Functional Genomics of Axons and Synapses to Understand Neurodegenerative Diseases

Functional genomics studies through transcriptomics, translatomics and proteomics have become increasingly important tools to understand the molecular basis of biological systems in the last decade. In most cases, when these approaches are applied to the nervous system, they are centered in cell bodies or somatodendritic compartments, as these are easier to isolate and, at least in vitro, contain most of the mRNA and proteins present in all neuronal compartments. However, key functional processes and many neuronal disorders are initiated by changes occurring far away from cell bodies, particularly in axons (axopathologies) and synapses (synaptopathies). Both neuronal compartments contain specific RNAs and proteins, which are known to vary depending on their anatomical distribution, developmental stage and function, and thus form the complex network of molecular pathways required for neuron connectivity. Modifications in these components due to metabolic, environmental, and/or genetic issues could trigger or exacerbate a neuronal disease. For this reason, detailed profiling and functional understanding of the precise changes in these compartments may thus yield new insights into the still intractable molecular basis of most neuronal disorders. In the case of synaptic dysfunctions or synaptopathies, they contribute to dozens of diseases in the human brain including neurodevelopmental (i.e., autism, Down syndrome, and epilepsy) as well as neurodegenerative disorders (i.e., Alzheimer’s and Parkinson’s diseases). Histological, biochemical, cellular, and general molecular biology techniques have been key in understanding these pathologies. Now, the growing number of omics approaches can add significant extra information at a high and wide resolution level and, used effectively, can lead to novel and insightful interpretations of the biological processes at play. This review describes current approaches that use transcriptomics, translatomics and proteomic related methods to analyze the axon and presynaptic elements, focusing on the relationship that axon and synapses have with neurodegenerative diseases.

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New Promising Therapeutic Avenues of Curcumin in Brain Diseases

Molecules ◽

10.3390/molecules27010236 ◽

2021 ◽

Vol 27 (1) ◽

pp. 236

Author(s):

Tarek Benameur ◽

Giulia Giacomucci ◽

Maria Antonietta Panaro ◽

Melania Ruggiero ◽

Teresa Trotta ◽

...

Keyword(s):

Neurodegenerative Diseases ◽

Curcuma Longa ◽

Brain Diseases ◽

Neuroprotective Effects ◽

Parkinson’S Diseases ◽

Brain Structure And Function ◽

Anti Oxidant ◽

And Function

Curcumin, the dietary polyphenol isolated from Curcuma longa (turmeric), is commonly used as an herb and spice worldwide. Because of its bio-pharmacological effects curcumin is also called “spice of life”, in fact it is recognized that curcumin possesses important proprieties such as anti-oxidant, anti-inflammatory, anti-microbial, antiproliferative, anti-tumoral, and anti-aging. Neurodegenerative diseases such as Alzheimer’s Diseases, Parkinson’s Diseases, and Multiple Sclerosis are a group of diseases characterized by a progressive loss of brain structure and function due to neuronal death; at present there is no effective treatment to cure these diseases. The protective effect of curcumin against some neurodegenerative diseases has been proven by in vivo and in vitro studies. The current review highlights the latest findings on the neuroprotective effects of curcumin, its bioavailability, its mechanism of action and its possible application for the prevention or treatment of neurodegenerative disorders.

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Molecular Basis for CPC-Sgo1 Interaction: Implications for Centromere Localisation and Function of the CPC

10.1101/2021.08.27.457910 ◽

2021 ◽

Author(s):

Maria Alba Abad ◽

Tanmay Gupta ◽

Michael A Hadders ◽

Amanda Meppelink ◽

J Pepijn Wopken ◽

...

Keyword(s):

Chromosome Segregation ◽

Molecular Basis ◽

Hot Spot ◽

Histone H3 ◽

Direct Interaction ◽

Histone H2a ◽

Chromosomal Passenger ◽

And Function ◽

Affinity Interaction

AbstractThe Chromosomal Passenger Complex (CPC; consisting of Borealin, Survivin, INCENP and Aurora B kinase) and Shugoshin 1 (Sgo1) are key regulators of chromosome bi-orientation, a process essential for error-free chromosome segregation. Their functions rely on their ability to associate with centromeres. Two histone phosphorylations, histone H3 Thr3 (H3T3ph; directly recognised by Survivin) and histone H2A Thr120 (H2AT120ph; indirectly recognised via Sgo1), together with CPC’s intrinsic ability to bind nucleosome, facilitate CPC centromere recruitment. The molecular basis for CPC-Sgo1 binding and how their direct interaction influences CPC centromere localisation and function are lacking. Here, using an integrative structure-function approach, we show that the histone H3-like Sgo1 N-terminal tail interacts with Survivin acting as a hot-spot for CPC-Sgo1 assembly, while downstream Sgo1 residues, mainly with Borealin contributes for high affinity interaction. Disruption of the Sgo1 N-terminal tail-Survivin interaction abolished CPC-Sgo1 assembly in vitro and perturbed centromere localisation and function of CPC. Our findings provide evidence that CPC binding to Sgo1 and histone H3 N-terminal tail are mutually exclusive, suggesting that these interactions will likely take place in a spatially/temporally restricted manner and provide a rationale for the Sgo1-mediated ‘kinetochore proximal centromere’ pool of CPC.

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A New Treatment Strategy for Parkinson's Disease through the Gut–Brain Axis

Cell Transplantation ◽

10.1177/0963689717721234 ◽

2017 ◽

Vol 26 (9) ◽

pp. 1560-1571 ◽

Cited By ~ 39

Author(s):

Dong Seok Kim ◽

Ho-Il Choi ◽

Yun Wang ◽

Yu Luo ◽

Barry J. Hoffer ◽

...

Keyword(s):

Risk Factor ◽

Neurodegenerative Diseases ◽

Physiological Role ◽

Open Label ◽

Effective Treatment Option ◽

Neuroprotective Effects ◽

Double Blind ◽

Parkinson’S Diseases ◽

Dipeptidyl Peptidase 4 Inhibitors

Molecular communications in the gut–brain axis, between the central nervous system and the gastrointestinal tract, are critical for maintaining healthy brain function, particularly in aging. Epidemiological analyses indicate type 2 diabetes mellitus (T2DM) is a risk factor for neurodegenerative disorders including Alzheimer's disease (AD) and Parkinson's diseases (PD) for which aging shows a major correlative association. Common pathophysiological features exist between T2DM, AD, and PD, including oxidative stress, inflammation, insulin resistance, abnormal protein processing, and cognitive decline, and suggest that effective drugs for T2DM that positively impact the gut–brain axis could provide an effective treatment option for neurodegenerative diseases. Glucagon-like peptide-1 (GLP-1)-based antidiabetic drugs have drawn particular attention as an effectual new strategy to not only regulate blood glucose but also decrease body weight by reducing appetite, which implies that GLP-1 could affect the gut–brain axis in normal and pathological conditions. The neurotrophic and neuroprotective effects of GLP-1 receptor (R) stimulation have been characterized in numerous in vitro and in vivo preclinical studies using GLP-1R agonists and dipeptidyl peptidase-4 inhibitors. Recently, the first open label clinical study of exenatide, a long-acting GLP-1 agonist, in the treatment of PD showed long-lasting improvements in motor and cognitive function. Several double-blind clinical trials of GLP-1R agonists including exenatide in PD and other neurodegenerative diseases are already underway or are about to be initiated. Herein, we review the physiological role of the GLP-1R pathway in the gut–brain axis and the therapeutic strategy of GLP-1R stimulation for the treatment of neurodegenerative diseases focused on PD, for which age is the major risk factor.

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Interaction of Neuromelanin with Xenobiotics and Consequences for Neurodegeneration; Promising Experimental Models

Antioxidants ◽

10.3390/antiox10060824 ◽

2021 ◽

Vol 10 (6) ◽

pp. 824

Author(s):

Andrea Capucciati ◽

Fabio A. Zucca ◽

Enrico Monzani ◽

Luigi Zecca ◽

Luigi Casella ◽

...

Keyword(s):

Animal Models ◽

Neurodegenerative Diseases ◽

Brain Aging ◽

Experimental Models ◽

Test Tube ◽

Age Related ◽

And Function ◽

Endogenous Metabolites ◽

High Degree

Neuromelanin (NM) accumulates in catecholamine long-lived brain neurons that are lost in neurodegenerative diseases. NM is a complex substance made of melanic, peptide and lipid components. NM formation is a natural protective process since toxic endogenous metabolites are removed during its formation and as it binds excess metals and xenobiotics. However, disturbances of NM synthesis and function could be toxic. Here, we review recent knowledge on NM formation, toxic mechanisms involving NM, go over NM binding substances and suggest experimental models that can help identifying xenobiotic modulators of NM formation or function. Given the high likelihood of a central NM role in age-related human neurodegenerative diseases such as Parkinson’s and Alzheimer’s, resembling such diseases using animal models that do not form NM to a high degree, e.g., mice or rats, may not be optimal. Rather, use of animal models (i.e., sheep and goats) that better resemble human brain aging in terms of NM formation, as well as using human NM forming stem cellbased in vitro (e.g., mid-brain organoids) models can be more suitable. Toxicants could also be identified during chemical synthesis of NM in the test tube.

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Structure and Function of an in vivo Assembled Type III-A CRISPR-Cas Complex Reveal Critical Roles of Dynamics in Activity Control

10.1101/2021.01.27.428455 ◽

2021 ◽

Author(s):

Sagar Sridhara ◽

Jay Rai ◽

Charlisa Whyms ◽

Walter Woodside ◽

Michael P Terns ◽

...

Keyword(s):

Molecular Basis ◽

Structure And Function ◽

Flanking Sequence ◽

Electron Cryomicroscopy ◽

Graphic Art ◽

Type Iii ◽

And Function ◽

Target Rna

AbstractThe small RNA-mediated immunity in bacteria depends on foreign RNA-activated and self RNA-inhibited enzymatic activities. The multi-subunit Type III-A CRISPR-Cas effector complex (Csm) exemplifies this principle, but its molecular basis for regulation remains unexplained. Recognition of the foreign RNA, or cognate target RNA (CTR), triggers its single-stranded deoxyribonuclease (DNase) and cyclic oligoadenylate (cOA) synthesis activities. The same activities remain dormant in the presence of the self-RNA, or noncognate target RNA (NTR) that differs from CTR only in its 3’-protospacer flanking sequence. Here we captured four structures of in vivo assembled Lactococcus lactis Csm (LlCsm) by electron cryomicroscopy representing both the active and the inactive states. Surprisingly, in absence of bound RNA, LlCsm largely forms a minimal assembly lacking the Csm2 subunit with a stably bound catalytic subunit Csm1. Comparison of the minimal LlCsm structure and activities, both in vitro and in vivo, with those of fully assembled LlCsm reveals a molecular mechanism responsible for the viral RNA-activated and self RNA-inhibited activity of Csm1 through protein dynamics.Graphic Art Summary

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Beneficial Effects of Epigallocatechin-3-O-Gallate, Chlorogenic Acid, Resveratrol, and Curcumin on Neurodegenerative Diseases

Molecules ◽

10.3390/molecules26020415 ◽

2021 ◽

Vol 26 (2) ◽

pp. 415

Author(s):

Ryuuta Fukutomi ◽

Tomokazu Ohishi ◽

Yu Koyama ◽

Monira Pervin ◽

Yoriyuki Nakamura ◽

...

Keyword(s):

Cardiovascular Diseases ◽

Neurodegenerative Diseases ◽

Molecular Basis ◽

Animal Experiments ◽

Polyphenolic Compounds ◽

Chlorogenic Acids ◽

Plant Polyphenols ◽

Beneficial Effects ◽

Parkinson’S Diseases ◽

Basic Experiments

Many observational and clinical studies have shown that consumption of diets rich in plant polyphenols have beneficial effects on various diseases such as cancer, obesity, diabetes, cardiovascular diseases, and neurodegenerative diseases (NDDs). Animal and cellular studies have indicated that these polyphenolic compounds contribute to such effects. The representative polyphenols are epigallocatechin-3-O-gallate in tea, chlorogenic acids in coffee, resveratrol in wine, and curcumin in curry. The results of human studies have suggested the beneficial effects of consumption of these foods on NDDs including Alzheimer’s and Parkinson’s diseases, and cellular animal experiments have provided molecular basis to indicate contribution of these representative polyphenols to these effects. This article provides updated information on the effects of these foods and their polyphenols on NDDs with discussions on mechanistic aspects of their actions mainly based on the findings derived from basic experiments.

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Unlocking the Complexity of Mitochondrial DNA: A Key to Understanding Neurodegenerative Disease Caused by Injury

Cells ◽

10.3390/cells10123460 ◽

2021 ◽

Vol 10 (12) ◽

pp. 3460

Author(s):

Larry N. Singh ◽

Shih-Han Kao ◽

Douglas C. Wallace

Keyword(s):

Mitochondrial Dna ◽

Neurodegenerative Diseases ◽

Neurodegenerative Disease ◽

Genetic Factors ◽

Mitochondrial Genetics ◽

Dna Variation ◽

Parkinson’S Diseases ◽

And Function ◽

The Impact

Neurodegenerative disorders that are triggered by injury typically have variable and unpredictable outcomes due to the complex and multifactorial cascade of events following the injury and during recovery. Hence, several factors beyond the initial injury likely contribute to the disease progression and pathology, and among these are genetic factors. Genetics is a recognized factor in determining the outcome of common neurodegenerative diseases. The role of mitochondrial genetics and function in traditional neurodegenerative diseases, such as Alzheimer’s and Parkinson’s diseases, is well-established. Much less is known about mitochondrial genetics, however, regarding neurodegenerative diseases that result from injuries such as traumatic brain injury and ischaemic stroke. We discuss the potential role of mitochondrial DNA genetics in the progression and outcome of injury-related neurodegenerative diseases. We present a guide for understanding mitochondrial genetic variation, along with the nuances of quantifying mitochondrial DNA variation. Evidence supporting a role for mitochondrial DNA as a risk factor for neurodegenerative disease is also reviewed and examined. Further research into the impact of mitochondrial DNA on neurodegenerative disease resulting from injury will likely offer key insights into the genetic factors that determine the outcome of these diseases together with potential targets for treatment.

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In vitro and in vivo effects of oxidative damage to deoxyguanosine

Biochemical Society Transactions ◽

10.1042/bst0320046 ◽

2004 ◽

Vol 32 (1) ◽

pp. 46-50 ◽

Cited By ~ 20

Author(s):

M.M. Greenberg

Keyword(s):

Molecular Basis ◽

Chemical Reactivity ◽

Structure And Function ◽

Dna Lesions ◽

Biological Studies ◽

And Function ◽

In Vivo Effects ◽

Significant Effort

Biochemical, biophysical and biological studies of oligonucleotides containing lesions at defined sites provide a molecular basis for the effects of DNA lesions. dG (deoxyguanosine) is the most easily oxidized of the four native nucleotides. The chemical reactivity of dG correlates with compilations of mutations, which reveal that a significant fraction of transitions or transversions involve dG. OxodG (7,8-dihydro-8-hydroxy-2´-deoxyguanosine) is widely recognized as an important lesion derived from the oxidation of dG, and significant effort has been expended in studies of its effects on DNA structure and function. Recently, the properties of other lesions derived from dG and/or the oxidation of OxodG have been uncovered. Studies on these lesions reveal that they too are biologically significant.

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Infectivity versus Seeding in Neurodegenerative Diseases Sharing a Prion-Like Mechanism

International Journal of Cell Biology ◽

10.1155/2013/583498 ◽

2013 ◽

Vol 2013 ◽

pp. 1-9 ◽

Cited By ~ 15

Author(s):

Natalia Fernández-Borges ◽

Hasier Eraña ◽

Saioa R. Elezgarai ◽

Chafik Harrathi ◽

Mayela Gayosso ◽

...

Keyword(s):

Neurodegenerative Diseases ◽

Molecular Mechanisms ◽

De Novo ◽

Infectious Agent ◽

Infection Process ◽

Biological Information ◽

Misfolded Proteins ◽

Parkinson’S Diseases

Prions are considered the best example to prove that the biological information can be transferred protein to protein through a conformational change. The term “prion-like” is used to describe molecular mechanisms that share similarities with the mammalian prion protein self-perpetuating aggregation and spreading characteristics. Since prions are presumably composed only of protein and are infectious, the more similar the mechanisms that occur in the different neurodegenerative diseases, the more these processes will resemble an infection.In vitroandin vivoexperiments carried out during the last decade in different neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's diseases (PD), and amyotrophic lateral sclerosis (ALS) have shown a convergence toward a unique mechanism of misfolded protein propagation. In spite of the term “infection” that could be used to explain the mechanism governing the diversity of the pathological processes, other concepts as “seeding” or “de novoinduction” are being used to describe thein vivopropagation and transmissibility of misfolded proteins. The current studies are demanding an extended definition of “disease-causing agents” to include those already accepted as well as other misfolded proteins. In this new scenario, “seeding” would be a type of mechanism by which an infectious agent can be transmitted but should not be used to define a whole “infection” process.

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Molecular architecture and functions of the neuronal cytoskeleton

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100157541 ◽

1990 ◽

Vol 48 (3) ◽

pp. 2-3

Author(s):

Nobutaka Hirokawa

Keyword(s):

Major Elements ◽

Molecular Structures ◽

Organelle Transport ◽

Molecular Architecture ◽

Neuronal Morphogenesis ◽

Microtubule Associated Proteins ◽

Associated Proteins ◽

And Function ◽

Small Clusters

In this symposium I will present our studies about the molecular architecture and function of the cytomatrix of the nerve cells. The nerve cell is a highly polarized cell composed of highly branched dendrites, cell body, and a single long axon along the direction of the impulse propagation. Each part of the neuron takes characteristic shapes for which the cytoskeleton provides the framework. The neuronal cytoskeletons play important roles on neuronal morphogenesis, organelle transport and the synaptic transmission. In the axon neurofilaments (NF) form dense arrays, while microtubules (MT) are arranged as small clusters among the NFs. On the other hand, MTs are distributed uniformly, whereas NFs tend to run solitarily or form small fascicles in the dendrites Quick freeze deep etch electron microscopy revealed various kinds of strands among MTs, NFs and membranous organelles (MO). These structures form major elements of the cytomatrix in the neuron. To investigate molecular nature and function of these filaments first we studied molecular structures of microtubule associated proteins (MAP1A, MAP1B, MAP2, MAP2C and tau), and microtubules reconstituted from MAPs and tubulin in vitro. These MAPs were all fibrous molecules with different length and formed arm like projections from the microtubule surface.

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