ArticleActa neuropathologica2012
Pattern of ubiquilin pathology in ALS and FTLD indicates presence of C9ORF72 hexanucleotide expansion.
Article in Acta neuropathologica, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 99 papers, 1 of them a synthesis that pooled it.
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Who cites it
99 citing papers in PubMed, 1 synthesis or guideline pooled it, 194 citations in OpenAlex.
- Survival and Prognostic Factors in C9orf72 Repeat Expansion Carriers: A Systematic Review and Meta-analysis.JAMA neurology · 2020Pooled it
- Hippocampal sclerosis dementia with the C9ORF72 hexanucleotide repeat expansion.Neurobiology of aging · 2014Trial
- UBQLN2 in neurodegenerative disease: mechanistic insights and emerging therapeutic potential.Biochemical Society transactions · 2025Review
- Frontotemporal lobar degeneration and amyotrophic lateral sclerosis: A bibliometric analysis.Medicine · 2025Article
- Interactome screening implicates BAG6 as a suppressor of UBQLN2 misfolding in ALS/FTD.Frontiers in molecular neuroscience · 2025Article
- Hippocampal aggregation signatures of pathogenic UBQLN2 in amyotrophic lateral sclerosis and frontotemporal dementia.Brain : a journal of neurology · 2024Article
- Distribution of ubiquilin 2 and TDP-43 aggregates throughout the CNS in UBQLN2 p.T487I-linked amyotrophic lateral sclerosis and frontotemporal dementia.Brain pathology (Zurich, Switzerland) · 2024Article
- Astrocyte-Neuron Interactions Contributing to Amyotrophic Lateral Sclerosis Progression.Advances in neurobiology · 2024Review
- Preclinical investigation in FAAH inhibition as a neuroprotective therapy for frontotemporal dementia using TDP-43 transgenic male mice.Journal of neuroinflammation · 2023Article
- Article
- Neuronal Puncta/Aggregate Formation by WT and Mutant UBQLN2.Methods in molecular biology (Clifton, N.J.) · 2023Article
- Cerebellar pathology in motor neuron disease: neuroplasticity and neurodegeneration.Neural regeneration research · 2022Review
- The Cyanotoxin 2,4-DAB Reduces Viability and Causes Behavioral and Molecular Dysfunctions Associated with Neurodegeneration in Larval Zebrafish.Neurotoxicity research · 2022Article
- RTL8 promotes nuclear localization of UBQLN2 to subnuclear compartments associated with protein quality control.Cellular and molecular life sciences : CMLS · 2022Article
- Structural variation analysis of 6,500 whole genome sequences in amyotrophic lateral sclerosis.NPJ genomic medicine · 2022Article
- Distinct brain-derived TDP-43 strains from FTLD-TDP subtypes induce diverse morphological TDP-43 aggregates and spreading patterns in vitro and in vivo.Neuropathology and applied neurobiology · 2021Article
- Review
- Ubiquilin proteins regulate EGFR levels and activity in lung adenocarcinoma cells.Journal of cellular biochemistry · 2021Article
- Proteinopathies as Hallmarks of Impaired Gene Expression, Proteostasis and Mitochondrial Function in Amyotrophic Lateral Sclerosis.Frontiers in neuroscience · 2021Review
- ALS/FTD mutations in UBQLN2 impede autophagy by reducing autophagosome acidification through loss of function.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
39 more citing papers are in PubMed but not listed here.
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Authors and funding
16 authors at 3 institutions in 2 countries.
Funding
Abstract
C9ORF72-hexanucleotide repeat expansions and ubiquilin-2 (UBQLN2) mutations are recently identified genetic markers in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). We investigate the relationship between C9ORF72 expansions and the clinical phenotype and neuropathology of ALS and FTLD. Genetic analysis and immunohistochemistry (IHC) were performed on autopsy-confirmed ALS (N = 75), FTLD-TDP (N = 30), AD (N = 14), and controls (N = 11). IHC for neurodegenerative disease pathology consisted of C9ORF72, UBQLN, p62, and TDP-43. A C9ORF72 expansion was identified in 19.4 % of ALS and 31 % of FTLD-TDP cases. ALS cases with C9ORF72 expansions frequently showed a bulbar onset of disease (57 %) and more rapid disease progression to death compared to non-expansion cases. Staining with C9ORF72 antibodies did not yield specific pathology. UBQLN pathology showed a highly distinct pattern in ALS and FTLD-TDP cases with the C9ORF72 expansion, with UBQLN-positive cytoplasmic inclusions in the cerebellar granular layer and extensive UBQLN-positive aggregates and dystrophic neurites in the hippocampal molecular layer and CA regions. These UBQLN pathologies were sufficiently unique to allow correct prediction of cases that were later confirmed to have C9ORF72 expansions by genetic analysis. UBQLN pathology partially co-localized with p62, and to a minor extent with TDP-43 positive dystrophic neurites and spinal cord skein-like inclusions. Our data indicate a pathophysiological link between C9ORF72 expansions and UBQLN proteins in ALS and FTLD-TDP that is associated with a highly characteristic pattern of UBQLN pathology. Our study indicates that this pathology is associated with alterations in clinical phenotype, and suggests that the presence of C9ORF72 repeat expansions may indicate a worse prognosis in ALS.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.