Phosphorylation, Dephosphorylation, and Multiprotein Assemblies Regulate Dynamic Behavior of Neuronal Cytoskeleton: A Mini-Review

Abstract

Cellular localization, assembly and abnormal aggregation of neurofilaments depend on phosphorylation. Pathological processes associated with neurodegeneration exhibit aberrant accumulation of microtubule associated aggregated forms of hyperphosphorylated neuronal protein tau in cell bodies. These processes are critical for the disease progression in patients suffering from Alzheimer’s disease, Parkinson’s disease, and Amyotrophic Lateral Sclerosis. In healthy cells, tau is localized in axons. Topographic regulation suggests that whereas the sites of synthesis of kinases and neurofilaments are the cell bodies, and sites of their functional assemblies are axons, phosphorylation/dephosphorylation are the key processes that arrange the molecules at their precise locations. Phosphorylation sites in the dynamic developmental and degenerative processes differ. Not all these processes are well understood. New advancements identify epigenetic factors involved in AD which account for the influence of age-related environment/genome interactions leading to the disease. Progress in proteomics highlights previously found major proteins and adds more to the list of those involved in AD. New key elements of specificity provide determinants of molecular recognition important for the assembly of macromolecular complexes. In this review, we discuss aberrant spatial distribution of neuronal polypeptides observed in neuropathies: aggregation, association with proteins of the neuronal cytoskeleton, and phosphorylation dependent dynamics. Particularly, we emphasize recent advancements in understanding the function and determinants of specific association of molecules involved in Alzheimer’s disease with respect to the topographic regulation of phosphorylation in neuronal cytoskeleton and implications for the design of new therapies. Further, we address the role of various filament systems in maintenance of the shape, rigidity and dynamics of the cytoskeleton.

Melatonin Rescues the Dendrite Collapse Induced by the Pro-Oxidant Toxin Okadaic Acid in Organotypic Cultures of Rat Hilar Hippocampus

“…In this regard, phosphorylation/dephosphorylation balance regulates key cellular structures and functions. Particularly, the cytoskeletal dynamics are controlled by the phosphorylation state of stabilizer and modulator proteins along the neurodevelopment [ 57 , 58 ], for instance in undifferentiated neuroblastoma cells [ 20 ], but also in immature or specialized mature neurons [ 59 , 60 ]. In turn, the dynamics of microtubules and microfilaments play a key role in axonogenesis and axon elongation, as well as in dendritogenesis and the increase of dendritic arbor complexity [ 57 , 58 ].…”

The Role of Serum Levels of Neurofilament Light (NfL) Chain as a Biomarker in Friedreich Ataxia

“…Neurofilaments are cytoskeletal proteins located in both the peripheral and central nervous system, particularly in larger myelinated axons. They play a significant role in axonal growth and the determination of axonal caliber (Hsieh et al, 1994 ; Kurochkina et al, 2018 ; Bott and Winckler, 2020 ). Logically, as axons are damaged and die in neurodegenerative processes, NfL should leak into the interstitial space, then into CSF and plasma.…”

Multiprotein Assemblies, Phosphorylation and Dephosphorylation in Neuronal Cytoskeleton

“…The cytoskeleton is the site of assembly of fibrous and globular filamentous protein aggregates. Phosphorylation and dephosphorylation regulate cellular localization, assembly of complexes, and abnormal aggregation of neurofilaments (1,2). Understanding microtubule dynamics, post-translational modifications, compartmental distribution, assembly of cellular components, and signaling linking neuronal dysfunction to neuropathies can lead to the development of new therapies.…”