Figure 1 - uploaded by Ariane Zamoner
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Distribution of cytoskeletal constituents into neurons. Neuronal cytoskeleton is composed by microfilaments, microtubules, and intermediate filaments. The microtubules are nucleated at the centrosome, then released and delivered to either the dendrites or the axon. Neurofilaments are abundant in axons and the spacing of neurofilaments is sensitive to the level of phosphorylation. The microfilaments are dispersed within the cells and they are most abundant near the plasma membrane.
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... of most animal cells is constituted by three interconnected filament subsystems: microfilaments (MFs), microtubules (MTs) and intermediate filaments (IFs). Compelling evidence from the last decades has brought convincing understanding for the highly regu- lated and interconnected interactions between the cytoskeletal elements giving support to sculpting and maintaining cell shape and sustaining all kinds of morphological alterations or internal organization, as well as their implications for the behavior of animal cells. Figure 1 demonstrates the organization of the cytoskeleton in ...
Citations
... Not only the dynamic microtubules and microfilaments, but intermediate filaments are also involved in the progression of AD. As there are a large number of longitudinally arranged phosphorylated neurofilaments inside the axons of a neuron which may increase the diameter of the axon, hence resulting in an enhanced axonal conduction rate [137]. On the opposite side, the hyperphosphorylated form of NF-L, NF-M, and NF-H and intermediate filament type-3 (vimentin) are also observed to contribute to the formation of NFTs [8]. ...
Alzheimer’s disease (AD), a multifactorial disease, is characterized by the accumulation of neurofibrillary tangles (NFTs) and amyloid beta (Aβ) plaques. AD is triggered via several factors like alteration in cytoskeletal proteins, a mutation in presenilin 1 (PSEN1), presenilin 2 (PSEN2), amyloid precursor protein (APP), and post-translational modifications (PTMs) in the cytoskeletal elements. Owing to the major structural and functional role of cytoskeletal elements, like the organization of axon initial segmentation, dendritic spines, synaptic regulation, and delivery of cargo at the synapse; modulation of these elements plays an important role in AD pathogenesis; like Tau is a microtubule-associated protein that stabilizes the microtubules, and it also causes inhibition of nucleo-cytoplasmic transportation by disrupting the integrity of nuclear pore complex. One of the major cytoskeletal elements, actin and its dynamics, regulate the dendritic spine structure and functions; impairments have been documented towards learning and memory defects. The second major constituent of these cytoskeletal elements, microtubules, are necessary for the delivery of the cargo, like ion channels and receptors at the synaptic membranes, whereas actin-binding protein, i.e., Cofilin’s activation form rod-like structures, is involved in the formation of paired helical filaments (PHFs) observed in AD. Also, the glial cells rely on their cytoskeleton to maintain synaptic functionality. Thus, making cytoskeletal elements and their regulation in synaptic structure and function as an important aspect to be focused for better management and targeting AD pathology. This review advocates exploring phytochemicals and Ayurvedic plant extracts against AD by elucidating their neuroprotective mechanisms involving cytoskeletal modulation and enhancing synaptic plasticity. However, challenges include their limited bioavailability due to the poor solubility and the limited potential to cross the blood–brain barrier (BBB), emphasizing the need for targeted strategies to improve therapeutic efficacy.
... Consequently, dysregulation of Ca 2þ homeostasis is an important event in driving disruption of assembly/ disassembly equilibrium as well as the interaction of cytoskeletal proteins with regulatory proteins or cell organelles. In particular, IF proteins are directly regulated by Ca 2þ levels, which cross-link signaling cascades and connect physiological or pathological extracellular signals with the IF cytoskeleton influencing multiple aspects of cell behavior (Zamoner and Pessoa-Pureur, 2017). ...
... It is important to note that the hypophosphorylated GFAP that we found in hypothyroid pups could be ascribed to downregulate protein kinases, given that specific phosphorylating sites for PKA, CaMKII and PKC are associated with GFAP phosphorylation (Zamoner and Pessoa-Pureur, 2017). Consequently, the restored phosphorylation level mediated by the short-term incubation with rT 3 could be related with restored kinase activities. ...
In the present study we provide evidence that 3,3',5'-triiodothyronine (reverse T3, rT3) restores neurochemical parameters induced by congenital hypothyroidism in rat hippocampus. Congenital hypothyroidism was induced by adding 0.05% propylthiouracil in the drinking water from gestation day 8 and continually up to lactation day 15. In the in vivo rT3 exposure, hypothyroid 12-day old pups were daily injected with rT3 (50 ng/kg body weight) or saline until day 14. In the ex vivo rT3 treatment, hippocampal slices from 15-day-old hypothyroid pups were incubated for 30 min with or without rT3 (1 nM). We found that ex vivo and/or in vivo exposure to rT3 failed in restoring the decreased (14)C-glutamate uptake; however, restored the phosphorylation of glial fibrillary acidic protein (GFAP), (45)Ca(2+) influx, aspartate transaminase (AST), glutamine synthetase (GS) and gamma-glutamate transferase (GGT) activities, as well as glutathione (GSH) levels in hypothyroid hippocampus. In addition, rT3 improved (14)C-2-deoxy-D-glucose uptake and lactate dehydrogenase (LDH) activity. Receptor agonists/antagonists (RGD peptide and AP-5), kinase inhibitors of p38MAPK, ERK1/2, CaMKII, PKA (SB239063, PD98059, KN-93 and H89, respectively), L-type voltage-dependent calcium channel blocker (nifedipine) and intracellular calcium chelator (BAPTA-AM) were used to determine the mechanisms of the nongenomic rT3 action on GGT activity. Using molecular docking analysis, we found rT3 interaction with αvβ3 integrin receptors, nongenomically activating signaling pathways (PKA, CaMKII, p38MAPK) that restored GGT activity. We provide evidence that rT3 is an active TH metabolite and our results represent an important contribution to elucidate the nonclassical mechanism of action of this metabolite in hypothyroidism.
In this study, we used an experimental model of congenital hypothyroidism to show that deficient thyroid hormones (TH) disrupt different neurochemical, morphological and functional aspects in the cerebral cortex of 15-day-old offspring. Our results showing decreased glutamine synthetase (GS) activity and Ca2+ overload in the cerebral cortex of hypothyroid pups suggest misregulated glutamate metabolism associated with developmentally induced TH deficiency. The 14C-MeAIB accumulation indicates upregulated System A activity and glutamine uptake by neurons. Energy metabolism in hypothyroid cortical slices was preserved, as demonstrated by unaltered glucose metabolism. We also found upregulated acetylcholinesterase activity, depleting acetylcholine from the synaptic cleft, pointing to disrupted cholinergic system. Increased reactive oxygen species (ROS) generation, lipid peroxidation, glutathione (GSH) depletion, which were associated with glutathione peroxidase, superoxide dismutase and gamma-glutamyltransferase downregulation suggest redox imbalance. Disrupted astrocyte cytoskeleton was evidenced by downregulated and hyperphosphorylated glial fibrillary acidic protein (GFAP). Morphological and structural characterization of the sensorimotor cerebral cortex (SCC) showed unaltered thickness of the SCC. However, decreased size of neurons on the layers II & III and IV in the right SCC and increased NeuN positive neurons in specific SCC layers, suggest that they are differently affected by the low TH levels during neurodevelopment. Hypothyroid pups presented increased number of foot-faults in the gridwalk test indicating affected motor functions. Taken together, our results show that congenital hypothyroidism disrupts glutamatergic and cholinergic neurotransmission, Ca2+ equilibrium, redox balance, cytoskeleton integrity, morphological and functional aspects in the cerebral cortex of young rats.
