Remodeling of the Actin/Spectrin Membrane-associated Periodic Skeleton, Growth Cone Collapse and F-Actin Decrease during Axonal Degeneration

Abstract

Axonal degeneration occurs in the developing nervous system for the appropriate establishment of mature circuits, and is also a hallmark of diverse neurodegenerative diseases. Despite recent interest in the field, little is known about the changes (and possible role) of the cytoskeleton during axonal degeneration. We studied the actin cytoskeleton in an in vitro model of developmental pruning induced by trophic factor withdrawal (TFW). We found that F-actin decrease and growth cone collapse (GCC) occur early after TFW; however, treatments that prevent axonal fragmentation failed to prevent GCC, suggesting independent pathways. Using super-resolution (STED) microscopy we found that the axonal actin/spectrin membrane-associated periodic skeleton (MPS) abundance and organization drop shortly after deprivation, remaining low until fragmentation. Fragmented axons lack MPS (while maintaining microtubules) and acute pharmacological treatments that stabilize actin filaments prevent MPS loss and protect from axonal fragmentation, suggesting that MPS destruction is required for axon fragmentation to proceed.

Cargo hold and delivery: Ankyrins, spectrins, and their functional patterning of neurons

“…However, even though neurons in mammalian systems experience some mechanical challenges under normal conditions (Heidemann & Bray, ; Šmít et al, ), whether these forces can cause damage in neurons with a disassembled MPS has not been shown. While this remains an open question, the role of the MPS in neuronal degeneration has started to emerge (Unsain et al, ; Wang, Simon, et al, ).…”

“…Trophic deprivation (TD) of DGR neurons, which induces axonal degeneration, results in an early and significant disruption of the MPS prior to axonal fragmentation (Unsain et al, ; Wang, Simon, et al, ). This early MPS disassembly after TD is independent of protein loss and of apoptotic pathway activation, as demonstrated in sensory axons that either overexpressed the apoptotic protein Bcl‐xL, or that lacked the apopotic factor Bax (Wang, Simon, et al, ).…”

Role of actin in organelle trafficking in neurons

“…A primary feature of several neurodegenerative diseases is axonal degeneration or dying back of neurons (Burke & O'Malley, ; Dadon‐Nachum, Melamed, & Offen, ; Fischer et al, ; Fischer & Glass, ; H. Li, Li, Yu, Shelbourne, & Li, ; Unsain et al, ). The actin‐based membrane periodic skeleton (MPS), present along the axon, is seen to be involved in this neuronal degeneration (Unsain et al, ; G. Wang et al, ). Actin and spectrin are the major components of the MPS (Xu et al, ).…”

“…Latrunculin A treatment destabilized actin, leading to MPS disassembly followed by axon degeneration. Treatment with actin stabilizers Curcurbitacin and Jasplakinolide resulted in reduced axon degeneration induced by trophic factor deprivation (Unsain et al, ; G. Wang et al, ). Knockdown of β‐spectrin also resulted in MPS disassembly, axon breakage and decreased axon length (Hammarlund et al, ; Lorenzo et al, ).…”

“…Knockdown of β‐spectrin also resulted in MPS disassembly, axon breakage and decreased axon length (Hammarlund et al, ; Lorenzo et al, ). Additionally, studies on the effect of trophic deprivation on actin‐spectrin based MPS structures in neurons show that MPS disassembly precedes the activation of the apoptotic pathway (Unsain et al, ; G. Wang et al, ). These studies suggest that MPS disassembly is an early event during neuronal degeneration.…”