Biology subjects

Haeusler, A.

Publications and source records attributed to Haeusler, A..

3 recordsLinked to original sources

bioRxiv2023

Glucose Hypometabolism Prompts RAN Translation and Exacerbates C9orf72-related ALS/FTD Phenotypes

The most prevalent genetic cause of both amyotrophic lateral sclerosis and frontotemporal dementia is a (GGGGCC)n nucleotide repeat expansion (NRE) occurring in the first intron of the C9orf72 gene (C9). Brain glucose hypometabolism is consistently observed in C9-NRE carriers, even at pre-symptomatic stages, although its potential role in disease pathogenesis is unknown. Here, we identified alterations in glucose metabolic pathways and ATP levels in the brain of asymptomatic C9-BAC mice. We found that, through activation of the GCN2 kinase, glucose hypometabolism drives the production of dipeptide repeat proteins (DPRs), impairs the survival of C9 patient-derived neurons, and triggers motor dysfunction in C9-BAC mice. We also found that one of the arginine-rich DPRs (PR) can directly contribute to glucose metabolism and metabolic stress. These findings provide a mechanistic link between energy imbalances and C9-ALS/FTD pathogenesis and support a feedforward loop model that opens several opportunities for therapeutic intervention.

neuroscience↗

bioRxiv2022

KapBeta2 is a modifier of the C9orf72-linked glycine-arginine dipeptide neurotoxicity

SummaryExpanded intronic G4C2 repeats in the C9orf72 gene cause several cases of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). These repeats are translated through a non-AUG-dependent mechanism into five different dipeptides (DPRs), including poly-glycine-arginine (GR), which is aggregation-prone and eventually neurotoxic. Here, we report that Kap{beta}2 and GR interact, co-aggregating in primary neurons in-vitro and CNS tissue in-vivo. Importantly, this interaction improves the overall survival of neurons expressing GR. Downregulation of Kap {beta}2 is detrimental to the survival of neurons only if GR is expressed, whereas increased Kap {beta}2 levels mitigate GR-mediated neurotoxicity. notably, we did not find any changes in TDP-43 localization nor in the dynamic properties of the GR aggregates when Kap{beta}2 was over-expressed. These findings support the design of therapeutic strategies aimed at modulating Kap {beta}2 levels as a potential new avenue for contrasting neurodegeneration in C9orf72-ALS/FTD.

neuroscience↗

bioRxiv2021

Astrocytic expression of ALS-causative mutant FUS leads to TNFa-dependent neurodegeneration in vivo

Genetic mutations that cause Amyotrophic Lateral Sclerosis (ALS), a progressively lethal motor neuron disease, are commonly found in ubiquitously expressed genes. In addition to direct defects within motor neurons, growing evidence suggests that dysfunction of non-neuronal cells is also an important driver of disease. Previously, we demonstrated that mutations in DNA/RNA binding protein Fused in Sarcoma (FUS) induce neurotoxic phenotypes in astrocytes in vitro, via activation of the NF-{kappa}B pathway and release of pro-inflammatory cytokine TNF. Here, we developed an intraspinal cord injection model to test whether astrocyte-specific expression of ALS-causative FUSR521G variant (mtFUS) causes neuronal damage in vivo. We show that mtFUS expression causes TNF upregulation, motor function deficits, and spinal motor neuron loss. We further demonstrate a lack of phenotype in TNF knockout animals expressing mtFUS, and prevention of neurodegeneration in mtFUS-transduced animals through administration of TNF neutralizing antibodies. Together, these studies strengthen evidence that astrocytes contribute to disease in ALS, establish that FUS-ALS astrocytes induce pathogenic changes to motor neurons in vivo, and provide insights identifying FUS-ALS specific potential therapeutic targets.

neuroscience↗