Amyloid Oligomers: A Joint Experimental/Computational Perspective on Alzheimer’s Disease, Parkinson’s Disease, Type II Diabetes, and Amyotrophic Lateral Sclerosis

Chemical Reviews, Journal Year: 2021, Volume and Issue: 121(4), P. 2545 - 2647

Published: Feb. 5, 2021

Protein misfolding and aggregation is observed in many amyloidogenic diseases affecting either the central nervous system or a variety of peripheral tissues. Structural dynamic characterization all species along pathways from monomers to fibrils challenging by experimental computational means because they involve intrinsically disordered proteins most diseases. Yet understanding how amyloid become toxic challenge developing treatment for these Here we review what computer, vitro, vivo, pharmacological experiments tell us about accumulation deposition oligomers (Aβ, tau), α-synuclein, IAPP, superoxide dismutase 1 proteins, which have been mainstream concept underlying Alzheimer's disease (AD), Parkinson's (PD), type II diabetes (T2D), amyotrophic lateral sclerosis (ALS) research, respectively, years.

Language: Английский

---

Role of astroglial toll-like receptors (TLRs) in central nervous system infections, injury and neurodegenerative diseases

Brain Behavior and Immunity, Journal Year: 2020, Volume and Issue: 91, P. 740 - 755

Published: Oct. 8, 2020

Central nervous system (CNS) innate immunity plays essential roles in infections, neurodegenerative diseases, and brain or spinal cord injuries. Astrocytes microglia are the principal cells that mediate CNS. Pattern recognition receptors (PRRs), expressed by astrocytes microglia, sense pathogen-derived endogenous ligands released damaged initiate immune response. Toll-like (TLRs) a well-characterized family of PRRs. The contribution microglial TLR signaling to CNS pathology has been extensively investigated. Even though assume wide variety key functions, information about role astroglial TLRs disease injuries is limited. Because display heterogeneity exhibit phenotypic plasticity depending on effectors present local milieu, they can exert both detrimental beneficial effects. modulators these paradoxical properties. goal current review highlight played diseases. We discuss host defense as well dissemination viral bacterial infections examine link between pathogenesis diseases evidence showing pivotal influence sterile inflammation injury. Finally, we define research questions areas warrant further investigations context astrocytes, TLRs, dysfunction.

Language: Английский

---

Lysosome dysfunction as a cause of neurodegenerative diseases: Lessons from frontotemporal dementia and amyotrophic lateral sclerosis

Neurobiology of Disease, Journal Year: 2021, Volume and Issue: 154, P. 105360 - 105360

Published: April 1, 2021

Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are fatal neurodegenerative disorders that thought to exist on a clinical pathological spectrum. FTD ALS linked by shared genetic causes (e.g. C9orf72 hexanucleotide repeat expansions) neuropathology, such as inclusions of ubiquitinated, misfolded proteins TAR DNA-binding protein 43; TDP-43) in the CNS. Furthermore, some genes cause or when mutated encode localize lysosome modulate endosome-lysosome function, including lysosomal fusion, cargo trafficking, acidification, autophagy, TFEB activity. In this review, we summarize evidence dysfunction, caused mutations C9orf72, GRN, MAPT, TMEM106B) toxic-gain function aggregation TDP-43 tau), is an important pathogenic disease mechanism ALS. Further studies into normal many these required will help uncover mechanisms dysfunction Mutations polymorphisms for also occur other age-dependent diseases, Alzheimer's APOE, PSEN1, APP) Parkinson's GBA, LRRK2, ATP13A2) disease. A more complete understanding common unique features across spectrum neurodegeneration guide development therapies devastating diseases.

Language: Английский

---

PINK1/Parkin-mediated mitophagy in neurodegenerative diseases

Ageing Research Reviews, Journal Year: 2022, Volume and Issue: 84, P. 101817 - 101817

Published: Dec. 9, 2022

Language: Английский

---

The Integral Role of RNA in Stress Granule Formation and Function

Frontiers in Cell and Developmental Biology, Journal Year: 2021, Volume and Issue: 9

Published: May 20, 2021

Stress granules (SGs) are phase-separated, membraneless, cytoplasmic ribonucleoprotein (RNP) assemblies whose primary function is to promote cell survival by condensing translationally stalled mRNAs, ribosomal components, translation initiation factors, and RNA-binding proteins (RBPs). While the protein composition of in compartmentalization dynamics assembly disassembly SGs has been a matter study for several years, role RNA these structures had remained largely unknown. species are, however, not passive members that itself can form homo heterotypic interactions with other molecules leading phase separation nucleation granules. also as molecular scaffolds recruiting multivalent RBPs their interactors higher-order structures. With development SG purification techniques coupled RNA-seq, transcriptomic landscape becoming increasingly understood, revealing enormous potential guide transient organelles. only formed under acute stress conditions but response different diseases such viral infections, cancer, neurodegeneration. Importantly, being recognized precursors pathological aggregates neurodegenerative diseases. In this review, we examine current evidence support playing significant formation explore concept therapeutic targets.

Language: Английский

---

Neurofilament Light Chain as Biomarker for Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

Frontiers in Neuroscience, Journal Year: 2021, Volume and Issue: 15

Published: June 21, 2021

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are two related currently incurable neurodegenerative diseases. ALS is characterized by degeneration of upper lower motor neurons causing relentless paralysis voluntary muscles, whereas in FTD, progressive atrophy the frontal temporal lobes brain results deterioration cognitive functions, language, personality, behavior. In contrast to Alzheimer’s disease (AD), FTD still lack a specific neurochemical biomarker reflecting neuropathology ex vivo . However, past 10 years, considerable progress has been made characterization neurofilament light chain (NFL) as cerebrospinal fluid (CSF) blood for both NFL structural component axonal cytoskeleton released into CSF consequence damage or degeneration, thus behaving general relatively non-specific marker neuroaxonal pathology. ALS, elevation its levels exceeds that observed most other neurological diseases, making it useful discrimination from mimic conditions potentially worthy consideration introduction diagnostic criteria. Moreover, correlates with progression rate negatively associated survival, providing prognostic information. patients, elevated compared healthy individuals and, lesser extent, patients forms dementia, but latter difference not sufficient enable satisfying performance at individual patient level. also several measures severity. Due technological progress, can now be quantified peripheral blood, where present much concentrations CSF, allowing less invasive sampling, scalability, longitudinal measurements. The promoted innovative studies demonstrating kinetics presymptomatic harboring gene mutations FTD. Especially generally stable over time, which, together their correlation rate, makes an ideal pharmacodynamic therapeutic trials. this review, we illustrate significance discuss unsolved issues potential future developments.

Language: Английский

---

The role of neuroinflammation in neurodegenerative diseases: current understanding and future therapeutic targets

Frontiers in Aging Neuroscience, Journal Year: 2024, Volume and Issue: 16

Published: April 12, 2024

Neuroinflammation refers to a highly complicated reaction of the central nervous system (CNS) certain stimuli such as trauma, infection, and neurodegenerative diseases. This is cellular immune response whereby glial cells are activated, inflammatory mediators liberated reactive oxygen nitrogen species synthesized. key process that helps protect brain from pathogens, but inappropriate, or protracted inflammation yields pathological states Parkinson’s disease, Alzheimer’s, Multiple Sclerosis, other disorders showcase various pathways neurodegeneration distributed in parts CNS. review reveals major neuroinflammatory signaling associated with neurodegeneration. Additionally, it explores promising therapeutic avenues, stem cell therapy, genetic intervention, nanoparticles, aiming regulate neuroinflammation potentially impede decelerate advancement these conditions. A comprehensive understanding intricate connection between diseases pivotal for development future treatment strategies can alleviate burden imposed by devastating disorders.

Language: Английский

---

Tauroursodeoxycholic acid: a potential therapeutic tool in neurodegenerative diseases

Translational Neurodegeneration, Journal Year: 2022, Volume and Issue: 11(1)

Published: June 4, 2022

Abstract Most neurodegenerative disorders are diseases of protein homeostasis, with misfolded aggregates accumulating. The process is mediated by numerous metabolic pathways, most which lead to apoptosis. In recent years, hydrophilic bile acids, particularly tauroursodeoxycholic acid (TUDCA), have shown important anti-apoptotic and neuroprotective activities, experimental clinical evidence suggesting their possible therapeutic use as disease-modifiers in diseases. Experimental on the mechanisms underlying TUDCA’s action derives from animal models Alzheimer’s disease, Parkinson’s Huntington’s diseases, amyotrophic lateral sclerosis (ALS) cerebral ischemia. Preclinical studies indicate that TUDCA exerts its effects not only regulating inhibiting apoptotic cascade, but also reducing oxidative stress, protecting mitochondria, producing an anti-neuroinflammatory action, acting a chemical chaperone maintain stability correct folding proteins. Furthermore, data phase II trials be safe potential disease-modifier ALS. ALS first disease being treated acids. While further accumulated for other stands promising treatment

Language: Английский

---

RhoA Signaling in Neurodegenerative Diseases

Cells, Journal Year: 2022, Volume and Issue: 11(9), P. 1520 - 1520

Published: May 1, 2022

Ras homolog gene family member A (RhoA) is a small GTPase of the Rho involved in regulating multiple signal transduction pathways that influence diverse range cellular functions. RhoA and many its downstream effector proteins are highly expressed nervous system, implying an important role for signaling neurons glial cells. Indeed, emerging evidence points toward aberrant neurodegenerative diseases such as Parkinson’s disease, Alzheimer’s Huntington’s amyotrophic lateral sclerosis. In this review, we summarize current knowledge regulation functions with emphasis on therapeutic potential inhibition neurodegeneration.

Language: Английский

---

Identification of Therapeutic Targets for Amyotrophic Lateral Sclerosis Using PandaOmics – An AI-Enabled Biological Target Discovery Platform

Frontiers in Aging Neuroscience, Journal Year: 2022, Volume and Issue: 14

Published: June 28, 2022

Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease with ill-defined pathogenesis, calling for urgent developments of new therapeutic regimens. Herein, we applied PandaOmics, an AI-driven target discovery platform, to analyze the expression profiles central nervous system (CNS) samples (237 cases; 91 controls) from public datasets, and direct iPSC-derived motor neurons (diMNs) (135 31 Answer ALS. Seventeen high-confidence eleven novel targets were identified will be released onto ALS.AI (http://als.ai/). Among proposed screened in c9ALS Drosophila model, verified 8 unreported genes (KCNB2, KCNS3, ADRA2B, NR3C1, P2RY14, PPP3CB, PTPRC, RARA) whose suppression strongly rescues eye neurodegeneration. Dysregulated pathways CNS diMN data characterize different stages development. Altogether, our study provides insights into ALS pathophysiology demonstrates how AI speeds up process, opens opportunities interventions.

Language: Английский

---