Speaker
Description
βII-spectrin, encoded by SPTBN1, binds F-actin to form a submembrane cytoskeletal lattice that organizes transmembrane proteins in neurons. We discovered that heterozygous SPTBN1 variants cause a neurodevelopmental disorder marked by developmental delay, intellectual disability, ASD, ADHD, epilepsy, and cortical deficits –SPTBN1 syndrome. Brain βII-spectrin haploinsuficient mice display developmental delays as well as cortical development and behavioral deficits in line with patients’ presentations, supporting a loss-of-function pathogenic mechanism. Notably, most probands carry missense variants within the N-terminal calponin homology domains (CHDs), which bind F-actin. However, the unique and/or shared mechanisms through which CHD variants cause these morphological alterations and impact downstream neuronal processes are unknown.
Here, we combine studies in stem cell-derived human neurons, mouse models and heterologous systems to investigate the molecular and cellular effects of SPTBN1 CHD syndrome variants. We find across disease models that endogenous heterozygous expression of a subset of these variants cause protein aggregates, which sequester wild-type and mutant βII-spectrin and other key protein partners. This alters the neuronal proteome and affect the integrity of the axon initial segment. Knock-in mice expressing aggregation-prone disease variants exhibit disruptions in cortical and cerebellar development and behavioral deficits that recapitulate patients’ clinical presentations. We demonstrate that βII-spectrin aggregates recruit the proteostasis machinery and are susceptible to targeted degradation by disaggregases and pharmacological chaperone activators. These findings offer potential therapeutic strategies to restore βII-spectrin function.
| Author(s) | Damaris N. Lorenzo*, Anastasia Slavutsky, Chadni Sanyal, Misha Bankulla, Ismael Ferrer |
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| Affiliation(s) | University of Pennsylvania Perelman School of Medicine |
