Partial Failure of Proteostasis Systems Counteracting TDP-43 Aggregates in Neurodegenerative Diseases

Frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) are progressive and fatal neurodegenerative disorders showing mislocalization and cytosolic accumulation of TDP-43 inclusions in the central nervous system. The decrease in the efficiency of the clearance systems in aging, as well as the presence of genetic mutations of proteins associated with cellular proteostasis in the familial forms of TDP-43 proteinopathies, suggest that a failure of these protein degradation systems is a key factor in the aetiology of TDP-43 associated disorders. Here we show that the internalization of human pre-formed TDP-43 aggregates in the murine neuroblastoma N2a cells promptly resulted in their ubiquitination and hyperphosphorylation by endogenous machineries, mimicking the post-translational modifications observed in patients. Moreover, our data identify mitochondria as the main responsible sites for the alteration of calcium homeostasis induced by TDP-43 aggregates, which, in turn, stimulates an increase in reactive oxygen species and, finally, caspase activation. The inhibition of TDP-43 proteostasis in the presence of selective inhibitors against the proteasome and macroautophagy systems revealed that these two systems are both severely involved in TDP-43 accumulation and have a strong influence on each other in neurodegenerative disorders associated with TDP-43.

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Healthy Gut, Healthy Brain: The Gut Microbiome in Neurodegenerative Disorders

Current Topics in Medicinal Chemistry ◽

10.2174/1568026620666200413091101 ◽

2020 ◽

Vol 20 (13) ◽

pp. 1142-1153 ◽

Cited By ~ 3

Author(s):

Sreyashi Chandra ◽

Md. Tanjim Alam ◽

Jhilik Dey ◽

Baby C. Pulikkaparambil Sasidharan ◽

Upasana Ray ◽

...

Keyword(s):

Gut Microbiota ◽

Neurodegenerative Disorders ◽

The Body ◽

Therapeutic Approaches ◽

Cns Disorders ◽

Physiological Conditions ◽

Pathological Conditions ◽

The Central Nervous System ◽

Present Understanding ◽

Lateral Sclerosis

Background: The central nervous system (CNS) known to regulate the physiological conditions of human body, also itself gets dynamically regulated by both the physiological as well as pathological conditions of the body. These conditions get changed quite often, and often involve changes introduced into the gut microbiota which, as studies are revealing, directly modulate the CNS via a crosstalk. This cross-talk between the gut microbiota and CNS, i.e., the gut-brain axis (GBA), plays a major role in the pathogenesis of many neurodegenerative disorders such as Parkinson’s disease (PD), Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS) and Huntington’s disease (HD). Objective: We aim to discuss how gut microbiota, through GBA, regulate neurodegenerative disorders such as PD, AD, ALS, MS and HD. Methods: In this review, we have discussed the present understanding of the role played by the gut microbiota in neurodegenerative disorders and emphasized the probable therapeutic approaches being explored to treat them. Results: In the first part, we introduce the GBA and its relevance, followed by the changes occurring in the GBA during neurodegenerative disorders and then further discuss its role in the pathogenesis of these diseases. Finally, we discuss its applications in possible therapeutics of these diseases and the current research improvements being made to better investigate this interaction. Conclusion: We concluded that alterations in the intestinal microbiota modulate various activities that could potentially lead to CNS disorders through interactions via the GBA.

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Inherited and Sporadic Amyotrophic Lateral Sclerosis and Fronto-Temporal Lobar Degenerations arising from Pathological Condensates of Phase Separating Proteins

Human Molecular Genetics ◽

10.1093/hmg/ddz162 ◽

2019 ◽

Vol 28 (R2) ◽

pp. R187-R196 ◽

Cited By ~ 2

Author(s):

Michael Fernandopulle ◽

GuoZhen Wang ◽

Jonathon Nixon-Abell ◽

Seema Qamar ◽

Varun Balaji ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Recent Work ◽

Neurodegenerative Disorders ◽

Low Complexity ◽

Present Review ◽

Sporadic Amyotrophic Lateral Sclerosis ◽

Missense Mutations ◽

Post Translational Modifications ◽

Intrinsically Disordered ◽

Lateral Sclerosis

Abstract Recent work on the biophysics of proteins with low complexity, intrinsically disordered domains that have the capacity to form biological condensates has profoundly altered the concepts about the pathogenesis of inherited and sporadic neurodegenerative disorders associated with pathological accumulation of these proteins. In the present review, we use the FUS, TDP-43 and A11 proteins as examples to illustrate how missense mutations and aberrant post-translational modifications of these proteins cause amyotrophic lateral sclerosis (ALS) and fronto-temporal lobar degeneration (FTLD).

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Neuroinflammation in neurodegenerative disorders: the roles of microglia and astrocytes

Translational Neurodegeneration ◽

10.1186/s40035-020-00221-2 ◽

2020 ◽

Vol 9 (1) ◽

Author(s):

Hyuk Sung Kwon ◽

Seong-Ho Koh

Keyword(s):

Central Nervous System ◽

Neurodegenerative Diseases ◽

Neurodegenerative Disorders ◽

Inflammatory Responses ◽

Therapeutic Drugs ◽

M1 Phenotype ◽

The Central Nervous System ◽

The Relationship ◽

Lateral Sclerosis ◽

M2 Phenotype

AbstractNeuroinflammation is associated with neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. Microglia and astrocytes are key regulators of inflammatory responses in the central nervous system. The activation of microglia and astrocytes is heterogeneous and traditionally categorized as neurotoxic (M1-phenotype microglia and A1-phenotype astrocytes) or neuroprotective (M2-phenotype microglia and A2-phenotype astrocytes). However, this dichotomized classification may not reflect the various phenotypes of microglia and astrocytes. The relationship between these activated glial cells is also very complicated, and the phenotypic distribution can change, based on the progression of neurodegenerative diseases. A better understanding of the roles of microglia and astrocytes in neurodegenerative diseases is essential for developing effective therapies. In this review, we discuss the roles of inflammatory response in neurodegenerative diseases, focusing on the contributions of microglia and astrocytes and their relationship. In addition, we discuss biomarkers to measure neuroinflammation and studies on therapeutic drugs that can modulate neuroinflammation.

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Pesticides and Neurodegenerative Disorders

10.1093/med/9780190490911.003.0008 ◽

2017 ◽

Author(s):

John W. McBurney

Keyword(s):

Neurodegenerative Disorders ◽

Neuronal Degeneration ◽

Lewy Bodies ◽

Food Choices ◽

Medical Professionals ◽

Mitochondrial Toxicity ◽

Oxygen Species ◽

Pesticide Exposures ◽

Global Population ◽

Lateral Sclerosis

Neurodegenerative diseases, which are characterized by neuronal degeneration, include Alzheimer disease (AD), Parkinson disease (PD), and amyotrophic lateral sclerosis (ALS). Their worldwide prevalence is increasing as the global population ages. The causes reflect interactions between genetics and environmental factors such as increasing urbanization, industrialization, and widespread use of chemicals, including insecticides, fungicides, and herbicides. Epidemiologic data suggest that exposure to many of these pesticides increases the risk of neurodegeneration. The best-defined mechanism for this association is mitochondrial toxicity resulting in increased reactive oxygen species. In PD and AD, the associated accumulation of aggregates of insoluble, misfolded proteins results in the formation of Lewy bodies and neurofibrillary tangles, respectively. Pesticide exposures can be reduced by modifying food choices and applying integrated pest management in schools, businesses, and homes. Medical professionals can counsel patients about limiting exposure to pesticides and decreasing the risk of neurodegenerative disorders.

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Neurodegenerative Disorders Progression

Advances in Medical Diagnosis, Treatment, and Care - Handbook of Research on Critical Examinations of Neurodegenerative Disorders ◽

10.4018/978-1-5225-5282-6.ch006 ◽

2019 ◽

pp. 129-152

Author(s):

Ramneek Kaur ◽

Harleen Kaur ◽

Rashi Rajput ◽

Sachin Kumar ◽

Rachana R. ◽

...

Keyword(s):

Neurodegenerative Disorders ◽

Neural Systems ◽

Diverse Group ◽

Key Factors ◽

Neuron Death ◽

Postsynaptic Activity ◽

Neural Transmission ◽

The Central Nervous System ◽

Neural Signaling ◽

Lateral Sclerosis

Neurodegenerative disorders (NDs) are a diverse group of disorders characterized by selective and progressive loss of neural systems that cause dysfunction of the central nervous system (CNS). The examples of NDs include Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and Huntington's disease (HD). The aggregated proteins block or disrupt the normal proteosomal turnover, autophagy, and become abnormally modified with time, generating toxicity via pathways thereby resulting in neurodegeneration and neuron death. The chapter highlights the understanding in the areas of AD, PD, HD as illustrative of major research so as to define the key factors and events in the improvement of NDs. It defines the physiological functioning of neural transmission (presynaptic, postsynaptic activity) at neural signaling pathway, then the dynamics of neuronal dysfunctioning and its molecular mechanism. Further, it also discusses the progression from synaptic dysfunction to transmission failure followed by NDs.

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Distinct Phospho-TDP-43 brain distribution in two cases of FTD, one associated with ALS

Dementia & Neuropsychologia ◽

10.1590/1980-57642016dn11-030006 ◽

2017 ◽

Vol 11 (3) ◽

pp. 249-254 ◽

Cited By ~ 3

Author(s):

Álvaro C.B. Guedes ◽

Ricardo Santin ◽

André S.R. Costa ◽

Keli C. Reiter ◽

Arlete Hilbig ◽

...

Keyword(s):

Entorhinal Cortex ◽

Frontotemporal Lobar Degeneration ◽

Scientific Literature ◽

Cognitive Disorder ◽

Brain Distribution ◽

Abnormal Protein ◽

Cellular Processes ◽

The Central Nervous System ◽

The Brain ◽

Lateral Sclerosis

ABSTRACT INTRODUCTION: TDP-43 is an intranuclear protein involved in many cellular processes. When altered, it shows a change in pattern of distribution, as well as in functioning, throughout the Central Nervous System structures. Frontotemporal Lobar Degeneration (FTLD) and Amyotrophic Lateral Sclerosis (ALS) are examples of TDP-43 proteinopathy. These disorders form a clinical spectrum, with some patients having a pure cognitive disorder while others also exhibit motor features. METHODS: We studied two donated brains from patients with a diagnosis of Frontotemporal Dementia (FTD), one of which was associated with ALS (ALS-FTD). After fixation and macroscopic examinations, sample analyses were performed. Specific regions were chosen for the application of immunohistochemistry (IHC) with anti-Aβ, AT8, anti-α-synuclein and anti-phospho-TDP-43. RESULTS: Both brains presented anti-phospho-TDP-43 positivity, but this was not equally distributed throughout the encephalic zones. In the FTD case, the studied brain presented phosphorylated TDP-43- in the frontal cortex, hippocampus, entorhinal cortex and mesencephalon; in the ALS-FTD case, the abnormal protein was also seen in the pons and medulla oblongata. The brain in the ALS-FTD case presented Aβ and AT8 positivity in the hippocampus and entorhinal cortex (Braak I and II). DISCUSSION: The hypothesis supported by scientific literature that these neurodegenerative diseases can have the same etiology with distinct encephalic region involvement is corroborated by the present study.

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Aging-Related Tau Astrogliopathy in Aging and Neurodegeneration

Brain Sciences ◽

10.3390/brainsci11070927 ◽

2021 ◽

Vol 11 (7) ◽

pp. 927

Author(s):

Heather McCann ◽

Briony Durand ◽

Claire E. Shepherd

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Neurodegenerative Disorders ◽

Frontotemporal Lobar Degeneration ◽

Chronic Traumatic Encephalopathy ◽

Neuronal Function ◽

Factors Associated ◽

The Central Nervous System ◽

Clinical Associations ◽

Potential Precursor

Astrocytes are of vital importance to neuronal function and the health of the central nervous system (CNS), and astrocytic dysfunction as a primary or secondary event may predispose to neurodegeneration. Until recently, the main astrocytic tauopathies were the frontotemporal lobar degeneration with tau (FTLD-tau) group of disorders; however, aging-related tau astrogliopathy (ARTAG) has now been defined. This condition is a self-describing neuropathology mainly found in individuals over 60 years of age. Astrocytic tau accumulates with a thorny or granular/fuzzy morphology and is commonly found in normal aging as well as coexisting with diverse neurodegenerative disorders. However, there are still many unknown factors associated with ARTAG, including the cause/s, the progression, and the nature of any clinical associations. In addition to FTLD-tau, ARTAG has recently been associated with chronic traumatic encephalopathy (CTE), where it has been proposed as a potential precursor to these conditions, with the different ARTAG morphological subtypes perhaps having separate etiologies. This is an emerging area of exciting research that encompasses complex neurobiological and clinicopathological investigation.

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The Microbiota-Gut-Brain Axis as a Key to Neuropsychiatric Disorders: A Mini Review

Journal of Clinical Medicine ◽

10.3390/jcm10204640 ◽

2021 ◽

Vol 10 (20) ◽

pp. 4640

Author(s):

Katarzyna Stopińska ◽

Maria Radziwoń-Zaleska ◽

Izabela Domitrz

Keyword(s):

Nervous System ◽

Neurodegenerative Disorders ◽

Essential Role ◽

Short Chain Fatty Acids ◽

Autism Spectrum ◽

Gut Flora ◽

Neuropsychological Disorders ◽

The Central Nervous System ◽

Gut Microorganisms ◽

Lateral Sclerosis

The central nervous system (CNS) is closely related to the gastrointestinal tract, mainly through regulating its function and homeostasis. Simultaneously, the gut flora affects the CNS and plays an essential role in the pathogenesis of neurologic and neuropsychological disorders such as Parkinson’s and Alzheimer’s disease, multiple sclerosis, amyotrophic lateral sclerosis or autism spectrum disorder. The population of gut microorganisms contains more than one billion bacteria. The most common are six phyla: Proteobacteria, Actinomyces, Verucomicrobia, Fusobacteria, and dominant Bacteroides with Firmicutes. The microbiota–gut–brain axis is a bidirectional nervous, endocrine, and immune communication between these two organs. They are connected through a variety of pathways, including the vagus nerve, the immune system, microbial metabolites such as short-chain fatty acids (SCFAs), the enteric nervous system, and hormones. Age, diet, antibiotics influence the balance of gut microorganisms and probably lead to the development of neurodegenerative disorders. In this article, a review is presented and discussed, with a specific focus on the changes of gut microbiota, gut–brain axis, related disorders, and the factors that influence gut imbalance.

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Molecular Chaperones in Neurodegeneration

Quality Control of Cellular Protein in Neurodegenerative Disorders - Advances in Medical Diagnosis, Treatment, and Care ◽

10.4018/978-1-7998-1317-0.ch014 ◽

2020 ◽

pp. 354-379 ◽

Cited By ~ 1

Author(s):

Mukesh Pandey ◽

Jahangir Nabi ◽

Nahida Tabassum ◽

Faheem Hyder Pottoo ◽

Renuka Khatik ◽

...

Keyword(s):

Neurodegenerative Disorders ◽

Protein Misfolding ◽

Protein Quality ◽

Prion Diseases ◽

Experimental Models ◽

Genetic Mutations ◽

Control Network ◽

Molecular Crowding ◽

Age Related ◽

Lateral Sclerosis

Cellular chaperones are essential players to this protein quality control network that functions to prevent protein misfolding, refold misfolded proteins, or degrade them, thereby maintaining neuronal proteostasis. Moreover, overexpression of cellular chaperones is considered to inhibit protein aggregation and apoptosis in various experimental models of neurodegeneration. Alterations or downregulation of chaperone machinery by age-related decline, molecular crowding, or genetic mutations are regarded as key pathological hallmarks of neurodegenerative disorders like Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and Prion diseases. Therefore, chaperones may serve as potential therapeutic targets in these diseases. This chapter presents a generalized view of misfolding and aggregation of proteins in neurodegeneration and then critically analyses some of the known cellular chaperones and their role in several neurodegenerative disorders.

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Role of Prostaglandins in Multiple Sclerosis

Current Pharmaceutical Design ◽

10.2174/1381612826666200107141328 ◽

2020 ◽

Vol 26 (7) ◽

pp. 730-742

Author(s):

Surendra Gulla ◽

Dakshayani Lomada ◽

Anusha Lade ◽

Reddanna Pallu ◽

Madhava C. Reddy

Keyword(s):

Multiple Sclerosis ◽

Central Nervous System ◽

Nervous System ◽

Neurodegenerative Disorders ◽

Cognitive Disability ◽

Demyelinating Disorder ◽

Mediators Of Inflammation ◽

The Central Nervous System ◽

Lateral Sclerosis

: Multiple sclerosis (MS) is an autoimmune demyelinating disorder with chronic inflammation in the central nervous system, manifested by both physical and cognitive disability. Neuroinflammation and neurodegeneration are the phenomena that appear in the central nervous system associated with various neurodegenerative disorders, including MS, Alzheimer’s diseases, amyotrophic lateral sclerosis and Parkinson’s disease. Prostaglandins are one of the major mediators of inflammation that exhibit an important function in enhancing neuroinflammatory and neurodegenerative processes. These mediators would help understand the pathophysiology of MS as the combination of antagonists or agonists of prostaglandins receptors could be beneficial during the treatment of MS. The present review focuses on the role played by different prostaglandins and the enzymes which produced them in the etiopathogenesis of MS.

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