The Central Role of Actin in Creutzfeldt-Jakob Disease: Unlocking Therapeutic Pathways.

Abstract

Creutzfeldt-Jakob disease (CJD) is a prion-caused condition characterized by progressive neurodegeneration and spongiform structural changes in the brain due to vacuolization and neuronal death. The disease is driven by the accumulation of abnormally folded prion proteins (PrPSc), derived from the normal cellular protein (PrPC). Actin, a fundamental protein essential for maintaining cellular structure and function, is critically involved in the pathophysiology of several neurodegenerative diseases, including Creutzfeldt-Jakob disease (CJD). In CJD, the dysregulation of actin-binding proteins such as cofilin and gelsolin significantly contributes to disease progression by disrupting actin turnover and cytoskeletal reorganization. The actin cytoskeleton is also essential for synaptic plasticity and the functionality of excitatory neurotransmitter receptors, such as glutamate-gated ion channels (AMPA) and N-methyl-D-aspartate (NMDA) receptors. As cytoskeletal integrity deteriorates, receptor dynamics become impaired, leading to disrupted calcium signaling and deficits in cognitive functions. Additionally, actin-based structures, known as tunneling nanotubes (TNTs), play crucial roles in prion spread by facilitating cell-to-cell transfer of prions. Simultaneously, the prion-infected neuronal environment promotes the formation of these structures, further driving disease progression. Targeting actin dynamics through the modulation of actin-binding proteins and related signaling pathways presents a promising avenue for therapeutic development. These approaches hold potential for addressing CJD for broader applications in neurodegenerative diseases characterized by cytoskeletal dysfunction. Current strategies focus on targeting cytoskeletal components such as microtubule stabilizers, actin-binding proteins, HDAC6 inhibitors, and small GTPases, further expanding the possibilities for effective treatments across various neurodegenerative conditions.