Anastasiya Rakovskaya, E. N. Volkova, Ekaterina Pchitskaya
Neuronal function relies on the precise coordination between intracellular calcium (Ca2+) signaling and the cytoskeletal architecture that underpins synaptic transmission, plasticity, and structural stability. Disruption of this calcium–cytoskeleton interplay has been noted in numerous neurodegenerative diseases. We discuss how Ca2+-dependent cytoskeletal remodeling governs long-term potentiation and depression, dendritic spine morphology, and presynaptic function, highlighting the functions of end-binding proteins, STIM (Stromal Interaction Molecule)/Orai-mediated store-operated calcium entry, and the spine apparatus. Disease-specific manifestations of cytoskeletal–calcium dysregulation are reviewed across Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, tauopathies, and prion disorders. Finally, we evaluate emerging therapeutic strategies targeting calcium homeostasis, cytoskeletal dynamics, and their downstream effectors, including multi-target approaches.