Notch signalling in adult neurons: a potential target for microtubule stabilization

Abstract

Cytoskeletal dysfunction has been proposed during the last decade as one of the main mechanisms involved in the aetiology of several neurodegenerative diseases. Microtubules are basic elements of the cytoskeleton and the dysregulation of microtubule stability has been demonstrated to be causative for axonal transport impairment, synaptic contact degeneration, impaired neuronal function leading finally to neuronal loss. Several pathways are implicated in the microtubule assembly/disassembly process. Emerging evidence is focusing on Notch as a microtubule dynamics regulator. We demonstrated that activation of Notch signalling results in increased microtubule stability and changes in axonal morphology and branching. By contrast, Notch inhibition leads to an increase in cytoskeleton plasticity with intense neurite remodelling. Until now, several microtubule-binding compounds have been tested and the results have provided proof of concept that microtubule-binding agents or compounds with the ability to stabilize microtubules may have therapeutic potential for the treatment of Alzheimer's disease and other neurodegenerative diseases. In this review, based on its key role in cytoskeletal dynamics modulation, we propose Notch as a new potential target for microtubule stabilization.

Late onset dHMN II caused by c.404C>G mutation in HSPB1 gene

“…This domain is related to mitochondrial movement, which is important to maintain the integrity of cellular cytoskeleton transport (Lee et al , ) . The mutation may lead to loss of the cytoskeleton stabilizing role of HSPB1, a known pathogenic pathway associated with neuronal degeneration (Bonini et al , ) . Overexpression of HSPB1‐S135F mutant protein reproduces motor neuropathy in mice (Lee et al , ) and leads to progressive degeneration of primary cultured mouse motor neurons associated with a disruption of neurofilament network (Zhai et al , ) .…”

VEGF-B selectively regenerates injured peripheral neurons and restores sensory and trophic functions

“…Interestingly, significant overexpression differences were found in some elements of the Notch, Wnt, and Semaphorin/ Plexin signaling pathways. It has been demonstrated that activation of Notch signaling results in increased microtubule stability and changes in axonal morphology and branching (21). Similarly, Wnt2 promotes cortical dendrite growth and dendritic spine formation and Wnt11 early neurogenesis (22,23).…”

Axonal Transport Defects in Alzheimer’s Disease

“…Aside from MT-stabilizing agents, Notch signaling has recently also emerged as a possible microtubule stability regulator. Notch signaling is being considered as a candidate for therapy [97]. The inhibition of HDAC6 to increase the level of acetylated atubulin is also a treatment method that is under consideration [72].…”