Genetic mutations in RNA-binding proteins and their roles in ALS

Chung

et al. 2019

Preprint

25Accumulation of RNA in the nucleus is one of the pathological features of C9orf72-associated 26 amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD), yet its potential 27 42 Staufen, may also be an important pathological feature of C9-ALS/FTD. 43 44 45 46 47 3 48 Author summary 49 Cytoplasmic accumulation of nuclear RNA-binding proteins (RBPs) is one of the common 50 pathological features of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia 51 (FTD). In C9orf72-associated ALS/FTD fly model, we found that Staufen, a double-stranded 52 (ds) RBP normally localized mostly in cytoplasm, accumulates in the nucleus in an RNA-53 dependent manner. Next, we checked wherein the nucleus Staufen accumulates and found that 54 Staufen partially co-localizes with heterochromatin and nucleolus. Interestingly, the expression 55 of Fibrillarin, a nucleolar protein, was significantly increased by C9orf72-derived PR toxicity 56 and further augmented by reduction in stau dosage, the gene encoding Staufen. When we 57 knocked down fib, the gene encoding Fibrillarin, PR-induced retinal degeneration was 58 exacerbated. This indicates that increased Fibrillarin expression by stau dosage reduction is 59 protective. Furthermore, when we reduced stau dosage in flies presenting PR toxicity, their 60 retinal degeneration and viability were largely rescued. Based on these data, we suggest that 61 nuclear accumulation of Staufen is an important feature of C9-ALS/FTD and suggest that 62 reducing stau dosage is a promising therapeutic target.

Section: Discussionmentioning

confidence: 99%

C9orf72-associated arginine-rich dipeptide repeats induce RNA-dependent accumulation of Staufen in nucleus

Chung

et al. 2019

Preprint

“…At the very C-terminal end is a nuclear localization signal. Aside from cancer, all three FET family members are mutated in ALS and in frontotemporal dementia (FTD) (Couthouis et al, 2012;Kapeli et al, 2017). FET proteins have been demonstrated to form higher order structures that cause liquid demixing and formation of membraneless organelles through aggregation in the PrLD (Altmeyer et al, 2015;Qamar et al, 2018;Tanikawa et al, 2018) or RNA binding (Maharana et al, 2018).…”

Section: Introductionmentioning

confidence: 99%

Androgen signaling connects short isoform production to breakpoint formation at Ewing sarcoma breakpoint region 1 via an R-loop-dependent mechanism

Nicholas

Hollenhorst

2020

Preprint

Ewing's sarcoma is most prevalent in adolescent males and is almost always the result of a chromosomal rearrangement that creases a fusion gene with EWSR1 as the 5' fusion partner.Why EWSR1 is more commonly rearranged than other, similar genes and why Ewing's sarcoma is predisposed to adolescent males is not known. We found that in prostate cancer, androgen signaling upregulated a 5' EWSR1 isoform by promoting usage of an intronic polyadenylation site proximal to the Ewing's sarcoma breakpoint hotspot. An intronic Androgen Receptor (AR) binding site was necessary for this upregulation. Strikingly, androgen signaling drove high levels of breakpoint formation in EWSR1. Androgen signaling also promoted R-loop formation and Rloops were necessary for breakpoint formation. These data suggest that aberrant androgen signaling leads to R-loop-mediated DNA damage at the EWSR1 breakpoint hotspot and subsequent misrepair could promote EWSR1 gene fusions in Ewing's sarcoma.

“…5 Currently, there are more than 37 known pathogenic mutation foci in TARDBP, 35 of which are concentrated in the heterogeneous nuclear ribonucleoprotein (hnRNP) area in the C-terminal, suggesting that the inhibition of the protein-binding site involved in the control of RNA splicing may have a relationship with the onset and development of ALS. 6 Previous reports revealed the clinical features of patients with TDP-43-mutated ALS. However, the available pathological analyses are not sufficient to fully characterize the pathological features of TDP-43-mutated ALS.…”

Section: Introductionmentioning

confidence: 99%

p.N345K mutation in TARDBP in a patient with familial amyotrophic lateral sclerosis: An autopsy case

et al. 2019

We report the neuropathology of a patient with a family history of amyotrophic lateral sclerosis (ALS) and a p. N345K mutation in the transactivation response DNAbinding protein 43 kDa (TDP-43) gene (TARDBP). A 62-year-old man had bulbar palsy with progressive weakness in the extremities. Neurological examination revealed evident upper motor neuron signs and lower motor neuron involvement corroborated by needle electromyography. The patient was diagnosed as having probable ALS according to the revised El Escorial diagnostic criteria and was eventually diagnosed with familial ALS. At 65 years of age, respiratory failure became critical, and artificial ventilation was initiated. At 70 years of age, the patient died from a urinary tract infection. Histopathological investigation showed Bunina bodies in the remaining motor neurons and anterolateral funicular myelin pallor in the spinal cord. TDP-43-positive cytoplasmic inclusions were quite rare in the spinal cord motor neurons, being predominantly present in the glial cells (especially astrocytes) of the spinal cord anterior horn. Although the reason for the preferential vulnerability of spinal glial cells to TARDBP mutations remains unclear, our findings indicate that TARDBP p.N345K mutation could have an influence on the topography of TDP-43 aggregation.