Aggregation and deposition of α-synuclein (α-syn) in Lewy bodies within dopamine neurons of substantia nigra (SN) is the pathological hallmark of Parkinson’s disease (PD). These toxic α-syn ...aggregates are believed to propagate from neuron-to-neuron and spread the α-syn pathology throughout the brain beyond dopamine neurons in a prion-like manner. Targeting propagation of such α-syn aggregates is of high interest but requires identifying pathways involving in this process. Evidence from previous Alzheimer’s disease reports suggests that EGFR may be involved in the prion-like propagation and seeding of amyloid-β. We show here that EGFR regulates the uptake of exogenous α-syn-PFFs and the levels of endogenous α-syn in cell cultures and a mouse model of α-syn propagation, respectively. Thus, we tested the therapeutic potentials of AZD3759, a highly selective BBB-penetrating EGFR inhibitor, in a preclinical mouse model of α-syn propagation. AZD3759 decreases activated EGFR levels in the brain and reduces phosphorylated α-synuclein (pSyn) pathology in brain sections, including striatum and SN. As AZD3759 is already in the clinic, this paper’s results suggest a possible repositioning of AZD3759 as a disease-modifying approach for PD.
Neurodegenerative disorders refer to a group of diseases commonly associated with abnormal protein accumulation and aggregation in the central nervous system. However, the exact role of protein ...aggregation in the pathophysiology of these disorders remains unclear. This gap in knowledge is due to the lack of experimental models that allow for the spatiotemporal control of protein aggregation, and the investigation of early dynamic events associated with inclusion formation. Here, we report on the development of a light-inducible protein aggregation (LIPA) system that enables spatiotemporal control of α-synuclein (α-syn) aggregation into insoluble deposits called Lewy bodies (LBs), the pathological hallmark of Parkinson disease (PD) and other proteinopathies. We demonstrate that LIPA-α-syn inclusions mimic key biochemical, biophysical, and ultrastructural features of authentic LBs observed in PD-diseased brains. In vivo, LIPA-α-syn aggregates compromise nigrostriatal transmission, induce neurodegeneration and PD-like motor impairments. Collectively, our findings provide a new tool for the generation, visualization, and dissection of the role of α-syn aggregation in PD.
The accumulation of various metabolites appears to be associated with diverse human diseases. However, the aetiological link between metabolic alteration and the observed diseases is still elusive. ...This includes the correlation between the abnormally high levels of homocysteine and quinolinic acid in Alzheimer's disease, as well as the accumulation of oncometabolites in malignant processes. Here, we suggest and discuss a possible mechanistic insight into metabolite accumulation in conditions such as neurodegenerative diseases and cancer. Our hypothesis is based on the demonstrated ability of metabolites to form amyloid-like structures in inborn error of metabolism disorders and the potential of such metabolite amyloids to promote protein aggregation. This notion can provide a new paradigm for neurodegeneration and cancer, as both conditions were linked to loss of function due to protein aggregation. Similar to the well-established observation of amyloid formation in many degenerative disorders, the formation of amyloids by tumour-suppressor proteins, including p53, was demonstrated in malignant states. Moreover, this new paradigm could fill the gap in understanding the high occurrence of specific types of cancer among genetic error of metabolism patients. This hypothesis offers a fresh view on the aetiology of some of the most abundant human maladies and may redirect the efforts towards new therapeutic developments.
Heparan sulfate proteoglycans (HSPGs) are cell surface receptors that are involved in the cellular uptake of pathologic amyloid proteins and viruses, including the novel coronavirus; severe acute ...respiratory syndrome coronavirus 2 (SARS-CoV-2). Heparin and heparan sulfate antagonize the binding of these pathogens to HSPGs and stop their cellular internalization, but the anticoagulant effect of these agents has been limiting their use in the treatment of viral infections. Heparin-binding peptides (HBPs) are suitable nonanticoagulant agents that are capable of antagonizing binding of heparin-binding pathogens to HSPGs. Here, we review and discuss the use of HBPs as viral uptake inhibitors and will address their benefits and limitations to treat viral infections. Furthermore, we will discuss a variant of these peptides that is in the clinic and can be considered as a novel therapy in coronavirus disease 2019 (COVID-19) infection. SIGNIFICANCE STATEMENT: The need to discover treatment modalities for COVID-19 is a necessity, and therapeutic interventions such as heparin-binding peptides (HBPs), which are used for other cases, can be beneficial based on their mechanisms of actions. In this paper, we have discussed the application of HBPs as viral uptake inhibitors in COVID-19 and explained possible mechanisms of actions and the therapeutic effects.
EGFR Aggregation in the Brain Tavassoly, Omid; Tavassoly, Iman
ACS chemical neuroscience,
06/2021, Letnik:
12, Številka:
11
Journal Article
Recenzirano
Recent findings showed that preformed fibrils (PFFs) of misfolded proteins, including α-synuclein (α-syn) and amyloid-β (Aβ), activate EGFR in cell cultures and animal models of amyloid propagation. ...Comparing these supramolecular structures to normal EGFR ligands such as EGF and HB-EGF suggests that these PFFs might trigger the formation of high order clustering of EGFR that stimulates the aggregation of EGFR tyrosine kinase domain (EGFR-TKD) which is known to form fibrils. Subsequently, self-assembled fibril of EGFR-TKDs itself can serve as a seed to induce aggregation of monomeric forms of misfolded proteins in cytoplasm or endosomes. In this model, EGFR serves as an amyloidogenic receptor to facilitate (1) cellular uptake of exogenous PFFs and (2) seeding of endogenous misfolded proteins.
Postinfection complications of coronavirus disease 2019 (COVID-19) are still unknown, and one of the long-term concerns in infected people are brain pathologies. The question is that severe acute ...respiratory syndrome coronavirus-2 (SARS-CoV-2) infection may be an environmental factor in accelerating the sporadic neurodegeneration in the infected population. In this regard, induction of protein aggregation in the brain by SARS-CoV-2 intact structure or a peptide derived from spike protein subunits needs to be considered in futures studies. In this paper, we discuss these possibilities using pieces of evidence from other viruses.
Nanopore analysis is an emerging technique that enables the investigation of the conformation of a single peptide or protein molecule. Briefly, a pore is inserted into a membrane under voltage clamp ...conditions. When a molecule interacts with the pore there is a change in the current, I, for a time, T. Small unfolded molecules can translocate the pore whereas folded or large molecules tend to simply bump into the pore and then diffuse away. Therefore, the parameters, I and T, are dependent on the conformation of the molecule at the instant at which it encounters the pore. Thus, multiple conformations can be detected simultaneously in a single sample. As well, the analysis can be performed under dilute conditions so that folding or dimerization of a peptide can be followed in real time, which is generally difficult to study for proteins that are prone to aggregate. In this report, we describe our initial analysis of (1) Aβ peptides, which are deposited as amyloid plaques in Alzheimer disease, (2) α-synuclein, which is implicated in Parkinson disease and (3) prion proteins whose misfolding is evident in transmissable spongiform encephalopathies. In each case conformational information can be obtained which may help in understanding the early steps in the misfolding pathways.
The pathological hallmark of Parkinson's disease (PD) is Lewy bodies that form within the brain from aggregated forms of α‐synuclein (α‐syn). These toxic α‐syn aggregates are transferred from cell to ...cell by release of fibrils from dying neurons into the extracellular environment, followed by their subsequent uptake by neighboring cells. This process leads to spreading of the pathology throughout the brain in a prion‐like manner. Identifying new pathways that hinder the internalization of such α‐syn fibrils is of high interest for their downstream potential exploitation as a way to create disease‐modifying therapeutics for PD. Here, we show that Thiamet‐G, a highly selective pharmacological agent that inhibits the glycoside hydrolase O‐GlcNAcase (OGA), blunts the cellular uptake of α‐syn fibrils. This effect correlates with increased nucleocytoplasmic levels of O‐linked N‐acetylglucosamine (O‐GlcNAc)‐modified proteins, and genetic knockdown of OGA expression closely phenocopies both these effects. These reductions in the uptake of α‐syn fibrils caused by inhibition of OGA are both concentration‐ and time‐dependent and are observed in multiple cell lines including mouse primary cortical neurons. Moreover, treatment of cells with the OGT inhibitor, 5SGlcNHex, increases the level of uptake of α‐syn PFFs, further supporting O‐GlcNAcylation of proteins driving these effects. Notably, this effect is mediated through an unknown mechanism that does not involve well‐characterized endocytotic pathways. These data suggest one mechanism by which OGA inhibitors might exert their protective effects in prion‐like neuropathologies and support exploration of OGA inhibitors as a potential disease‐modifying approach to treat PD.
Increases in cellular levels of O‐linked N‐acetylglucosamine (O‐GlcNAc)‐modified proteins, induced by inhibition of the glycoside hydrolase O‐GlcNAcase (OGA) using a highly selective inhibitor, blunt the uptake of α‐synuclein fibrils. This effect is phenocopied by siRNA‐mediated knockdown of OGA, and inhibition of OGT increases the uptake of α‐synuclein fibrils. The effects are mediated through a pathway that is independent of general endocytosis.
The delivery of hydrophobic therapeutic agents to tumors is a challenge in the treatment of cancers. Here, we review recent advances in coiled-coil protein origami and discuss a proposed programmable ...protein origami structure, switchable by a protein kinase A/phosphatase switch, as an example of functionalization for designing future protein nanorobots.
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