Nuclear import receptors are recruited by FG-nucleoporins to rescue hallmarks of TDP-43 proteinopathy.

BACKGROUND: Cytoplasmic mislocalization and aggregation of TAR DNA-binding protein-43 (TDP-43) is a hallmark of the amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD) disease spectrum, causing both nuclear loss-of-function and cytoplasmic toxic gain-of-function phenotypes. While TDP-43 proteinopathy has been associated with defects in nucleocytoplasmic transport, this process is still poorly understood. Here we study the role of karyopherin-ß1 (KPNB1) and other nuclear import receptors in regulating TDP-43 pathology. METHODS: We used immunostaining, immunoprecipitation, biochemical and toxicity assays in cell lines, primary neuron and organotypic mouse brain slice cultures, to determine the impact of KPNB1 on the solubility, localization, and toxicity of pathological TDP-43 constructs. Postmortem patient brain and spinal cord tissue was stained to assess KPNB1 colocalization with TDP-43 inclusions. Turbidity assays were employed to study the dissolution and prevention of aggregation of recombinant TDP-43 fibrils in vitro. Fly models of TDP-43 proteinopathy were used to determine the effect of KPNB1 on their neurodegenerative phenotype in vivo. RESULTS: We discovered that several members of the nuclear import receptor protein family can reduce the formation of pathological TDP-43 aggregates. Using KPNB1 as a model, we found that its activity depends on the prion-like C-terminal region of TDP-43, which mediates the co-aggregation with phenylalanine and glycine-rich nucleoporins (FG-Nups) such as Nup62. KPNB1 is recruited into these co-aggregates where it acts as a molecular chaperone that reverses aberrant phase transition of Nup62 and TDP-43. These findings are supported by the discovery that Nup62 and KPNB1 are also sequestered into pathological TDP-43 aggregates in ALS/FTD postmortem CNS tissue, and by the identification of the fly ortholog of KPNB1 as a strong protective modifier in Drosophila models of TDP-43 proteinopathy. Our results show that KPNB1 can rescue all hallmarks of TDP-43 pathology, by restoring its solubility and nuclear localization, and reducing neurodegeneration in cellular and animal models of ALS/FTD. CONCLUSION: Our findings suggest a novel NLS-independent mechanism where, analogous to its canonical role in dissolving the diffusion barrier formed by FG-Nups in the nuclear pore, KPNB1 is recruited into TDP-43/FG-Nup co-aggregates present in TDP-43 proteinopathies and therapeutically reverses their deleterious phase transition and mislocalization, mitigating neurodegeneration.

Diffusion-weighted imaging-documented bilateral small embolic stroke involving multiple vascular territories may indicate occult cancer: A retrospective case series and a brief review of the literature.

Diffusion-weighted imaging (DWI) MRI is very sensitive for detecting small embolic brain infarctions. Stroke as the first manifestation of cancer is extremely rare. We performed a retrospective study to identify the clinical and DWI features of patients with acute ischemic stroke as the first manifestation of occult cancer. A total of five patients in our hospital from January 2017 to May 2019 were analyzed. We also reviewed the literature and seven case series (16 patients) were included. Most of these patients were aged in their sixties and lung cancer was the most common type of occult cancer. Patients showed various presentations of ischemic stroke. All of the patients showed small multiple lesions on DWI that involved mostly the anterior or both anterior and posterior territories. The lesions were mostly in both the supratentorium and infratentorium, with the mechanisms of embolic and watershed infarcts. These features were useful for identifying the causes of embolic stroke. Therefore, patients with small bilateral embolic stroke, especially those involved in multiple vascular territories, should be examined for concealed malignancy.

Efficacy of perioperative anticonvulsant prophylaxis in seizure-naïve glioma patients: A meta-analysis.

The efficacy of perioperative seizure prophylaxis in seizure-naïve glioma patients is still controversial. Thus we conducted this meta-analysis to assess the effectiveness of perioperative prophylactic antiepileptic drugs (AEDs) on postoperative seizures in seizure-naïve glioma for the first time. We systematically searched PubMed, Embase, Weipu (VIP) and Chinese National Knowledge Infrastructure (CNKI) until July 5, 2019 for eligible studies. Fixed or random model was used to calculate the odds ratios in STATA 12.0 software. Subgroup analyses of early postoperative seizure, late postoperative seizure, high-grade glioma (WHOIII-IV) and phenytoin (PHT) or phenobarbital (PB) prophylaxis were conducted. Altogether 1143 seizure-naïve glioma patients from 9 studies were included in this meta-analysis, containing 643 prophylaxed and 503 non-prophylaxed patients. No significant association was detected between perioperative seizure prophylaxis and postoperative seizure occurrence in glioma patients without preoperative seizure history (OR = 0.91, 95% CI = 0.65-1.26, P = 0.56). Perioperative AED prophylaxis showed no significant benefit to postoperative seizures when stratified by early postoperative seizure(within the first postoperative week), late postoperative seizure (after the first postoperative week), high-grade glioma and PHT or PB prophylaxis (all P > 0.05). Current evidence indicated that perioperative seizure prophylaxis did not reduce the occurrence of postoperative seizure in seizure-naïve glioma patients. The pros and cons of perioperative seizure prophylaxis should be considered before the start of perioperative AEDs treatment.