β-III-spectrin Spinocerebellar Ataxia Type 5 Mutation Reveals a Dominant Cytoskeletal Mechanism That Underlies Dendritic Arborization

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2017 Oct 29

PMID 29078305

Citations 19

Authors

Adam W Avery

David D Thomas

Thomas S Hays

Affiliations

Soon will be listed here.

Abstract

A spinocerebellar ataxia type 5 (SCA5) L253P mutation in the actin-binding domain (ABD) of β-III-spectrin causes high-affinity actin binding and decreased thermal stability in vitro. Here we show in mammalian cells, at physiological temperature, that the mutant ABD retains high-affinity actin binding. Significantly, we provide evidence that the mutation alters the mobility and recruitment of β-III-spectrin in mammalian cells, pointing to a potential disease mechanism. To explore this mechanism, we developed a SCA5 model in which an equivalent mutant β-spectrin is expressed in neurons that extend complex dendritic arbors, such as Purkinje cells, targeted in SCA5 pathogenesis. The mutation causes a proximal shift in arborization coincident with decreased β-spectrin localization in distal dendrites. We show that SCA5 β-spectrin dominantly mislocalizes α-spectrin and ankyrin-2, components of the endogenous spectrin cytoskeleton. Our data suggest that high-affinity actin binding by SCA5 β-spectrin interferes with spectrin-actin cytoskeleton dynamics, leading to a loss of a cytoskeletal mechanism in distal dendrites required for dendrite stabilization and arbor outgrowth.

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