Cofilin expression induces cofilin-actin rod formation and disrupts synaptic structure and function in Aplysia synapses

Abstract

Cofilin-actin rods are inclusion-like structures that are induced by certain chemical or physical stresses in cultured cells, and the rods formed in neurons are thought to be associated with neurodegeneration. Here, we cloned an Aplysia cofilin homolog and overexpressed it in cultured neurons. Overexpressed cofilin formed rod-like structures that included actin. The overall neuronal morphology was unaffected by cofilin overexpression; however, a decrease in number of synaptic varicosities was observed. Consistent with this structural change by cofilin overexpression, the synaptic strength was reduced, and furthermore, the long-term facilitation elicited by repeated pulses of 5-hydroxytryptamine was impaired in sensory-to-motor synapses. However, cofilin overexpression did not induce programmed cell death. These findings suggest that the formation of cofilin-actin rod-like structures can lead to neurodegeneration, and this might be a mechanism of rundown of neuronal and synaptic function without cell death in neurodegenerative diseases.neurodegeneration ͉ Hirano body ͉ long-term facilitation

Accumulation of Citrullinated Proteins by Up-Regulated Peptidylarginine Deiminase 2 in Brains of Scrapie-Infected Mice

“…Cofilin 1 is an actin-binding protein that modulates neuronal actin dynamics and synaptic plasticity. 57,58 Peptidylprolyl isomerase A has multiple roles in protein refolding, signal transduction, and cell cycle regulation. 59 Peroxiredoxin 1 is a thiol-specific multifunctional antioxidant enzyme whose major role is a defense against oxidative stress through peroxidase activity.…”

Neuroprotective roles of the P2Y2 receptor

“…As discussed above, P2Y 2 R/ α v integrin interaction enables nucleotides to stimulate Rac and Rho and induce cytoskeletal rearrangements [24,95], well-established signaling pathways that regulate the outgrowth and stabilization of dendritic spines [99,158]. The P2Y 2 R agonist UTP has been shown to increase levels of neurofilament M and neurofilaments that promote neurite outgrowth [159].…”

“…Results indicate that mutation of the RGD sequence to Arg-Gly-Glu (RGE), a motif that does not bind well to integrins [98], prevented the binding of the P2Y 2 R to α v β 3/5 integrins and inhibited nucleotide-induced G o , G 12 , Rho, and Rac activation [24,95]. G o -dependent Rac and G 12 -dependent Rho activation are known to mediate cytoskeletal rearrangements and cell migration through a mechanism involving the activation of LIM kinase-dependent cofilin phosphorylation, a key regulator of actin polymerization [99], and studies indicate that activation of the P2Y 2 R promotes cytoskeletal rearrangements and cell migration that are abolished by mutation of the RGD motif to RGE [24,95]. Thus, it appears that the ability of the P2Y 2 R to increase cell chemokinesis is dependent upon P2Y 2 R association with α v β 3/5 integrins that stimulates signaling pathways involved in cytoskeletal reorganization required for cell motility.…”

LIM-kinase 1 in regulation of cognitive and locomotor functions of Drosophila melanogaster

“…Синаптическая дисфунк-ция напрямую коррелирует с нарушениями когнитивных функций у пациентов с болезнью Альцгеймера (Masliah et al, 2000). Данные на Aplysia kurodai показали, что микроинъекции кофилина в нейроны приводят к форми-рованию кофилин-актиновых комплексов, потере синап-сов и нарушению синаптической пластичности (Jang et al, 2005). Наибольшее количество кофилин-актиновых включений у крыс при обработке синтетическими диме-рами и тримерами амилоида β было обнаружено в облас-ти зубчатой извилины (зубчатой фасции), которая играет важную роль в ассоциативном обучении и формировании памяти (Davis et al, 2011).…”