Poly-A Binding Protein-1 Localization to a Subset of TDP-43 Inclusions in Amyotrophic Lateral Sclerosis Occurs More Frequently in Patients Harboring an Expansion in<i>C9orf72</i>

McGurk, Leeanne; Lee, Virginia M.; Trojanowksi, John Q.; Deerlin, Vivianna M. Van; Lee, Edward B.; Bonini, Nancy M.

doi:10.1097/nen.0000000000000102

Cited by 53 publications

(56 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…PPIA regulates expression of known TDP-43 RNA targets and is necessary for the assembly of TARDBP in hnRNP complexes [14]. Several other genes, including progranulin (PGRN), valosin-containing protein (VCP), and C9ORF72, are also reported to relate to TDP-43 proteinopathies [15][16][17][18].…”

Section: Biochemical Characters Of Tdp-43mentioning

confidence: 96%

The Role of TDP-43 in Alzheimer’s Disease

Chang

Tan

et al. 2015

Mol Neurobiol

View full text Add to dashboard Cite

The transactive response DNA binding protein (TDP-43) has long been characterized as a main hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U, also known as FTLD-TDP). Several studies have indicated TDP-43 deposits in Alzheimer's disease (AD) brains and have robust connection with AD clinical phenotype. FTLD-U, which was symptomatically connected with AD, may be predictable for the comprehension of the role TDP-43 in AD. TDP-43 may contribute to AD through both β-amyloid (Aβ)-dependent and Aβ-independent pathways. In this article, we summarize the latest studies concerning the role of TDP-43 in AD and explore TDP-43 modulation as a potential therapeutic strategy for AD. However, to date, little of pieces of the research on TDP-43 have been performed to investigate the role in AD; more investigations need to be confirmed in the future.

show abstract

Section: Biochemical Characters Of Tdp-43mentioning

confidence: 96%

The Role of TDP-43 in Alzheimer’s Disease

Chang

Tan

et al. 2015

Mol Neurobiol

View full text Add to dashboard Cite

show abstract

“…Like TDP-43, RBM-45 is mainly nuclear, but migrates to cytoplasm and co-localizes in SGs to associate with Kelch-like ECH-Associated protein 1, a component of anti-oxidant machinery (Bakkar et al, 2015). Furthermore, TDP-43 co-localizes in cytoplasmic inclusions with Poly-A binding protein - 1 (PABP-1); a stress granules marker (McGurk et al, 2014). …”

Section: Introductionmentioning

confidence: 99%

“…Strikingly, these patients develop numerous p62-positive, TDP-43-negative inclusions in the dentate gyrus, neocortex, and cerebellum (Al-Sarraj et al, 2011; Boxer et al, 2011; DeJesus-Hernandez et al, 2011). Furthermore, patients with the C9orf72 hexanucleotide expansion also have RBM45 inclusions and PABP-1 (Collins et al, 2012; McGurk et al, 2014). C9orf72 mutations appear to promote mis-localization of TDP-43 to the cytoplasm, in addition to causing malformed RNA molecules (Zhang et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

TDP-43/FUS in motor neuron disease: Complexity and challenges

Guerrero

Wang

Mitra

et al. 2016

Progress in Neurobiology

107

122

View full text Add to dashboard Cite

Amyotrophic lateral sclerosis (ALS), a common motor neuron disease affecting two per 100,000 people worldwide, encompasses at least five distinct pathological subtypes, including, ALS-SOD1, ALS-C9orf72, ALS-TDP-43, ALS-FUS and Guam-ALS. The etiology of a major subset of ALS involves toxicity of the TAR DNA-binding protein-43 (TDP-43). A second RNA/DNA binding protein, fused in sarcoma/translocated in liposarcoma (FUS/TLS) has been subsequently associated with about 1% of ALS patients. While mutations in TDP-43 and FUS have been linked to ALS, the key contributing molecular mechanism(s) leading to cell death are still unclear. One unique feature of TDP-43 and FUS pathogenesis in ALS is their nuclear clearance and simultaneous cytoplasmic aggregation in affected motor neurons. Since the discoveries in the last decade implicating TDP-43 and FUS toxicity in ALS, a majority of studies have focused on their cytoplasmic aggregation and disruption of their RNA-binding functions. However, TDP-43 and FUS also bind to DNA, although the significance of their DNA binding in disease-affected neurons has been less investigated. A recent observation of accumulated genomic damage in TDP-43 and FUS-linked ALS and association of FUS with neuronal DNA damage repair pathways indicate a possible role of deregulated DNA binding function of TDP-43 and FUS in ALS. In this review, we discuss the different ALS disease subtypes, crosstalk of etiopathologies in disease progression, available animal models and their limitations, and recent advances in understanding the specific involvement of RNA/DNA binding proteins, TDP-43 and FUS, in motor neuron diseases.

show abstract

“…Deletion of the RNA-binding domains in TDP43 and FUS both prevents their inclusion in stress granules and reduces their toxicity [34,[39][40][41]. Moreover, components of stress granules have been detected in TDP43-rich cytoplasmic deposits in spinal neurons of patients with ALS [56,99,101], but are less common in cortical neurons [102]. These results may be explained by the preferential accumulation of fulllength TDP43 in spinal neurons of patients with ALS, in contrast to the deposition of carboxy-terminal fragments of TDP43 in cortical neurons [103].…”

Section: Rna Granulesmentioning

confidence: 99%

Linking RNA Dysfunction and Neurodegeneration in Amyotrophic Lateral Sclerosis

Barmada

2015

Neurotherapeutics

View full text Add to dashboard Cite

The degeneration of motor neurons in amyotrophic lateral sclerosis (ALS) inevitably causes paralysis and death within a matter of years. Mounting genetic and functional evidence suggest that abnormalities in RNA processing and metabolism underlie motor neuron loss in sporadic and familial ALS. Abnormal localization and aggregation of essential RNA-binding proteins are fundamental pathological features of sporadic ALS, and mutations in genes encoding RNA processing enzymes cause familial disease. Also, expansion mutations occurring in the noncoding region of C9orf72-the most common cause of inherited ALS-result in nuclear RNA foci, underscoring the link between abnormal RNA metabolism and neurodegeneration in ALS. This review summarizes the current understanding of RNA dysfunction in ALS, and builds upon this knowledge base to identify converging mechanisms of neurodegeneration in ALS. Potential targets for therapy development are highlighted, with particular emphasis on early and conserved pathways that lead to motor neuron loss in ALS.

show abstract

Poly-A Binding Protein-1 Localization to a Subset of TDP-43 Inclusions in Amyotrophic Lateral Sclerosis Occurs More Frequently in Patients Harboring an Expansion inC9orf72

Cited by 53 publications

References 49 publications

The Role of TDP-43 in Alzheimer’s Disease

The Role of TDP-43 in Alzheimer’s Disease

TDP-43/FUS in motor neuron disease: Complexity and challenges

Linking RNA Dysfunction and Neurodegeneration in Amyotrophic Lateral Sclerosis

Contact Info

Product

Resources

About