Background And Objectives: Pathogenic variations in fused in sarcoma are among the most common genetic causes of amyotrophic lateral sclerosis (ALS) worldwide. They are supposedly characterized by a homogeneous pure motor phenotype with early-onset and short disease duration. However, a few mutated cases with a very late disease onset and slow progression have been reported. To analyze genotype-phenotype correlations and identify the prognostic factors in -ALS cases.
Methods: We identified and cross-sectionally analyzed 22 -ALS patient histories from a single-center cohort of 2,615 genetically tested patients and reviewed 289 previously published -ALS cases. Survival analysis was performed by Kaplan-Meier survival curves, followed by the log-rank test and multivariate Cox analysis.
Results: Survival of -ALS is age-dependent: In our cohort, early-onset cases had a rapid disease progression and short survival ( = 0.000003) while the outcome of -mutated patients with mid-to-late onset did not differ from non--ALS patients ( = 0.437). Meta-analysis of literature data confirmed this trend ( = 0.00003). This survival pattern is not observed in other ALS-related genes in our series. We clustered -ALS patients in 3 phenotypes: (1) axial ALS, with upper cervical and dropped-head onset in mid-to-late adulthood; (2) benign ALS, usually with a late-onset and slow disease progression; and (3) juvenile ALS, often with bulbar onset and preceded by learning disability or mild mental retardation. Those phenotypes arise from different mutations.
Discussion: We observed specific genotype-phenotype correlations of -ALS and identified age at onset as the most critical prognostic factor. Our results demonstrated that mutations underlie a specific subtype of ALS and enable a careful stratification of newly diagnosed -ALS cases for clinical course and potential therapeutic windows. This will be crucial in the light of incoming gene-specific therapy.
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http://dx.doi.org/10.1212/NXG.0000000000200011 | DOI Listing |
Nat Commun
December 2024
Department of Biochemistry, McGill University, Montreal, QC, Canada.
Proteostasis is maintained through regulated protein synthesis and degradation and chaperone-assisted protein folding. However, this is challenging in neuronal projections because of their polarized morphology and constant synaptic proteome remodeling. Using high-resolution fluorescence microscopy, we discover that hippocampal and spinal cord motor neurons of mouse and human origin localize a subset of chaperone mRNAs to their dendrites and use microtubule-based transport to increase this asymmetric localization following proteotoxic stress.
View Article and Find Full Text PDFFEBS Lett
December 2024
School of Pharmacy at Fukuoka, International University of Health and Welfare, Fukuoka, Japan.
Fused in sarcoma (FUS) is a causative factor of amyotrophic lateral sclerosis (ALS) and is believed to propagate pathologically by transmission from cell to cell. However, the mechanism underlying FUS release from cells, which is a critical step for the propagation system, remains poorly understood. This study conducted an analysis of the release of human and mouse FUS from neurons, revealing that human FUS is significantly released into the media compared to its mouse counterpart.
View Article and Find Full Text PDFDiscov Med
December 2024
Department of Urology, The 908th Hospital of Joint Logistic Support Force of PLA, 330000 Nanchang, Jiangxi, China.
Background: Bladder cancer (BC) is a malignant tumor that begins in the cells of the bladder, characterized by poor cell differentiation and strong invasion capacity, with a high incidence rate. Identifying key molecules that enhance BC cells' cisplatin sensitivity can help improve the clinical efficacy of BC treatment. Hence, this study aimed to determine the expression level of long non-coding RNA (lncRNA) ADAM Metallopeptidase with Thrombospondin Type 1 Motif 9 Antisense RNA 1 () in BC and explore its related mechanism underlying the amplification of cisplatin sensitivity.
View Article and Find Full Text PDFWorld J Clin Oncol
December 2024
Department of Pathology, Peking University People's Hospital, Beijing 100044, China.
Background: Primary squamous cell carcinoma (SCC) of the middle ear is rare, with non-keratinizing basaloid types being exceptionally uncommon. Distinguishing these cancers, often caused by viral factors (, human papillomavirus or Epstein-Barr virus), or specific genetic alterations (, bromodomain-containing protein 4-nuclear protein in or gene fused with FLI chromosomal rearrangement), from other cranial conditions, is difficult. The recently identified DEK::AFF2 non-keratinizing SCC (NKSCC) is a novel subtype, fitting the World Health Organization classification of head and neck neoplasms.
View Article and Find Full Text PDFNeurosci Insights
December 2024
Department of Neurosurgery, Center for Neuroregeneration, Houston Methodist Research Institute, Houston, TX, USA.
Mitochondrial dysfunction plays a pivotal role in the progression of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Alzheimer's, and Parkinson's disease. Recent discoveries have highlighted the involvement of DNA damage and repair processes, particularly mitochondrial DNA (mtDNA) damage, in these conditions. This commentary reflects on our recent findings, demonstrating the RNA/DNA binding protein fused in sarcoma (FUS)'s crucial role in maintaining mtDNA integrity through interactions with mitochondrial DNA ligase IIIα (mtLig3).
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