guide therapeutic strategies in this rapidly progressive and invariably fatal disease.

show abstract

Section: Resultsmentioning

confidence: 99%

In vitro prion-like behaviour of TDP-43 in ALS

Smethurst

Newcombe²,

Troakes

et al. 2016

Neurobiology of Disease

Self Cite

115

102

View full text Add to dashboard Cite

show abstract

“…It is nevertheless possible that these pathologies target different neuronal populations within the MTL [Galton et al, ]. For instance, granule cells of the dentate gyrus have generally been found to be spared until late stages of AD [Ohm, ] while they often showed cytoplasmic inclusions in patients with TDP‐43 Type C [Kao et al, ; Mackenzie et al, ; Rossor et al, ; Sampathu et al, ]. MTL atrophy may therefore reflect, at least partly, loss of different cell populations that present with distinct connectivity.…”

Section: Discussionmentioning

confidence: 99%

Distinct white matter injury associated with medial temporal lobe atrophy in Alzheimer's versus semantic dementia

Bejanin

Desgranges

Joie

et al. 2016

Human Brain Mapping

View full text Add to dashboard Cite

This study aims at further understanding the distinct vulnerability of brain networks in Alzheimer's disease (AD) versus semantic dementia (SD) investigating the white matter injury associated with medial temporal lobe (MTL) atrophy in both conditions. Twenty-six AD patients, twenty-one SD patients, and thirty-nine controls underwent a high-resolution T1-MRI scan allowing to obtain maps of grey matter volume and white matter density. A statistical conjunction approach was used to identify MTL regions showing grey matter atrophy in both patient groups. The relationship between this common grey matter atrophy and white matter density maps was then assessed within each patient group. Patterns of grey matter atrophy were distinct in AD and SD but included a common region in the MTL, encompassing the hippocampus and amygdala. This common atrophy was associated with alterations in different white matter areas in AD versus SD, mainly including the cingulum and corpus callosum in AD, while restricted to the temporal lobe - essentially the uncinate and inferior longitudinal fasciculi - in SD. Complementary analyses revealed that these relationships remained significant when controlling for global atrophy or disease severity. Overall, this study provides the first evidence that atrophy of the same MTL region is related to damage in distinct white matter fibers in AD and SD. These different patterns emphasize the vulnerability of distinct brain networks related to the MTL in these two disorders, which might underlie the discrepancy in their symptoms. These results further suggest differences between AD and SD in the neuropathological processes occurring in the MTL. Hum Brain Mapp 38:1791-1800, 2017. © 2017 Wiley Periodicals, Inc.

show abstract

“…While SGs are dynamic assemblies, these aggregates may have a fibrillar architecture [73,74]. FUS and hnRNPA1 are examples of such SG proteins, with long, low-complexity IDRs that are mutated in ALS patients [75,33].…”

Section: Materials States Of Membraneless Organelles: Liquids Hydrogementioning

confidence: 99%

Protein Phase Separation: A New Phase in Cell Biology

Boeynaems

Alberti

Fawzi

et al. 2018

Trends in Cell Biology

1,637

1,517

View full text Add to dashboard Cite

Cellular compartments and organelles organize biological matter. Most well-known organelles are separated by a membrane boundary from their surrounding milieu. There are also many so-called membraneless organelles and recent studies suggest that these organelles, which are supramolecular assemblies of proteins and RNA molecules, form via protein phase separation. Recent discoveries have shed light on the molecular properties, formation, regulation, and function of membraneless organelles. A combination of techniques from cell biology, biophysics, physical chemistry, structural biology, and bioinformatics are starting to help establish the molecular principles of an emerging field, thus paving the way for exciting discoveries, including novel therapeutic approaches for the treatment of age-related disorders.

show abstract

Detection of TDP‐43 oligomers in frontotemporal lobar degeneration–TDP

Cited by 26 publications

References 41 publications

In vitro prion-like behaviour of TDP-43 in ALS

In vitro prion-like behaviour of TDP-43 in ALS

Distinct white matter injury associated with medial temporal lobe atrophy in Alzheimer's versus semantic dementia

Protein Phase Separation: A New Phase in Cell Biology

Contact Info

Product

Resources

About