ADF/Cofilin-Actin Rods in Neurodegenerative Diseases

Abstract

Dephosphorylation (activation) of cofilin, an actin binding protein, is stimulated by initiators of neuronal dysfunction and degeneration including oxidative stress, excitotoxic glutamate, ischemia, and soluble forms of β-amyloid peptide (Aβ). Hyperactive cofilin forms rod-shaped cofilin-saturated actin filament bundles (rods). Other proteins are recruited to rods but are not necessary for rod formation. Neuronal cytoplasmic rods accumulate within neurites where they disrupt synaptic function and are a likely cause of synaptic loss without neuronal loss, as occurs early in dementias. Different rod-inducing stimuli target distinct neuronal populations within the hippocampus. Rods form rapidly, often in tandem arrays, in response to stress. They accumulate phosphorylated tau that immunostains for epitopes present in “striated neuropil threads,” characteristic of tau pathology in Alzheimer disease (AD) brain. Thus, rods might aid in further tau modifications or assembly into paired helical filaments, the major component of neurofibrillary tangles (NFTs). Rods can occlude neurites and block vesicle transport. Some rod-inducing treatments cause an increase in secreted Aβ. Thus rods may mediate the loss of synapses, production of excess Aβ, and formation of NFTs, all of the pathological hallmarks of AD. Cofilin-actin rods also form within the nucleus of heat-shocked neurons and are cleared from cells expressing wild type huntingtin protein but not in cells expressing mutant or silenced huntingtin, suggesting a role for nuclear rods in Huntington disease (HD). As an early event in the neurodegenerative cascade, rod formation is an ideal target for therapeutic intervention that might be useful in treatment of many different neurological diseases.

Cofilin under control of β-arrestin-2 in NMDA-dependent dendritic spine plasticity, long-term depression (LTD), and learning

“…Indeed, the overexpression of active nonphosphorylatable cofilin S3A in β-arrestin-1 KO neurons resulted in the formation of structures resembling cofilin-actin rods (Fig. 2B) that have been reported in conditions of cellular stress (35,36). These results suggest that both the ability of β-arrestin-2 to control NMDA-induced spine remodeling and the β-arrestin-1-dependent development of mature spines depend on cofilin activation.…”

“…In support of this, overexpression of constitutively active cofilin S3A in β-arrestin-1 KO neurons leads to formation of cofilin-actin rods, structures formed under conditions of cellular stress when cofilin is excessively active (23,35,36,45). In contrast, overexpression of phosphomimetic cofilin S3D restores mature dendritic spines in β-arrestin-1 KO neurons and prevents rod formation, most likely through competitive inhibition of cofilin dephosphorylation by SSH.…”

Remodeling of actin filaments by ADF/cofilin proteins

“…While cofilin was originally viewed as a protein that severed and depolymerized actin filaments, it is now understood to play more diverse roles in regulating the assembly of cellular actin pools, including the formation of stable actin-cofilin rods that are associated with neurodegeneration (8). Recent findings demonstrate that the activity of cofilin is modulated by almost any perturbation of normal cell physiology (9) and identify this protein as a "functional node in cell biology" (9).…”

Focus on ADF/Cofilin: Beyond Actin Cytoskeletal Regulation

“…It has been reported that the appearance of cofilin-actin rod-enriched inclusion bodies is a pathological feature widely existed in a broad spectrum of neurodegenerative diseases [15,59]. Cofilinactin rods are rapidly formed in response to neural stress [60].…”

“…The phosphorylated state of ADF/cofilin affects the activity and stability of this protein on actin cytoskeletal organization and subsequent cell physiology [14]. Furthermore, recent studies have addressed the importance of ADF/cofilin on neurology and nephrology [15,16]. In this paper, we will discuss the biochemical mechanisms of ADF/cofilin.…”