Cofilin Rods And Neurodegeneration

Author:

Cichon, Joseph Michael

Graduate Program:

Biology

Degree:

Master of Science

Document Type:

Master Thesis

Date of Defense:

None

Committee Members:

Dr Gong Chen, Thesis Advisor/Co-Advisor
Gong Chen, Thesis Advisor/Co-Advisor
Bernhard Luscher, Thesis Advisor/Co-Advisor

Keywords:

cofilin
actin
LIM kinase
cytoskeleton
synapse

Abstract:

Early stages of neurodegeneration are characterized by synaptic loss and slow cognitive decline. Cofilin/actin rods (rods) have been implicated in neurodegenerative disorders, but the precise molecular composition and regulation remain unclear. Classically, rods are thought to be composed of F-actin filaments bound with cofilin. Here, we show that enhancing actin polymerization during cofilin rod induction does not exacerbate rod but rather inhibits cofilin rod formation. Cofilin rods even form and persist after substantial actin depolymerization. Live fluorescence imaging of rods reveals highly concentrated cofilin but not G-actin. Thus, we propose that cofilin rods are composed of cofilin filaments bound with G-actin, not the opposite. Consistent with our hypothetical model, cofilin rods can be dissolved by LIM kinase (LIMK), which phosphorylates and inactivates cofilin. Dephosphorylation of cofilin by the phosphatase slingshot increases cofilin rod formation. The formation of cofilin rods in postsynaptic dendritic branches leads to local disassembly of pre- and postsynaptic components, and disrupts intracellular organelle trafficking. Moreover, dissolution of rods by LIMK restores pre- and postsynaptic proteins at distal dendrites. We conclude that cofilin, not actin, is the core component of rod structures, and the removal of cofilin rods by LIMK may facilitate potential clinical treatments of neurodegenerative disorders.