Actin and Diseases of the Nervous System

Abstract

Abnormal regulation of the actin cytoskeleton results in several pathological conditions affecting primarily the nervous system. Those of genetic origin arise during development, but others manifest later in life. Actin regulation is also affected profoundly by environmental factors that can have sustained consequences for the nervous system. Those consequences follow from the fact that the actin cytoskeleton is essential for a multitude of cell biological functions ranging from neuronal migration in cortical development and dendritic spine formation to NMDA receptor activity in learning and alcoholism. Improper regulation of actin, causing aggregation, can contribute to the neurodegeneration of amyloidopathies, such as Down's syndrome and Alzheimer's disease. Much progress has been made in understanding the molecular basis of these diseases.

Keywords: Actin-depolymerizing factor; Alzheimer; Cofilin; Down’s syndrome; Neurodegeneration; Rod.

Fig. 1

The enhancement of actin filament turnover by ADF/cofilin proteins. Included are sev-eral modes of ADF/cofilin regulation including roles for other actin-binding proteins in nucleotide exchange

Fig. 2

Mutations in filamin A (aka actin-binding protein 280; ABP280) cause defects in neu-ronal migration that can be devastating for the development of the forebrain. Filamin is an actin filament cross-linking protein that also links transmembrane proteins to the underlying cytoskeleton. The effects of its mutation range from mental retardation to schizophrenia (adapted from Lambert and Goffinet 2001)

Fig. 3

Filamin A (FLNa) could seriously impact actin dynamics in the leading edge of migrat-ing neurons by stimulating Pak autophosphorylation and hence Pak activity. Pak has multiple effects on ADF/cofilin phosphorylation: it phosphorylates slingshot (an inactivation) and phos-phorylates LIMK (an activation). The phosphorylation of both slingshot and LIMK reduces ADF/cofilin activity. Adding to the complexity of these interactions is the fact that pPak feeds back on the phosphorylation of FLNa. Bold arrows symbolize activation; dashed arrows symbolize inactivation

Fig. 4

In 4–8 h Xenopus laevis cultures, growth cones are attracted by a BMP7 gradient via LIMK which inactivates ADF/cofilin. However, the appearance of TRPC1 after overnight culture tilts the LIMK/slingshot balance toward slingshot (SSH), thus converting the BMP7 gradient to repulsion of the growth cone. The repulsion requires Ca²⁺ activation of slingshot via calcineurin (CaN). Bold arrows symbolize activation; dashed arrows symbolize inactivation (adapted from Wen et al. 2007).

Fig. 5

This cartoon depicts the heterogeneity of dendritic spine morphology in both mature and developing brain. Alterations in spine morphology have been correlated with significant changes in human behavior and are largely a function of the regulation of actin, the major cytoskeletal protein found within these structures (adapted from Sekino et al. 2007)

Fig. 6

This schematic illustrates the hypothetical feed-forward model of neurodegeneration that may occur when actin-cofilin rods are generated in neuronal amyloidogenic conditions. In the absence of amyloid accumulation, rod formation may also contribute to synaptic dysfunction