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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 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 (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 novel 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 lifespan deficits in two distinct mouse models of TDP-43 proteinopathy. Because many toxic proteins can be cleared along the autophagy-lysosome axis, targeted reduction of Nlk represents a potential approach to therapy development for multiple neurodegenerative disorders.

ORGANISM(S): Mus musculus

PROVIDER: GSE235312 | GEO | 2023/06/24

REPOSITORIES: GEO

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Project description:Knowledge about the nature and timepoint of pathomolecular alterations preceding onset of symptoms in amyotrophic lateral sclerosis (ALS) is largely lacking. It could not only pave the way for valuable therapeutic targets but might also govern future concepts of pre-manifest disease modifying treatments. MicroRNAs (miRNAs) are central regulators of transcriptome plasticity and participate in pathogenic cascades and/or mirror cellular adaptation to insults. We obtained expression profiles of miRNAs as well as other non-coding RNAs (ncRNAs) in the serum of sporadic ALS patients (sALS), familial ALS cases (fALS), asymptomatic mutation carriers and healthy controls. We observed a strikingly homogenous ncRNA profile in fALS patients that, to a large extend, was independent to the underlying disease gene and different to heterogeneous ncRNA signatures in sALS patients. Moreover, we identified 68 significantly dysregulated ncRNAs in pre-manifest ALS mutation carriers, more than 20 years before the estimated time window of disease onset. 91% of ncRNA alterations in mutation carriers overlapped with the fALS patients revealing progressive changes towards and during the disease. Our data thus demonstrate a high epigenetic heterogeneity amongst sALS patients and suggest common denominators regarding molecular pathogenesis of different ALS genes. We describe the earliest pathomolecular alterations in ALS known to date, which provide a basis for the development of predictors of disease onset as well as the discovery of novel therapeutic targets and strongly argue for studies evaluating pre-symptomatic disease-modifying treatment in ALS. Serum ncRNA pofiles of sporadic and familiar ALS patients as well as asymptomatic ALS mutation carriers were compared to age and gender matched healthy controls using a total of 53 Affymetrix miRNA 3.0 arrays. In detail, a total of 9 fALS patients (analyzed in 6 arrays) were compared to 10 controls, a total of 18 ALS mutation carriers (analyzed in 12 arrays) were compared to 8 controls and 18 sALS patients were compared to 16 controls.

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

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