Distinct TDP-43 pathology in ALS patients with ataxin 2 intermediate-length polyQ expansions

Hart, Michael P.; Brettschneider, Johannes; Lee, Virginia M.‐Y.; Trojanowski, John Q.; Gitler, Aaron D.

doi:10.1007/s00401-012-0985-5

Cited by 40 publications

(27 citation statements)

References 55 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Only pTDP-43 skein-like accumulations were observed in tissue from the 5 ALS patient samples examined (Table 3). This is consistent with previous findings suggesting that skein-like inclusions are the predominant pathology in ATXN2 -ALS spinal cord motor neurons (43). From the 4 cases, 11 skein-like accumulations were observed in total (Table 3), with PABP-1 colocalizing with 47% of TDP-43 skein-like inclusions (Figs.…”

Section: Resultssupporting

confidence: 94%

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

McGurk

Lee

Trojanowksi³

et al. 2014

J Neuropathol Exp Neurol

View full text Add to dashboard Cite

Amyotrophic lateral sclerosis (ALS) is an adult-onset motor neuron disease in which the loss of spinal cord motor neurons leads to paralysis and death within a few years of clinical disease onset. In almost all cases of ALS, TAR DNA binding protein of 43 kDa (TDP-43) forms cytoplasmic neuronal inclusions. A second causative gene for a subset of ALS is fused in sarcoma (FUS), an RNA binding protein that also forms cytoplasmic inclusions in spinal cord motor neurons. Poly A binding protein 1 (PABP-1) is a marker of stress granules, i.e. accumulations of proteins and RNA indicative of translational arrest in cells under stress. We report on the colocalization PABP-1 to both TDP-43 and FUS inclusions in 4 patient cohorts: ALS without a mutation, ALS with an intermediate poly glutamine repeat expansion in ATXN2, ALS with a GGGGCC-hexanucleotide repeat expansion in C9orf72, and ALS with basophilic inclusion body disease. Notably, PABP-1 colocalization to TDP-43 was twice as frequent in ALS with C9orf72 expansions compared to ALS with no mutation. This study highlights PABP-1 as a protein important to the pathology of ALS and indicates that the proteomic profile of TDP-43 inclusions in ALS may be different depending on the causative genetic mutation.

show abstract

Section: Resultssupporting

confidence: 94%

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

McGurk

Lee

Trojanowksi³

et al. 2014

J Neuropathol Exp Neurol

View full text Add to dashboard Cite

show abstract

“…Importantly, in vitro experiments showed that the expression products of ATXN2 with intermediate CAG repeats could interact with FUS [75], a DNA/RNA binding protein, which when mutated could cause fALS as a result of impaired RNA intracellular trafficking [75], [76]. In addition, TDP-43 cytoplasmic inclusions in motor neurons of ALS patients harboring intermediate PolyQ repeats primarily showed skein-like or filamentous TDP-43 pathology, whereas ALS cases without ataxin-2 polyQ expansions (n = 13) exhibited abundant large round TDP-43 inclusions [63], [77], and accumulated activated caspase 3 in motor neurons, an upstream event in the TDP-43 disease pathway. The product of ATXN2 with intermediate CAG repeat expansion could increase the presence of TDP-43 in the cytoplasm in a RNA dependent manner [43].…”

Section: Discussionmentioning

confidence: 99%

Intermediate CAG Repeat Expansion in the ATXN2 Gene Is a Unique Genetic Risk Factor for ALS−A Systematic Review and Meta-Analysis of Observational Studies

et al. 2014

View full text Add to dashboard Cite

Amyotrophic lateral sclerosis (ALS) is a rare degenerative condition of the motor neurons. Over 10% of ALS cases are linked to monogenic mutations, with the remainder thought to be due to other risk factors, including environmental factors, genetic polymorphisms, and possibly gene-environmental interactions. We examined the association between ALS and an intermediate CAG repeat expansion in the ATXN2 gene using a meta-analytic approach. Observational studies were searched with relevant disease and gene terms from MEDLINE, EMBASE, and PsycINFO from January 2010 through to January 2014. All identified articles were screened using disease terms, gene terms, population information, and CAG repeat information according to PRISMA guidelines. The final list of 17 articles was further evaluated based on the study location, time period, and authors to exclude multiple usage of the same study populations: 13 relevant articles were retained for this study. The range 30–33 CAG repeats in the ATXN2 gene was most strongly associated with ALS. The meta-analysis revealed that the presence of an intermediate CAG repeat (30-33) in the ATXN2 gene was associated with an increased risk of ALS [odds ratio (OR) = 4.44, 95%CI: 2.91–6.76)] in Caucasian ALS patients. There was no significant difference in the association of this CAG intermediate repeat expansion in the ATXN2 gene between familial ALS cases (OR = 3.59, 1.58–8.17) and sporadic ALS cases (OR = 3.16, 1.88–5.32). These results indicate that the presence of intermediate CAG repeat expansion in the ATXN2 gene is a specific genetic risk factor for ALS, unlike monogenic mutations with an autosomal dominant transmission mode, which cause a more severe phenotype of ALS, with a higher prevalence in familial ALS.

show abstract

“…Finally, it is noteworthy that in addition to the mutations noted above that cause ALS/FTLD-TDP, multiple pathogenic mutations in four other genes (including those encoding ataxin-2, optineurin, NIPA1 and angiogenin) for ALS and/or FTLD-TDP have been discovered that also are linked to TDP-43 pathology thereby suggesting that ALS and FTLD share similar disease mechanisms all of which involve TDP-43 pathology [86, 115, 119, 145]. …”

Section: Tdp-43 Proteinopathies (Ftld-tdp and Als)mentioning

confidence: 99%

Frontotemporal lobar degeneration: defining phenotypic diversity through personalized medicine

et al. 2014

Self Cite

View full text Add to dashboard Cite

Frontotemporal lobar degeneration (FTLD) comprises two main classes of neurodegenerative diseases characterized by neuronal/glial proteinaceous inclusions (ie. proteinopathies) including tauopathies (i.e. FTLD-Tau) and TDP-43 proteinopathies (i.e. FTLD-TDP) while other very rare forms of FTLD are known such as FTLD with FUS pathology (FTLD-FUS). This review focuses mainly on FTLD-Tau and FLTD-TDP, which may present as several clinical syndromes: a behavioral/dysexecutive syndrome (behavioral-variant frontotemporal dementia); language disorders (primary progressive aphasia variants); and motor disorders (amyotrophic lateral sclerosis, corticobasal syndrome, progressive supranuclear palsy syndrome). There is considerable heterogeneity in clinical presentations of underlying neuropathology and current clinical criteria do not reliably predict underlying proteinopathies ante-mortem. In contrast, molecular etiologies of hereditary FTLD are consistently associated with specific proteinopathies. These include MAPT mutations with FTLD-Tau and GRN, C9orf72, VCP and TARDBP with FTLD-TDP. The last decade has seen a rapid expansion in our knowledge of the molecular pathologies associated with this clinically and neuropathologically heterogeneous group of FTLD diseases. Moreover, in view of current limitations to reliably diagnose specific FTLD neuropathologies prior to autopsy, we summarize the current state of the science in FTLD biomarker research including neuroimaging, biofluid and genetic analyses. We propose that combining several of these biomarker modalities will improve diagnostic specificity in FTLD through a personalized medicine approach. The goals of these efforts are to enhance power for clinical trials focused on slowing or preventing progression of spread of tau, TDP-43 and other FTLD-associated pathologies and work towards the goal of defining clinical endophenotypes of FTD.

show abstract

Distinct TDP-43 pathology in ALS patients with ataxin 2 intermediate-length polyQ expansions

Cited by 40 publications

References 55 publications

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

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

Intermediate CAG Repeat Expansion in the ATXN2 Gene Is a Unique Genetic Risk Factor for ALS−A Systematic Review and Meta-Analysis of Observational Studies

Frontotemporal lobar degeneration: defining phenotypic diversity through personalized medicine

Contact Info

Product

Resources

About