A Mini Review on the Effectiveness of Peptoids as Therapeutic Interventions against Neurodegenerative Diseases

2021 ◽  
Vol 22 ◽  
Author(s):  
Subha Sankar Paul ◽  
Goutam Biswas
Keyword(s):  
Neurodegenerative Diseases ◽  
Neurodegenerative Disease ◽  
Production Cost ◽  
Therapeutic Interventions ◽  
Proteolytic Degradation ◽  
Important Criterion ◽  
Targeted Therapeutics ◽  
Aggregation Inhibitors ◽  
Cellular Permeability ◽  
Cell Signaling Pathways

: Neurodegenerative diseases emerged as one of the major age-associated diseases in the recent years. Hence, the urge for understanding the mechanism and to find targeted therapeutics becomes inevitable. Peptide-based compounds emerged as one of the important tools for its therapy. But due to a lack of tolerability, specificity and proteolytic degradation, it loses its applicability in a wider sense. Thus, the search for suitable alternatives or peptidomimetics becomes an important criterion for neurotherapeutics. One of the versatile peptidomimetics are N-substituted glycines or Peptoids, which retain many properties of peptides but are successful in evading the drawbacks of peptides. Peptoids are manifested with greater cellular permeability, less immunogenicity and their ability to be administered intra-nasally. These properties enhance their potential as neurotherapeutics with respect to their peptide counterpart. Recently, peptoids have been explored towards neurotherapeutic applications as aggregation inhibitors, cell signaling pathways modulator, and as agents for inhibiting inflammations via multiple mechanisms. Peptoids, due to their versatility and low production cost, are becoming popular among peptidomimetics as potential neurotherapeutic agents. In this review, the diverse applications of peptoids with respect to neurodegenerative disease have been explored.

scholarly journals Utilising Induced Pluripotent Stem Cells in Neurodegenerative Disease Research: Focus on Glia

2021 ◽  
Vol 22 (9) ◽  
pp. 4334
Author(s):  
Katrina Albert ◽  
Jonna Niskanen ◽  
Sara Kälvälä ◽  
Šárka Lehtonen
Keyword(s):  
Stem Cells ◽  
Neurodegenerative Diseases ◽  
Neurodegenerative Disease ◽  
Induced Pluripotent Stem Cells ◽  
Glial Cells ◽  
Pluripotent Stem Cells ◽  
Cell Types ◽  
Human Ipscs ◽  
Induced Pluripotent

Induced pluripotent stem cells (iPSCs) are a self-renewable pool of cells derived from an organism’s somatic cells. These can then be programmed to other cell types, including neurons. Use of iPSCs in research has been two-fold as they have been used for human disease modelling as well as for the possibility to generate new therapies. Particularly in complex human diseases, such as neurodegenerative diseases, iPSCs can give advantages over traditional animal models in that they more accurately represent the human genome. Additionally, patient-derived cells can be modified using gene editing technology and further transplanted to the brain. Glial cells have recently become important avenues of research in the field of neurodegenerative diseases, for example, in Alzheimer’s disease and Parkinson’s disease. This review focuses on using glial cells (astrocytes, microglia, and oligodendrocytes) derived from human iPSCs in order to give a better understanding of how these cells contribute to neurodegenerative disease pathology. Using glia iPSCs in in vitro cell culture, cerebral organoids, and intracranial transplantation may give us future insight into both more accurate models and disease-modifying therapies.

scholarly journals Non-coding RNA suppresses FUS aggregation caused by mechanistic shear stress on pipetting in a sequence-dependent manner

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Nesreen Hamad ◽  
Ryoma Yoneda ◽  
Masatomo So ◽  
Riki Kurokawa ◽  
Takashi Nagata ◽  
...  
Keyword(s):  
Shear Stress ◽  
Neurodegenerative Diseases ◽  
Suppressive Effect ◽  
Dependent Manner ◽  
Aggregation State ◽  
Fused In Sarcoma ◽  
Sequence Dependent ◽  
Non Coding Rna ◽  
Aggregation Inhibitors ◽  
Amorphous Aggregation

AbstractFused in sarcoma/translocated in liposarcoma (FUS/TLS) is a multitasking RNA/DNA binding protein. FUS aggregation is implicated in various neurodegenerative diseases. RNA was suggested to modulate phase transition of FUS. Here, we found that FUS transforms into the amorphous aggregation state as an instant response to the shear stress caused by usual pipetting even at a low FUS concentration, 100 nM. It was revealed that non-coding RNA can suppress the transformation of FUS into aggregates. The suppressive effect of RNA on FUS aggregation is sequence-dependent. These results suggested that the non-coding RNA could be a prospective suppressor of FUS aggregation caused by mechanistic stress in cells. Our finding might pave the way for more research on the role of RNAs as aggregation inhibitors, which could facilitate the development of therapies for neurodegenerative diseases.

The Cryo-EM Effect: Structural Biology of Neurodegenerative Disease Proteostasis Factors

2021 ◽  
Author(s):  
Benjamin C Creekmore ◽  
Yi-Wei Chang ◽  
Edward B Lee
Keyword(s):  
Neurodegenerative Diseases ◽  
Protein Aggregation ◽  
Neurodegenerative Disease ◽  
Electron Tomography ◽  
Ubiquitin Proteasome System ◽  
26S Proteasome ◽  
X Ray Crystallography ◽  
New Information ◽  
A Cell ◽  
Regulate Protein

Abstract Neurodegenerative diseases are characterized by the accumulation of misfolded proteins. This protein aggregation suggests that abnormal proteostasis contributes to aging-related neurodegeneration. A better fundamental understanding of proteins that regulate proteostasis may provide insight into the pathophysiology of neurodegenerative disease and may perhaps reveal novel therapeutic opportunities. The 26S proteasome is the key effector of the ubiquitin-proteasome system responsible for degrading polyubiquitinated proteins. However, additional factors, such as valosin-containing protein (VCP/p97/Cdc48) and C9orf72, play a role in regulation and trafficking of substrates through the normal proteostasis systems of a cell. Nonhuman AAA+ ATPases, such as the disaggregase Hsp104, also provide insights into the biochemical processes that regulate protein aggregation. X-ray crystallography and cryo-electron microscopy (cryo-EM) structures not bound to substrate have provided meaningful information about the 26S proteasome, VCP, and Hsp104. However, recent cryo-EM structures bound to substrate have provided new information about the function and mechanism of these proteostasis factors. Cryo-EM and cryo-electron tomography data combined with biochemical data have also increased the understanding of C9orf72 and its role in maintaining proteostasis. These structural insights provide a foundation for understanding proteostasis mechanisms with near-atomic resolution upon which insights can be gleaned regarding the pathophysiology of neurodegenerative diseases.

New Approaches to Profile the Microbiome for Treatment of Neurodegenerative Disease

2021 ◽  
pp. 1-29
Author(s):  
David R. Elmaleh ◽  
Matthew A. Downey ◽  
Ljiljana Kundakovic ◽  
Jeremy E. Wilkinson ◽  
Ziv Neeman ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Neurodegenerative Disease ◽  
Gut Microbiome ◽  
Treatment Options ◽  
Treatment Strategies ◽  
Modern Society ◽  
Aging Brain ◽  
New Approaches ◽  
Microbiome Profile ◽  
Carry Over

Progressive neurodegenerative diseases represent some of the largest growing treatment challenges for public health in modern society. These diseases mainly progress due to aging and are driven by microglial surveillance and activation in response to changes occurring in the aging brain. The lack of efficacious treatment options for Alzheimer’s disease (AD), as the focus of this review, and other neurodegenerative disorders has encouraged new approaches to address neuroinflammation for potential treatments. Here we will focus on the increasing evidence that dysbiosis of the gut microbiome is characterized by inflammation that may carry over to the central nervous system and into the brain. Neuroinflammation is the common thread associated with neurodegenerative diseases, but it is yet unknown at what point and how innate immune function turns pathogenic for an individual. This review will address extensive efforts to identify constituents of the gut microbiome and their neuroactive metabolites as a peripheral path to treatment. This approach is still in its infancy in substantive clinical trials and requires thorough human studies to elucidate the metabolic microbiome profile to design appropriate treatment strategies for early stages of neurodegenerative disease. We view that in order to address neurodegenerative mechanisms of the gut, microbiome and metabolite profiles must be determined to pre-screen AD subjects prior to the design of specific, chronic titrations of gut microbiota with low-dose antibiotics. This represents an exciting treatment strategy designed to balance inflammatory microglial involvement in disease progression with an individual’s manifestation of AD as influenced by a coercive inflammatory gut.

Mechanisms of neuronal death in disease: defining the models and the players

2008 ◽  
Vol 415 (2) ◽  
pp. 165-182 ◽  
Author(s):  
Elena M. Ribe ◽  
Esther Serrano-Saiz ◽  
Nsikan Akpan ◽  
Carol M. Troy
Keyword(s):  
Neurodegenerative Diseases ◽  
Neuronal Death ◽  
Neurological Disease ◽  
Neurodegenerative Disorder ◽  
Cellular Level ◽  
Therapeutic Interventions ◽  
Common Cause ◽  
Life And Death ◽  
Caspase Family ◽  
Common Neurodegenerative Disorder

Dysregulation of life and death at the cellular level leads to a variety of diseases. In the nervous system, aberrant neuronal death is an outstanding feature of neurodegenerative diseases. Since the discovery of the caspase family of proteases, much effort has been made to determine how caspases function in disease, including neurodegenerative diseases. Although many papers have been published examining caspases in neuronal death and disease, the pathways have not been fully clarified. In the present review, we examine the potential players in the death pathways, the current tools for examining these players and the models for studying neurological disease. Alzheimer's disease, the most common neurodegenerative disorder, and cerebral ischaemia, the most common cause of neurological death, are used to illustrate our current understanding of death signalling in neurodegenerative diseases. A better understanding of the neuronal death pathways would provide targets for the development of therapeutic interventions for these diseases.

scholarly journals Utilizing 3D Arterial Spin Labeling to Identify Cerebrovascular Leak and Glymphatic Obstruction in Neurodegenerative Disease

Diagnostics ◽  
2021 ◽  
Vol 11 (10) ◽  
pp. 1888
Author(s):  
Charles R. Joseph
Keyword(s):  
Neurodegenerative Disease ◽  
Therapeutic Interventions ◽  
Contrast Imaging ◽  
Neurologic Diseases ◽  
Pros And Cons ◽  
Potential Methods ◽  
Fluid Leak ◽  
Protein Synthesis And Degradation ◽  
Synthesis And Degradation ◽  
Do So

New approaches are required to successfully intervene therapeutically in neurodegenerative diseases. Addressing the earliest phases of disease, blood brain barrier (BBB) leak before the accumulation of misfolded proteins has significant potential for success. To do so, however, a reliable, noninvasive and economical test is required. There are two potential methods of identifying the BBB fluid leak that results in the accumulation of normally excluded substances which alter neuropil metabolism, protein synthesis and degradation with buildup of misfolded toxic proteins. The pros and cons of dynamic contrast imaging (DCI or DCE) and 3D TGSE PASL are discussed as potential early identifying methods. The results of prior publications of the 3D ASL technique and an overview of the associated physiologic challenges are discussed. Either method may serve well as reliable physiologic markers as novel therapeutic interventions directed at the vasculopathy of early neurodegenerative disease are developed. They may serve well in addressing other neurologic diseases associated with either vascular leak and/or reduced glymphatic flow.

scholarly journals P38α MAPK Signaling—A Robust Therapeutic Target for Rab5-Mediated Neurodegenerative Disease

2020 ◽  
Vol 21 (15) ◽  
pp. 5485
Author(s):  
Ursula A. Germann ◽  
John J. Alam
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Diseases ◽  
Neurodegenerative Disease ◽  
Therapeutic Target ◽  
Kinase Inhibitors ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Therapeutic Effects ◽  
P38α Kinase

Multifactorial pathologies, involving one or more aggregated protein(s) and neuroinflammation are common in major neurodegenerative diseases, such as Alzheimer’s disease and dementia with Lewy bodies. This complexity of multiple pathogenic drivers is one potential explanation for the lack of success or, at best, the partial therapeutic effects, respectively, with approaches that have targeted one specific driver, e.g., amyloid-beta, in Alzheimer’s disease. Since the endosome-associated protein Rab5 appears to be a convergence point for many, if not all the most prominent pathogenic drivers, it has emerged as a major therapeutic target for neurodegenerative disease. Further, since the alpha isoform of p38 mitogen-activated protein kinase (p38α) is a major regulator of Rab5 activity and its effectors, a biology that is distinct from the classical nuclear targets of p38 signaling, brain-penetrant selective p38α kinase inhibitors provide the opportunity for significant therapeutic advances in neurogenerative disease through normalizing dysregulated Rab5 activity. In this review, we provide a brief summary of the role of Rab5 in the cell and its association with neurodegenerative disease pathogenesis. We then discuss the connection between Rab5 and p38α and summarize the evidence that through modulating Rab5 activity there are therapeutic opportunities in neurodegenerative diseases for p38α kinase inhibitors.

scholarly journals Natural Antioxidant Anthocyanins—A Hidden Therapeutic Candidate in Metabolic Disorders with Major Focus in Neurodegeneration

Nutrients ◽  
2019 ◽  
Vol 11 (6) ◽  
pp. 1195 ◽  
Author(s):  
Rahat Ullah ◽  
Mehtab Khan ◽  
Shahid Ali Shah ◽  
Kamran Saeed ◽  
Myeong Ok Kim
Keyword(s):  
Oxidative Stress ◽  
Metabolic Syndrome ◽  
Neurodegenerative Diseases ◽  
Metabolic Disorders ◽  
Antioxidant Defense System ◽  
Vital Role ◽  
Therapeutic Interventions ◽  
Substantial Contribution ◽  
Future Research ◽  
Commercial Sources

All over the world, metabolic syndrome constitutes severe health problems. Multiple factors have been reported in the pathogenesis of metabolic syndrome. Metabolic disorders result in reactive oxygen species (ROS) induced oxidative stress, playing a vital role in the development and pathogenesis of major health issues, including neurological disorders Alzheimer’s disease (AD) Parkinson’s disease (PD). Considerable increasing evidence indicates the substantial contribution of ROS-induced oxidative stress in neurodegenerative diseases. An imbalanced metabolism results in a defective antioxidant defense system, free radicals causing inflammation, cellular apoptosis, and tissue damage. Due to the annual increase in financial and social burdens, in addition to the adverse effects associated with available synthetic agents, treatment diversion from synthetic to natural approaches has occurred. Antioxidants are now being considered as convincing therapeutic agents against various neurodegenerative disorders. Therefore, medicinal herbs and fruits currently receive substantially more attention as commercial sources of antioxidants. In this review, we argue that ROS-targeted therapeutic interventions with naturally occurring antioxidant flavonoid, anthocyanin, and anthocyanin-loaded nanoparticles might be the ultimate treatment against devastating illnesses. Furthermore, we elucidate the hidden potential of the neuroprotective role of anthocyanins and anthocyanin-loaded nanoparticles in AD and PD neuropathies, which lack sufficient attention compared with other polyphenols, despite their strong antioxidant potential. Moreover, we address the need for future research studies of native anthocyanins and nano-based-anthocyanins, which will be helpful in developing anthocyanin treatments as therapeutic mitochondrial antioxidant drug-like regimens to delay or prevent the progression of neurodegenerative diseases, such as AD and PD.

scholarly journals ER stress in neurodegenerative disease: from disease mechanisms to therapeutic interventions

2017 ◽  
Vol 4 (1) ◽  
Author(s):  
Felipe Cabral-Miranda ◽  
Claudio Hetz
Keyword(s):  
Endoplasmic Reticulum ◽  
Neurodegenerative Diseases ◽  
Er Stress ◽  
Major Element ◽  
Neuronal Loss ◽  
Therapeutic Interventions ◽  
Unfolded Protein ◽  
Disease Mechanisms ◽  
The Unfolded Protein Response ◽  
Protein Response

AbstractThe conception that protein aggregates composed by misfolded proteins underlies the occurrence of several neurodegenerative diseases suggests that this phenomenon may have a common origin, ultimately driven by disruption of proteostasis control. The unfolded protein response (UPR) embodies a major element of the proteostasis network, which is engaged by endoplasmic reticulum (ER) stress. Chronic ER stress may operate as a possible mechanism of neurodegeneration, contributing to synaptic alterations, neuroinflammation and neuronal loss. In this review we discuss most recent findings relating ER stress and the development of distinct neurodegenerative diseases, and the possible strategies for disease intervention.

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