Pathological TDP‐43 distinguishes sporadic amyotrophic lateral sclerosis from amyotrophic lateral sclerosis with <i>SOD1</i> mutations

Mackenzie, Ian R.; Bigio, Eileen H.; Ince, Paul G.; Geser, Felix; Neumann, Manuela; Cairns, Nigel J.; Kwong, Linda K.; Forman, Mark S.; Ravits, John; Stewart, Heather; Eisen, Andrew; McClusky, Leo; Kretzschmar, Hans A.; Monoranu, Camelia; Highley, J. Robin; Kirby, Janine; Siddique, Teepu; Shaw, Pamela J.; Lee, Virginia M.‐Y.; Trojanowski, John Q.

doi:10.1002/ana.21147

Cited by 842 publications

(739 citation statements)

References 32 publications

Supporting

Mentioning

687

Contrasting

Unclassified

Order By: Relevance

“…Although pathogenic roles of endoplasmic reticulum stress and mitochondrial damage are implied in ALS 47,48 , a role for internal Ca 2 þ storage vesicles in TDP-43 pathology, however, has not been demonstrated. TDP-43 pathology is rarely, if ever, observed in the motor neurons of patients with SOD1-associated ALS or in SOD1 Tg animals 24,49 .…”

Section: )mentioning

confidence: 99%

A role for calpain-dependent cleavage of TDP-43 in amyotrophic lateral sclerosis pathology

et al. 2012

View full text Add to dashboard Cite

Both mislocalization of TDP-43 and downregulation of RNA-editing enzyme ADAR2 colocalize in the motor neurons of amyotrophic lateral sclerosis patients, but how they are linked is not clear. Here we demonstrate that activation of calpain, a Ca 2 þ -dependent cysteine protease, by upregulation of Ca 2 þ -permeable AMPA receptors generates carboxyterminal-cleaved TDP-43 fragments and causes mislocalization of TDP-43 in the motor neurons expressing glutamine/arginine site-unedited GluA2 of conditional ADAR2 knockout (AR2) mice that mimic the amyotrophic lateral sclerosis pathology. These abnormalities are inhibited in the AR2res mice that express Ca 2 þ -impermeable AMPA receptors in the absence of ADAR2 and in the calpastatin transgenic mice, but are exaggerated in the calpastatin knockout mice. Additional demonstration of calpain-dependent TDP43 fragments in the spinal cord and brain of amyotrophic lateral sclerosis patients, and high vulnerability of amyotrophic lateral sclerosis-linked mutant TDP43 to cleavage by calpain support the crucial role of the calpain-dependent cleavage of TDP43 in the amyotrophic lateral sclerosis pathology.

show abstract

Section: )mentioning

confidence: 99%

A role for calpain-dependent cleavage of TDP-43 in amyotrophic lateral sclerosis pathology

et al. 2012

View full text Add to dashboard Cite

show abstract

“…Motor neuron degeneration is associated primarily with the pathological aggregation of ubiquitin, fused in sarcoma protein, and the transactive response DNA binding protein (TAR) DNAbinding protein of 43-kDa in the cytoplasm of motor neuron cell bodies [114,115]. In addition, ALS has also been associated with an important impairment of energy metabolism [116].…”

Section: Alsmentioning

confidence: 99%

Acetyltransferases (HATs) as Targets for Neurological Therapeutics

et al. 2013

View full text Add to dashboard Cite

The acetylation of histone and non-histone proteins controls a great deal of cellular functions, thereby affecting the entire organism, including the brain. Acetylation modifications are mediated through histone acetyltransferases (HAT) and deacetylases (HDAC), and the balance of these enzymes regulates neuronal homeostasis, maintaining the pre-existing acetyl marks responsible for the global chromatin structure, as well as regulating specific dynamic acetyl marks that respond to changes and facilitate neurons to encode and strengthen longterm events in the brain circuitry (e.g., memory formation). Unfortunately, the dysfunction of these finely-tuned regulations might lead to pathological conditions, and the deregulation of the HAT/HDAC balance has been implicated in neurological disorders. During the last decade, research has focused on HDAC inhibitors that induce a histone hyperacetylated state to compensate acetylation deficits. The use of these inhibitors as a therapeutic option was efficient in several animal models of neurological disorders. The elaboration of new cell-permeant HAT activators opens a new era of research on acetylation regulation. Although pathological animal models have not been tested yet, HAT activator molecules have already proven to be beneficial in ameliorating brain functions associated with learning and memory, and adult neurogenesis in wild-type animals. Thus, HAT activator molecules contribute to an exciting area of research.

show abstract

“…19 Interestingly, TDP-43 pathology is not found in SOD1-associated FALS suggesting that mechanistically ALS is heterogeneous. 20 TDP-43 is a 414-amino acid nuclear protein encoded by the TARDBP gene on chromosome 1p36.2. It was originally identified as a 43 kd transcription repressor that binds to the TAR-DNA element of HIV, and, because of its molecular weight of 43 kDa, it was named TDP-43.…”

Section: Introductionmentioning

confidence: 99%

TARDBP mutations in amyotrophic lateral sclerosis with TDP-43 neuropathology: a genetic and histopathological analysis

Deerlin

Leverenz

Bekris

et al. 2008

The Lancet Neurology

Self Cite

631

448

View full text Add to dashboard Cite

Pathological TDP‐43 distinguishes sporadic amyotrophic lateral sclerosis from amyotrophic lateral sclerosis with SOD1 mutations

Cited by 842 publications

References 32 publications

A role for calpain-dependent cleavage of TDP-43 in amyotrophic lateral sclerosis pathology

A role for calpain-dependent cleavage of TDP-43 in amyotrophic lateral sclerosis pathology

Acetyltransferases (HATs) as Targets for Neurological Therapeutics

TARDBP mutations in amyotrophic lateral sclerosis with TDP-43 neuropathology: a genetic and histopathological analysis

Contact Info

Product

Resources

About