Presymptomatic Developmental Changes in a Xenopus ALS/FTD Model
Francesca van Tartwijk, Lucia Wunderlich, Ioanna Mela, Stanislaw Makarchuk, Maximilian Jakobs et al.
(see article e2148232024)
Variants of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) exhibit issues in condensation and localization of the RNA-binding protein (RBP) fused in sarcoma (FUS). In this issue, van Tartwijk et al. investigated whether RBP-associated alterations in axonal cytoskeletal organization and branching occur in an in vivo Xenopus (a type of aquatic frog) model of FUS-associated disease as is the case with neurodevelopmental diseases. Two existing Xenopus ALS/FTD mutant models were used: FUS(P525L) and FUS(16R). The authors found that both mutants reduced axonal complexity in vivo. They explored whether this was cue-dependent ex vivo because they also observed an axon defect that they suspected to arise from cue signaling errors. They developed a combined fluorescence and atomic force microscopy approach to discover that mutant FUS reduced actin density in the growth cone, suggesting that FUS mutant Xenopus acquired defects early in axon development. This identification of presymptomatic developmental changes in axonal organization advances our understanding of familial disease variants.
Four different kinds of GFP-tagged FUS mRNA constructs were injected into embryos at the four-cell stage. Pictured is FUS(P525L)-GFP localization in vivo. See van Tartwijk et al. for more details.
New Insights into How Deep Brain Stimulation Works
Raghavan Gopalakrishnan, David Cunningham, Olivia Hogue, Madeleine Schroedel, Brett Campbell et al.
(see article e2149232024)
Cerebellar dentate deep brain stimulation (DN-DBS) has shown promise as a treatment poststroke, but the mechanisms through which it works remain unknown. Herein, Gopalakrishnan et al. investigated corticocerebellar network changes associated with long-term DN-DBS treatment because previous findings from their lab revealed that corticocerebellar networks stay active to maintain motor control following stroke. In this issue, they investigated the excitability of the ipsilesional cortex, the DN, and their interaction after 4–8 months of DN-DBS treatment. Ten human participants showed improved motor control, significantly altered ipsilesional premotor cortex activity, and diminished coherence between the cerebral cortex and the cerebellum. The scientists also observed that DN connectivity with the ipselesional cortex was predictive of DN-DBS–associated motor control outcomes. Thus, the ipselesional cortex becomes less dependent on cerebellocortical inputs and more engaged in motor control as patients recover from stroke with DN-DBS. These novel mechanistic insights are informative for the field and advance our understanding of how DN-DBS works.
Footnotes
This Week in The Journal was written by Paige McKeon
