Abstract
The cytoskeleton is one of the most mobile and complex cell structures. It is involved in cellular transport, cell division, cell shape formation and adaptation in response to extra- and intracellular stimuli, endo- and exocytosis, migration, and invasion. These processes are crucial for normal cellular physiology and are affected in several pathological processes, including neurodegenerative diseases, and cancer. Some proteins, participating in clathrin-mediated endocytosis (CME), play an important role in actin cytoskeleton reorganization, and formation of invadopodia in cancer cells and are also deregulated in neurodegenerative disorders. However, there is still limited information about the factors contributing to the regulation of their expression. MicroRNAs are potent negative regulators of gene expression mediating crosstalk between different cellular pathways in cellular homeostasis and stress responses. These molecules regulate numerous genes involved in neuronal differentiation, plasticity, and degeneration. Growing evidence suggests the role of microRNAs in the regulation of endocytosis, cell motility, and invasiveness. By modulating the levels of such microRNAs, it may be possible to interfere with CME or other processes to normalize their function. In malignancy, the role of microRNAs is undoubtful, and therefore changing their levels can attenuate the carcinogenic process. Here we review the current advances in our understanding of microRNAs regulating actin cytoskeleton dynamics, CME and cell motility with a special focus on neurodegenerative diseases, and cancer. We investigate whether current literature provides an evidence that microRNA-mediated regulation of essential cellular processes, such as CME and cell motility, is conserved in neurons, and cancer cells. We argue that more research effort should be addressed to study the neuron-specific functions on microRNAs. Disease-associated microRNAs affecting essential cellular processes deserve special attention both from the view of fundamental science and as future neurorestorative or anti-cancer therapies.
Highlights
Since the discovery of microRNA in 1993 [1], these 18–25 nt non-coding molecules have been recognized as important post-transcriptional regulators of physiological and pathological processes in different tissues and organs
Reviewing the literature on microRNAdependent regulation of protein expression, we aim to evaluate this hypothesis and find published evidence on whether microRNAs regulating cytoskeleton dynamics, as well as tightly linked clathrin-mediated endocytosis (CME) and cellular migration processes, are critical for both neurodegeneration, and cancer
After delivery of molecular cargo and uncoating, the vesicles can be assembled again from free components for the round of endocytosis. The complexity of this process can be partially reflected by the quantity of proteins participating at different steps of clathrin-coated vesicle (CCV) formation: to date, nearly 60 distinct proteins are known to be involved in CME in yeasts, with 85% of those being homologous to mammalian endocytic proteins [67]
Summary
Since the discovery of microRNA in 1993 [1], these 18–25 nt non-coding molecules have been recognized as important post-transcriptional regulators of physiological and pathological processes in different tissues and organs. Reviewing the literature on microRNAdependent regulation of protein expression, we aim to evaluate this hypothesis and find published evidence on whether microRNAs regulating cytoskeleton dynamics, as well as tightly linked clathrin-mediated endocytosis (CME) and cellular migration processes, are critical for both neurodegeneration, and cancer We suggest that such microRNAs will be very interesting and important subject for more in-depth future studies both from the point of basic biology as well as possible therapeutic agents and/or targets. Connor-Robson et al [88] demonstrated that the G2019S mutation in the LKKR2 gene in iPSC-derived dopaminergic neurons led to significant deregulation of CME in synaptic vesicles by decreasing levels of endophilin I-III, dynamin 2, and various RAB proteins resulting in a functional impairment of the process These data provide more evidence of LRRK2-associated disruption of endocytosis in PD development. This suggests a role of miR-133b-3p in the disturbance of receptor-mediated endocytosis following PFOA exposure [126]
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