Abstract
Cofilin is an actin-binding protein that plays a major role in the regulation of actin dynamics, an essential cellular process. This protein has emerged as a crucial molecule for functions of the nervous system including motility and guidance of the neuronal growth cone, dendritic spine organization, axonal branching, and synaptic signalling. Recently, other important functions in cell biology such as apoptosis or the control of mitochondrial function have been attributed to cofilin. Moreover, novel mechanisms of cofilin function regulation have also been described. The activity of cofilin is controlled by complex regulatory mechanisms, with phosphorylation being the most important, since the addition of a phosphate group to cofilin renders it inactive. Due to its participation in a wide variety of key processes in the cell, cofilin has been related to a great variety of pathologies, among which neurodegenerative diseases have attracted great interest. In this review, we summarized the functions of cofilin and its regulation, emphasizing how defects in these processes have been related to different neurodegenerative diseases.
Highlights
In 1980, Bamburg et al identified a protein that acted as an actin disassembly factor in chicken brain extracts [1]
Actin microfilaments (F-actin) are linear polymers composed of globular actin monomers (G-actin), which are polarized with a barbed end, where the addition of available actin monomers bound to ATP occurs, and a pointed end, where actin bound to ADP is released [3]
The addition and release of actin monomers allows actin microfilaments to be a dynamic structure capable of responding to stimuli. These actin dynamics are possible thanks to accessory proteins such as the Arp2/3 complex and formin, involved in actin nucleation, a process of the formation of a complex composed of actin monomers from which an actin filament can elongate; profilin, involved in microfilament elongation; or ADF/cofilin, involved in actin disassembly, its function has been shown to vary depending on cofilin concentration relative to actin [4], as Figure 1 shows
Summary
In 1980, Bamburg et al identified a protein that acted as an actin disassembly factor in chicken brain extracts [1]. At low cofilin/actin ratios, cofilin binds to the ADP-actin region of the F-actin, and it severs filaments in a persistent way creating new barbed and pointed ends. At higher cofilin/actin ratios, many cofilin subunits pieces of F-actin generated by severing can nucleate filament growth or enhance depolybind to ADP-actin, induce conformational changes in theratios, microfilament modifying merization if ATP-actin is limited [5]. At low cosubunits can be can released from the and and a barbed end,end, where actin subunits can cofilin/actin ratios, cofilin binds to ADP-actin of filaments severs it, creating pointed barbed ends. Cofilin competes with tau for microtubule binding, displacing tau and cofilin; Drp, dynamin-related protein 1; HTT, huntingtin; LIMK, LIM-domain containing kinase; promoting tauopathies. Amyloid β; APP, amyloid precursor protein; CIN, chronophin; COF, PLD1, phospholipase D1; PP1/PP2, protein phosphatase 1 and 2; PRKN, parkin; SSH1, slingshot; cofilin; Drp, dynamin-related protein 1; HTT, huntingtin; LIMK, LIM-domain containing kinase; TESK, testis-specific kinase
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