Reduction of nemo-like kinase increases lysosome biogenesis and ameliorates TDP-43–related neurodegeneration

Abstract

Protein aggregation is a hallmark of many neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). Although mutations in TARDBP , encoding transactive response DNA-binding protein 43 kDa (TDP-43), account for less than 1% of all ALS cases, TDP-43–positive aggregates are present in nearly all ALS patients, including patients with sporadic ALS (sALS) or carrying other familial ALS–causing (fALS-causing) mutations. Interestingly, TDP-43 inclusions are also present in subsets of patients with frontotemporal dementia, Alzheimer’s disease, and Parkinson’s disease; therefore, methods of activating intracellular protein quality control machinery capable of clearing toxic cytoplasmic TDP-43 species may alleviate disease-related phenotypes. Here, we identify a function of nemo-like kinase (Nlk) as a negative regulator of lysosome biogenesis. Genetic or pharmacological reduction of Nlk increased lysosome formation and improved clearance of aggregated TDP-43. Furthermore, Nlk reduction ameliorated pathological, behavioral, and life span deficits in 2 distinct mouse models of TDP-43 proteinopathy. Because many toxic proteins can be cleared through the autophagy/lysosome pathway, targeted reduction of Nlk represents a potential approach to therapy development for multiple neurodegenerative disorders.

Localized T3 production modifies the transcriptome and promotes the hepatocyte-like lineage in iPSC-derived hepatic organoids

“…As indicated, 2 primary antibodies were used during the same incubation only if they were prepared in different species as described in ref. 42 Cells and organoids were then washed with PBS, and the appropriate secondary antibodies (Supplemental Table 4) were added for 2 hours at RT. Nuclei were visualized with DAPI.…”

Two-sample Mendelian randomization analysis of 91 circulating inflammatory protein levels and amyotrophic lateral sclerosis

“…Recent focus in ALS research has centered on systemic inflammation, especially the role of circulating inflammatory proteins ( Henkel et al, 2004 ; Murdock et al, 2015 ; Zondler et al, 2016 ). Studies have linked proteins like PIKFYVE kinase and TDP-43 to neuronal damage in ALS, associating their inhibition or misfolding with neuronal injury ( Gleixner et al, 2022 ; Shao et al, 2022 ; Tejwani et al, 2023 ). This growing body of evidence underscores the importance of these proteins as both biomarkers and potential therapeutic targets ( Akiyama et al, 2022 ; Jiang et al, 2022 ; Hosaka et al, 2023 ).…”