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Spectrins: molecular organizers and targets of neurological disorders

Abstract

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.

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Fig. 1: Cellular localization and organization of neuronal spectrins.
Fig. 2: Tetrameric assembly and structural domains of neuronal spectrins.
Fig. 3: Deficiencies in mouse models of neuronal spectrin dysfunction.
Fig. 4: Spectrin variants associated with neurological disorders.
Fig. 5: Major phenotypes in humans with spectrinopathies of the nervous system.

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Acknowledgements

The authors apologize to those colleagues whose work could not be cited because of space limitations. This work was supported by National Institute of Mental Health (NIMH) grant R01MH127848 and National Institute of Neurological Disorders and Stroke (NINDS) grant R01NS110810.

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Glossary

Axon initial segment

(AIS). The domain 20–60 μm long at the proximal axon–soma interface that has a high density of voltage-gated ion channels and other membrane proteins responsible for the initiation of the action potential.

De novo variants

Changes in the sequence of a gene that are seen for the first time in an individual but are not present in the parents.

Gain-of-function

A missense mutation (altered amino acid sequence) that results in enhanced or abnormal protein function.

Haploinsufficient

A gene for which 50% of normal protein expression is insufficient for normal function and may result in disease.

Juxtaparanode

A region adjacent to each side of a paranode in myelinated axons.

Knock-in mouse

A mouse in which an endogenous gene sequence of interest is altered by a one-for-one substitution with a transgene or by adding gene sequences that are not found within the locus.

Knockout mouse

A mouse in which expression of a gene of interest is inactivated.

Loss-of-function

A mutation that abolishes protein function, often by partial or complete loss of protein expression.

Nodes of Ranvier

(NoR). Ion channel-rich gaps along a myelinated axon that expose the neuronal membrane to the extracellular space and speed up the propagation of the action potential along the axon.

Paranode

A region adjacent to each edge of nodes of Ranvier (NoR) in myelinated axons.

Pinceaux terminals

The terminals of the Pinceau, a paintbrush-like network of cerebellar basket cell axon branchlets embracing the axon initial segment (AIS) of Purkinje neurons.

Postsynaptic density

(PSD). The protein-dense molecular network located beneath the membrane of dendritic spines of excitatory neurons.

Probands

The first individuals in a family who are suspected to be at risk of or affected by a genetic condition.

Somatodendritic

A neuronal region that includes the cell body and dendrites but excludes the axon.

Spectrinopathies

Diseases associated with loss or aberrant function of spectrins.

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Lorenzo, D.N., Edwards, R.J. & Slavutsky, A.L. Spectrins: molecular organizers and targets of neurological disorders. Nat Rev Neurosci 24, 195–212 (2023). https://doi.org/10.1038/s41583-022-00674-6

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