Lack of TDP-43 abnormalities in mutant SOD1 transgenic mice shows disparity with ALS

Robertson, Janice; Sanelli, Teresa; Xiao, Shangxi; Yang, Wencheng; Horne, Patrick; Hammond, Robert; Pioro, Erik P.; Strong, Michael J.

doi:10.1016/j.neulet.2007.03.066

Cited by 107 publications

(96 citation statements)

References 12 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Remarkably, while pathological TDP-43 was a consistent feature in non-SOD1-fALS, TDP-43 was not detected in the UBI of any patients with SOD1 mutations [35,36]. Consistent with these findings is the reported absence of TDP-43 immunoreactivity in inclusions in mutant SOD1 (G93A) transgenic mice [39]. In contrast, in Guam ALS and parkinsonism-dementia complex (PDC), a disease of unknown etiology affecting the Chamorro populations and characterized by extensive tau pathology, TDP-43 inclusions were detected in the spinal cord of both ALS and PDC cases but not in controls [40].…”

Section: Tdp-43 Pathology In Ftld-u and Alsmentioning

confidence: 77%

TDP-43: a novel neurodegenerative proteinopathy

Forman¹,

Trojanowski²,

Lee³

2007

Current Opinion in Neurobiology

111

View full text Add to dashboard Cite

SummaryOver the past decade it has become clear that there is significant overlap in the clinical spectrum of frontotemporal lobar degeneration and amyotrophic lateral sclerosis. The identification of TDP-43 as the major disease protein in the pathology of both frontotemporal lobar degeneration with ubiquitin inclusions and amyotrophic lateral sclerosis provides the first molecular link for these diseases. Pathological TDP-43 is abnormally phosphorylated, ubiquitinated, and cleaved to generate carboxyterminal fragments in affected brain regions. The normal nuclear expression of TDP-43 is also reduced leading to the hypothesis that sequestration of TDP-43 in pathological inclusions contributes to disease pathogenesis. Thus, TDP-43 is the newest member of the growing list of neurodegenerative proteinopathies, but unique in that it lacks features of brain amyloidosis.

show abstract

Section: Tdp-43 Pathology In Ftld-u and Alsmentioning

confidence: 77%

TDP-43: a novel neurodegenerative proteinopathy

Forman¹,

Trojanowski²,

Lee³

2007

Current Opinion in Neurobiology

111

View full text Add to dashboard Cite

show abstract

“…Cytoplasmic aggregation of TDP-43 has been identified as a pathological feature in ALS 15,16,17,18,19 . Typically TDP-43 is found in the nucleus of all cells from a normal individual, although it tends to move between the cytosol and nucleus 15,17 .…”

Section: Introductionmentioning

confidence: 99%

“…Typically TDP-43 is found in the nucleus of all cells from a normal individual, although it tends to move between the cytosol and nucleus 15,17 . However, in ALS aggregated forms of TDP-43 are detected in the cytoplasm of select neurons and glia with lower concentrations found in the nucleus suggesting the movement of TDP-43 from the nucleus to the cytoplasm during disease progression 16,20 .…”

Section: Introductionmentioning

confidence: 99%

Novel Atomic Force Microscopy Based Biopanning for Isolation of Morphology Specific Reagents against TDP-43 Variants in Amyotrophic Lateral Sclerosis

Williams

Venkataraman

Tian

et al. 2015

JoVE

View full text Add to dashboard Cite

Because protein variants play critical roles in many diseases including TDP-43 in Amyotrophic Lateral Sclerosis (ALS), alpha-synuclein in Parkinson's disease and beta-amyloid and tau in Alzheimer's disease, it is critically important to develop morphology specific reagents that can selectively target these disease-specific protein variants to study the role of these variants in disease pathology and for potential diagnostic and therapeutic applications. We have developed novel atomic force microscopy (AFM) based biopanning techniques that enable isolation of reagents that selectively recognize disease-specific protein variants. There are two key phases involved in the process, the negative and positive panning phases. During the negative panning phase, phages that are reactive to off-target antigens are eliminated through multiple rounds of subtractive panning utilizing a series of carefully selected off-target antigens. A key feature in the negative panning phase is utilizing AFM imaging to monitor the process and confirm that all undesired phage particles are removed. For the positive panning phase, the target antigen of interest is fixed on a mica surface and bound phages are eluted and screened to identify phages that selectively bind the target antigen. The target protein variant does not need to be purified providing the appropriate negative panning controls have been used. Even target protein variants that are only present at very low concentrations in complex biological material can be utilized in the positive panning step. Through application of this technology, we acquired antibodies to protein variants of TDP-43 that are selectively found in human ALS brain tissue. We expect that this protocol should be applicable to generating reagents that selectively bind protein variants present in a wide variety of different biological processes and diseases. Video LinkThe video component of this article can be found at

show abstract

“…FTLD-U [6,7]. Recently, the transactive response (TAR) DNA-binding protein 43 (TDP-43) was identified as the major disease protein in UBIs that accumulate in the central nervous system (CNS) of patients with FTLD-U as well as in patients with sporadic and familial ALS [8], but not in the majority of patients with familial ALS (FALS) due to SOD-1 gene mutations [8][9][10][11][12]. These data provided compelling evidence that FTLD-U and ALS represent a clinicopathological spectrum of the same neurodegenerative disorder, i.e.…”

Section: Introductionmentioning

confidence: 99%

A90V TDP‐43 variant results in the aberrant localization of TDP‐43 in vitro

et al. 2008

View full text Add to dashboard Cite

TAR DNA-binding protein-43 (TDP-43) is a highly conserved, ubiquitously expressed nuclear protein that was recently identified as the disease protein in frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U) and amyotrophic lateral sclerosis (ALS). Pathogenic TDP-43 gene (TARDBP) mutations have been identified in familial ALS kindreds, and here we report a TARDBP variant (A90V) in a FTLD/ALS patient with a family history of dementia. Significantly, A90V is located between the bipartite nuclear localization signal sequence of TDP-43 and the in vitro expression of TDP-43-A90V led to its sequestration with endogenous TDP-43 as insoluble cytoplasmic aggregates. Thus, A90V may be a genetic risk factor for FTLD/ALS because it predisposes nuclear TDP-43 to redistribute to the cytoplasm and form pathological aggregates.

show abstract

Lack of TDP-43 abnormalities in mutant SOD1 transgenic mice shows disparity with ALS

Cited by 107 publications

References 12 publications

TDP-43: a novel neurodegenerative proteinopathy

TDP-43: a novel neurodegenerative proteinopathy

Novel Atomic Force Microscopy Based Biopanning for Isolation of Morphology Specific Reagents against TDP-43 Variants in Amyotrophic Lateral Sclerosis

A90V TDP‐43 variant results in the aberrant localization of TDP‐43 in vitro

Contact Info

Product

Resources

About