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NERVOUS SYSTEM CELL BIOLOGY

Formation of actin-ADF/cofilin rods transiently retards decline of mitochondrial potential and ATP in stressed neurons

Department of Biochemistry and Molecular Biology and the Molecular, Cellular, and Integrative Neuroscience Program, Colorado State University, Fort Collins, Colorado

Submitted 9 February 2006 ; accepted in final form 21 May 2006

When neurons in culture are transiently stressed by inhibition of ATP synthesis, they rapidly form within their neurites rodlike actin inclusions that disappear when the insult is removed. Oxidative stress, excitotoxic insults, and amyloid -peptide oligomers also induce rods. Immunostaining of neurites indicates that these rods also contain the majority of the actin filament dynamizing proteins, actin-depolymerizing factor (ADF) and cofilin (AC). If the rods reappear within 24 h after the stress is removed, the neurite degenerates distal to the rod but with no increase in neuronal death. Here, rods were generated in cultured rat E18 hippocampal cells by overexpression of a green fluorescent protein chimera of AC. Surprisingly, we have found that, for a short period (60 min) immediately after initial rod formation, the loss of mitochondrial membrane potential (_m) and ATP in neurites with rods is slower than in neurites without them. The _m was monitored with the fluorescent dye tetramethylrhodamine methyl ester, and ATP was monitored with the fluorescent ion indicator mag-fura 2. Actin in rods is less dynamic than is filamentous actin in other cytoskeletal structures. Because _m depends on cellular ATP and because ATP hydrolysis associated with actin filament turnover is responsible for a large fraction of neuronal energy consumption (50%), the formation of rods transiently protects neurites by slowing filament turnover and its associated ATP hydrolysis.

actin dynamics; neurodegeneration; actin inclusions; neuroprotection; ischemia

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