Molecular Mechanisms of Neurodegenerative Disorders

Abstract:: Various neurodegenerative disorders have molecular origin but some common molecular mechanisms. In the current scenario, there are very few treatment regimens present for advanced neurodegenerative diseases. In this context, there is an urgent need for alternate options in the form of natural compounds with an ameliorating effect on patients. There have been individual scattered experiments trying to identify potential values of various intracellular metabolites. Purines and Pyrimidines, which are vital molecules governing various aspects of cellular biochemical reactions, have been long sought as crucial candidates for the same, but there are still many questions that go unanswered. Some critical functions of these molecules associated with neuromodulation activities have been identified. They are also known to play a role in foetal neurodevelopment, but there is a lacuna in understanding their mechanisms. In this review, we have tried to assemble and identify the importance of purines and pyrimidines, connecting them with the prevalence of neurodegenerative diseases. The leading cause of this class of diseases is protein misfolding and the formation of amyloids. A direct correlation between loss of balance in cellular homeostasis and amyloidosis is yet an unexplored area. This review aims at bringing the current literature available under one umbrella serving as a foundation for further extensive research in this field of drug development in neurodegenerative diseases.

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Cannabidiol induces autophagy via ERK1/2 activation in neural cells

Scientific Reports ◽

10.1038/s41598-021-84879-2 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Talita A. M. Vrechi ◽

Anderson H. F. F. Leão ◽

Ingrid B. M. Morais ◽

Vanessa C. Abílio ◽

Antonio W. Zuardi ◽

...

Keyword(s):

Central Nervous System ◽

Neurodegenerative Disorders ◽

Molecular Mechanisms ◽

Cannabis Sativa ◽

Autophagic Flux ◽

Neural Cells ◽

Human Neuroblastoma ◽

Trpv1 Receptor ◽

The Central Nervous System ◽

Catabolic Process

AbstractAutophagy is a lysosomal catabolic process essential to cell homeostasis and is related to the neuroprotection of the central nervous system. Cannabidiol (CBD) is a non-psychotropic phytocannabinoid present in Cannabis sativa. Many therapeutic actions have been linked to this compound, including autophagy activation. However, the precise underlying molecular mechanisms remain unclear, and the downstream functional significance of these actions has yet to be determined. Here, we investigated CBD-evoked effects on autophagy in human neuroblastoma SH-SY5Y and murine astrocyte cell lines. We found that CBD-induced autophagy was substantially reduced in the presence of CB1, CB2 and TRPV1 receptor antagonists, AM 251, AM 630 and capsazepine, respectively. This result strongly indicates that the activation of these receptors mediates the autophagic flux. Additionally, we demonstrated that CBD activates autophagy through ERK1/2 activation and AKT suppression. Interestingly, CBD-mediated autophagy activation is dependent on the autophagy initiator ULK1, but mTORC1 independent. Thus, it is plausible that a non-canonical pathway is involved. Our findings collectively provide evidence that CBD stimulates autophagy signal transduction via crosstalk between the ERK1/2 and AKT kinases, which represent putative regulators of cell proliferation and survival. Furthermore, our study sheds light on potential therapeutic cannabinoid targets that could be developed for treating neurodegenerative disorders.

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Pharmacoepigenomic Interventions as Novel Potential Treatments for Alzheimer’s and Parkinson’s Diseases

International Journal of Molecular Sciences ◽

10.3390/ijms19103199 ◽

2018 ◽

Vol 19 (10) ◽

pp. 3199 ◽

Cited By ~ 16

Author(s):

Oscar Teijido ◽

Ramón Cacabelos

Keyword(s):

Neurodegenerative Disorders ◽

Molecular Mechanisms ◽

Pathological Process ◽

Epigenetic Mechanisms ◽

Dietary Interventions ◽

Parkinson’S Diseases ◽

The World ◽

Multifactorial Disorders ◽

Late Stages ◽

Potential Use

Cerebrovascular and neurodegenerative disorders affect one billion people around the world and result from a combination of genomic, epigenomic, metabolic, and environmental factors. Diagnosis at late stages of disease progression, limited knowledge of gene biomarkers and molecular mechanisms of the pathology, and conventional compounds based on symptomatic rather than mechanistic features, determine the lack of success of current treatments, including current FDA-approved conventional drugs. The epigenetic approach opens new avenues for the detection of early presymptomatic pathological events that would allow the implementation of novel strategies in order to stop or delay the pathological process. The reversibility and potential restoring of epigenetic aberrations along with their potential use as targets for pharmacological and dietary interventions sited the use of epidrugs as potential novel candidates for successful treatments of multifactorial disorders involving neurodegeneration. This manuscript includes a description of the most relevant epigenetic mechanisms involved in the most prevalent neurodegenerative disorders worldwide, as well as the main potential epigenetic-based compounds under investigation for treatment of those disorders and their limitations.

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Catechins as Tools to Understand the Molecular Basis of Neurodegeneration

Molecules ◽

10.3390/molecules25163571 ◽

2020 ◽

Vol 25 (16) ◽

pp. 3571

Author(s):

Karla Martinez Pomier ◽

Rashik Ahmed ◽

Giuseppe Melacini

Keyword(s):

Phenolic Compounds ◽

Neurodegenerative Disorders ◽

Molecular Basis ◽

Protein Misfolding ◽

Molecular Mechanisms ◽

Amyloid Aggregation ◽

Amyloid Aggregates ◽

Parkinson’S Diseases ◽

Pharmacokinetic Properties ◽

Self Association

Protein misfolding as well as the subsequent self-association and deposition of amyloid aggregates is implicated in the progression of several neurodegenerative disorders including Alzheimer’s and Parkinson’s diseases. Modulators of amyloidogenic aggregation serve as essential tools to dissect the underlying molecular mechanisms and may offer insight on potential therapeutic solutions. These modulators include green tea catechins, which are potent inhibitors of amyloid aggregation. Although catechins often exhibit poor pharmacokinetic properties and bioavailability, they are still essential tools for identifying the drivers of amyloid aggregation and for developing other aggregation modulators through structural mimicry. As an illustration of such strategies, here we review how catechins have been used to map the toxic surfaces of oligomeric amyloid-like species and develop catechin-based phenolic compounds with enhanced anti-amyloid activity.

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Pharmacological Modulators of Tau Aggregation and Spreading

Brain Sciences ◽

10.3390/brainsci10110858 ◽

2020 ◽

Vol 10 (11) ◽

pp. 858

Author(s):

Antonio Dominguez-Meijide ◽

Eftychia Vasili ◽

Tiago Fleming Outeiro

Keyword(s):

Tau Protein ◽

Neurodegenerative Disorders ◽

Molecular Mechanisms ◽

Mechanisms Of Action ◽

Tau Aggregation ◽

The Brain ◽

Pharmacological Modulators

Tauopathies are neurodegenerative disorders characterized by the deposition of aggregates composed of abnormal tau protein in the brain. Additionally, misfolded forms of tau can propagate from cell to cell and throughout the brain. This process is thought to lead to the templated misfolding of the native forms of tau, and thereby, to the formation of newer toxic aggregates, thereby propagating the disease. Therefore, modulation of the processes that lead to tau aggregation and spreading is of utmost importance in the fight against tauopathies. In recent years, several molecules have been developed for the modulation of tau aggregation and spreading. In this review, we discuss the processes of tau aggregation and spreading and highlight selected chemicals developed for the modulation of these processes, their usefulness, and putative mechanisms of action. Ultimately, a stronger understanding of the molecular mechanisms involved, and the properties of the substances developed to modulate them, will lead to the development of safer and better strategies for the treatment of tauopathies.

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Formation of Hirano Bodies after Inducible Expression of a Modified Form of an Actin-Cross-Linking Protein

Eukaryotic Cell ◽

10.1128/ec.00379-08 ◽

2009 ◽

Vol 8 (6) ◽

pp. 852-857 ◽

Cited By ~ 10

Author(s):

Juan F. Reyes ◽

Karen Stone ◽

Jeanie Ramos ◽

Andrew Maselli

Keyword(s):

Neurodegenerative Disorders ◽

Molecular Mechanisms ◽

Expression System ◽

Inducible Expression ◽

Postmortem Brain ◽

Vector System ◽

Actin Binding ◽

Cell Cortex ◽

Hirano Bodies ◽

Cytoplasmic Inclusions

ABSTRACT Hirano bodies are cytoplasmic inclusions composed mainly of actin and actin-associated proteins. The formation of Hirano bodies during various neurodegenerative disorders, including Alzheimer's disease and amyotrophic lateral sclerosis, has been reported. Although the underlying molecular mechanisms that lead to the formation of these inclusions in the brain are not known, expression of the C-terminal fragment (CT) (amino acids 124 to 295) from the endogenous 34-kDa actin-binding protein of Dictyostelium discoideum leads to the formation of actin inclusions in vivo. In the current study, we report the development of an inducible expression system to study the early phases of Hirano body formation using an inducible promoter system (rnrB). By fusing the CT to a green fluorescent protein (CT-GFP), we monitored protein expression and localization by fluorescence microscopy, flow cytometry, and Western blot analysis. We observed an increase in the number and size of inclusions formed following induction of the CT-GFP vector system. Time-lapse microscopy studies revealed that the CT-GFP foci associated with the cell cortex and fused to form a single large aggregate. Transmission electron microscopy further demonstrates that these inclusions have a highly ordered ultrastructure, a pathological hallmark of Hirano bodies observed in postmortem brain samples from patients with various neurodegenerative disorders. Collectively, this system provides a method to visualize and characterize the events that surround early actin inclusion formation in a eukaryotic model.

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Age-related changes in microglial physiology: the role for healthy brain ageing and neurodegenerative disorders

e-Neuroforum ◽

10.1515/nf-2016-a057 ◽

2017 ◽

Vol 23 (4) ◽

Cited By ~ 4

Author(s):

Olga Garaschuk

Keyword(s):

Neurodegenerative Disorders ◽

Healthy Aging ◽

Molecular Mechanisms ◽

Brain Parenchyma ◽

Immune Defense ◽

Synaptic Activity ◽

Mammalian Brain ◽

Age Related ◽

Brain Ageing ◽

The Brain

AbstractMicroglia are the main immune cells of the brain contributing, however, not only to brain’s immune defense but also to many basic housekeeping functions such as development and maintenance of functional neural networks, provision of trophic support for surrounding neurons, monitoring and modulating the levels of synaptic activity, cleaning of accumulating extracellular debris and repairing microdamages of the brain parenchyma. As a consequence, age-related alterations in microglial function likely have a manifold impact on brain’s physiology. In this review, I discuss the recent data about physiological properties of microglia in the adult mammalian brain; changes observed in the brain innate immune system during healthy aging and the probable biological mechanisms responsible for them as well as changes occurring in humans and mice during age-related neurodegenerative disorders along with underlying cellular/molecular mechanisms. Together these data provide a new conceptual framework for thinking about the role of microglia in the context of age-mediated brain dysfunction.

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Unique structural features of the mitochondrial AAA+ protease AFG3L2 reveal the molecular basis for activity in health and disease

10.1101/551085 ◽

2019 ◽

Author(s):

Cristina Puchades ◽

Bojian Ding ◽

Albert Song ◽

R. Luke Wiseman ◽

Gabriel C. Lander ◽

...

Keyword(s):

Neurodegenerative Disorders ◽

Molecular Basis ◽

Molecular Mechanisms ◽

Structural Data ◽

Structural Features ◽

Genetic Mutations ◽

Biological Functions ◽

Catalytic Core ◽

Structural Framework ◽

Health And Disease

AbstractMitochondrial AAA+ quality control proteases regulate diverse aspects of mitochondrial biology through specialized protein degradation, but the underlying molecular mechanisms that define the diverse activities of these enzymes remain poorly defined. The mitochondrial AAA+ protease AFG3L2 is of particular interest, as genetic mutations localized throughout AFG3L2 are linked to diverse neurodegenerative disorders. However, a lack of structural data has limited our understanding of how mutations impact enzymatic activity. Here, we used cryo-EM to determine a substrate-bound structure of the catalytic core of human AFG3L2. This structure identifies multiple specialized structural features within AFG3L2 that integrate with conserved structural motifs required for hand-over-hand ATP-dependent substrate translocation to engage, unfold and degrade targeted proteins. Mapping disease-relevant AFG3L2 mutations onto our structure demonstrates that many of these mutations localize to these unique structural features of AFG3L2 and distinctly influence its activity and stability. Our results provide a molecular basis for neurological phenotypes associated with different AFG3L2 mutations, and establish a structural framework to understand how different members of the AAA+ superfamily achieve specialized, diverse biological functions.

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The Role of Gut Microbiota in Aging and Aging Related Neurodegenerative Disorders: Insights from Drosophila Model

Life ◽

10.3390/life11080855 ◽

2021 ◽

Vol 11 (8) ◽

pp. 855

Author(s):

Yan Kong ◽

Liyuan Wang ◽

Baichun Jiang

Keyword(s):

Gut Microbiota ◽

Neurodegenerative Disorders ◽

Molecular Mechanisms ◽

Physiological Function ◽

Time Dependent ◽

Model Organisms ◽

Gi Tract ◽

Drosophila Model ◽

Increased Susceptibility

Aging is characterized by a time dependent impairment of physiological function and increased susceptibility to death. It is the major risk factor for neurodegeneration. Neurodegenerative disorders including Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the main causes of dementia in the old population. Gut microbiota is a community of microorganisms colonized in the gastrointestinal (GI) tract. The alteration of gut microbiota has been proved to be associated with aging and aging related neurodegeneration. Drosophila is a powerful tool to study microbiota-mediated physiological and pathological functions. Here, we summarize the recent advances using Drosophila as model organisms to clarify the molecular mechanisms and develop a therapeutic method targeting microbiota in aging and aging-related neurodegenerative disorders.

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Tau Accumulation via Reduced BAG3-mediated Autophagy Is Required for GGGGCC Repeat Expansion-Induced Neurodegeneration

10.1101/727008 ◽

2019 ◽

Author(s):

Xue Wen ◽

Ping An ◽

Hexuan Li ◽

Zijian Zhou ◽

Yimin Sun ◽

...

Keyword(s):

Tau Protein ◽

Neurodegenerative Disorders ◽

Motor Performance ◽

Molecular Mechanisms ◽

Repeat Expansion ◽

Cag Repeats ◽

Reduced Activity ◽

Lateral Sclerosis

SUMMARYExpansions of trinucleotide or hexanucleotide repeats lead to several neurodegenerative disorders including Huntington disease (HD, caused by the expanded CAG repeats (CAGr) in the HTT gene) and amyotrophic lateral sclerosis (ALS, could be caused by the expanded GGGGCC repeats (G4C2r) in the C9ORF72 gene), of which the molecular mechanisms remain unclear. Here we demonstrate that loss of the Drosophila orthologue of tau protein (dtau) significantly rescued in vivo neurodegeneration, motor performance impairments, and shortened life-span in Drosophila models expressing mutant HTT protein with expanded CAGr or the expanded G4C2r. Importantly, expression of human tau (htau4R) restored the disease-relevant phenotypes that were mitigated by the loss of dtau, suggesting a conserved role of tau in neurodegeneration. We further discovered that G4C2r expression increased dtau accumulation, possibly due to reduced activity of BAG3-mediated autophagy. Our study reveals a conserved role of tau in G4C2r-induced neurotoxicity in Drosophila models, providing mechanistic insights and potential therapeutic targets.

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