Spectrins: molecular organizers and targets of neurological disorders

Spectrins are cytoskeletal proteins that are expressed ubiquitously in the mammalian nervous system. Pathogenic variants in SPTAN1, SPTBN1, SPTBN2 and SPTBN4, four of the six genes encoding neuronal spectrins, cause neurological disorders. Despite their structural similarity and shared role as molecular organizers at the cell membrane, spectrins vary in expression, subcellular localization and specialization in neurons, and this variation partly underlies non-overlapping disease presentations across spectrinopathies. Here, we summarize recent progress in discerning the local and long-range organization and diverse functions of neuronal spectrins. We provide an overview of functional studies using mouse models, which, together with growing human genetic and clinical data, are helping to illuminate the aetiology of neurological spectrinopathies. These approaches are all critical on the path to plausible therapeutic solutions. Spectrins are abundant cytoskeletal proteins with multifaceted roles in the nervous system whose dysfunction leads to neurological syndromes. In this review, Lorenzo et al. provide an update on the neurobiology of spectrins and the genetics of neuronal spectrinopathies, together with insights into the pathophysiology of these disorders.

Automated summary

Spectrins, encoded by genes such as SPTAN1, SPTBN1, SPTBN2 and SPTBN4, are implicated in neurological disorders. This review summarizes the diverse functions and organization of neuronal spectrins and provides insights into the pathophysiology of spectrinopathies, aided by functional studies in mouse models.