Actin Cytoskeleton and Neuronal Aging

Actin cytoskeleton critical for neuronal membrane integrity

C-terminus of HSC70 Interacting Protein (CHIP), an E3-ubiquitin ligase, acts as a co-chaperone that regulates core chaperone machinery in protein folding, refolding, aggregation, and degradation processes³. Given its interaction with heat shock proteins like HSC70, CHIP is particularly important for protecting cells from thermal stress. CHIP has also been shown to be neuroprotective, but until recently, the mechanisms underlying this role were unknown. Dias et al. ablated CHIP in induced pluripotent stem cell (iPSC)-derived cortical neurons. They performed a proteomic analysis using Sequential Window Acquisition of all Theoretical Mass Spectra (SWATH-MS) and subsequent pathway analyses to determine proteomic changes between CHIP knockout and wild-type iPSCs that identified multiple membrane- and cytoskeletal-related proteins and pathways⁴, specifically, those involved in actin cytoskeleton signaling and membrane integrity networks. They then shared phenotypic data that confirmed differences in membrane and actin cytoskeletal homeostasis in the absence of CHIP function and that the absence of CHIP resulted in impaired membrane integrity and repair mechanisms⁴.

Compromised neuronal membranes are observed during physiological aging, acute traumatic brain injury, and neurodegenerative diseases⁵. The cell membrane is essential to any cell, maintaining distinct environments in the intra- and extracellular space, participating in signaling and cell-cell communication, and mediating cellular adhesion and motility. Cell membrane integrity is critical to neuronal function. Neurons have a highly polarized plasma membrane with distinct features⁶. The plasma membranes of the neuronal cell body and dendrites contain cell surface receptors that sense extracellular signaling molecules. Axonal membranes facilitate the transmission of nerve impulses and regulate myelination through glial signaling. Additionally, synaptic membranes are involved in the release and uptake of signaling molecules crucial for cellular communication. The actin cytoskeleton is critical for cell membrane integrity. The findings from Dias et al. suggest that the regulation of the actin cytoskeletal and membrane integrity explains the neuroprotective function of CHIP.

Actin filament reorganization in neuronal ischemic injury

In addition to physiological aging, actin dynamics play a role in neuronal injury and neurodegeneration. Ischemic stroke occurs due to a loss of oxygen and glucose supply that results from blocked cerebral blood vessels. The resulting neuronal damage is caused by a variety of biological processes. Neuronal swelling occurs quickly following a stroke due to ionic imbalance caused by an influx of ions through multiple entry routes, including cation entry through N-methyl-D-aspartate (NMDA) receptors and chloride entry through the SLC26A11 ion exchanger⁷. This ionic imbalance results in neuronal depolarization that spreads far beyond the site of initial injury.

Calabrese et al. revealed a role for altered actin dynamics in neuronal ischemic injury. In response to oxygen and glucose deprivation, cultured rat brain hippocampal neurons demonstrate actin reorganization in vitro. They further demonstrated that inducing stroke in mice caused neuronal actin reorganization⁸. Similarly, activation of NMDA receptors resulted in similar neuronal actin reorganization, suggesting that NMDA receptor activation was responsible for actin reorganization caused by stroke, specifically F-actin depolymerization within spines and polymerization into stable filaments within the dendrite shaft and soma⁸. Finally, they showed that this characteristic reorganization relied on F-actin polymerization factor inverted formin-2 (INF2)⁸.

Tau-driven F-actin stabilization in Alzheimer’s disease and related tauopathies

Alzheimer’s disease (AD) and other tauopathies are characterized by deposits of pathogenic tau isoforms in the brain. There remains disagreement about the driver of AD neurodegeneration, but decades of research have been conducted to understand the potential role of tau aggregates in disease pathology. One recently identified mechanism involves the tau-induced overstabilization of F-actin, which results in changes in nuclear and heterochromatin architecture, activation of retrotransposons, and neuronal cell cycle reentry⁹.  The presence of pathogenic tau leads to elevated levels of moesin, a protein that anchors the cytoskeleton to the plasma membrane and an activator of the epithelial-to-mesenchymal transition (EMT). Moesin is important for establishing neuronal polarity in developing neurons⁹. In the context of cancer, moesin has been shown to cause overstabilization of F-actin¹⁰ while expression of transgenic human tau in otherwise healthy Drosophila was sufficient to upregulate moesin, and the brains of these Drosophila reveal several indicators of AD-like disease¹¹.

Conclusion

Actin cytoskeletal dynamics are critical for healthy neuronal aging and are impaired in multiple neurological disorders. Specifically, stabilization of F-actin appears to be one risk factor for pathogenic neuronal aging in several contexts and could be a novel therapeutic target. Of course, the studies discussed in this newsletter largely utilize aging and disease models, and additional studies and clinical trials are needed to validate the translation of these findings to human conditions. However, there are growing indications that these findings can accurately apply to human pathologies. For instance, postmortem evaluations of brains from patients with AD reveal highly stable bundles of F-actin called Hirano bodies^9,12. Further, transcriptomic analyses of human AD brains are consistent with the hypothesis that tau-induced actin stabilization, neurotoxicity, and cell cycle activation depend on moesin¹¹. Additionally, histological specimens of human AD brains revealed that moesin was localized with disease-associated phosphotau and F-actin¹¹.