Molecular targets and approaches to restore autophagy and lysosomal capacity in neurodegenerative disorders

Background & Objective: Hydrogen sulfide [H2S] has been widely known as a toxic gas for more than 300 years in the scientific community. However, the understanding about this small molecule has changed after the discovery of involvement of H2S in physiological and pathological mechanisms in brain. H2S is a third gasotransmitter and neuromodulator after carbon monoxide [CO] and nitric oxide [NO]. H2S plays an important role in memory and cognition by regulating long-term potentiation [LTP] and calcium homeostasis in neuronal cells. The disturbances in endogenous H2S levels and trans-sulfuration pathway have been implicated in neurodegenerative disorders like Alzheimer’s disease, Parkinson disease, stroke and traumatic brain injury. According to the results obtained from various studies, H2S not only behaves as neuromodulator but also is a potent antioxidant, anti-inflammatory and anti-apoptotic molecule suggesting its neuroprotective potential. Conclusion: Recently, there is an increased interest in developing H2S releasing pharmaceuticals to target various neurological disorders. This review covers the information about the involvement of H2S in neurodegenerative diseases, its molecular targets and its role as potential therapeutic molecule.

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Recent High-Resolution Structures of Amyloids Involved in Neurodegenerative Diseases

Frontiers in Aging Neuroscience ◽

10.3389/fnagi.2021.782617 ◽

2021 ◽

Vol 13 ◽

Author(s):

Rodrigo Diaz-Espinoza

Keyword(s):

Electron Microscopy ◽

High Resolution ◽

Neurodegenerative Diseases ◽

Neurodegenerative Disorders ◽

Solid State Nmr ◽

Molecular Level ◽

Molecular Targets ◽

Protein Tau ◽

Isolation Methods

Amyloids are highly ordered aggregates composed of proteins or peptides. They are involved in several pathologies, including hallmark neurodegenerative disorders such as Alzheimer’s (AD) and Parkinson’s (PD). Individuals affected by these diseases accumulate in their brains amyloids inclusions composed of misfolded forms of a peptide (Aβ) and a protein (Tau) in AD and α-synuclein protein (α-Sn) in PD. Tau and α-Sn aggregates are also present in other neurodegenerative diseases. The insoluble nature and heterogeneity of amyloids have hampered their study at the molecular level. However, the use of solid state NMR and Cryogenic-electron microscopy along with fine-tuned modulation of the aggregation in vitro and improved isolation methods of brain-derived amyloids has allowed the elucidation of these elusive conformations at high resolution. In this work, we review the latest progress on the recent amyloid structures reported for Aβ, Tau, and α-Sn. The two-fold symmetry emerges as a convergent feature in the tridimensional arrangement of the protofilaments in the fibrillary structure of these pathological amyloids, with many of them exhibiting a Greek-key topology as part of their overall architecture. These specific features can serve as novel guides to seek potential molecular targets in drug design efforts.

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3-Iodothyronamine and Derivatives: New Allies Against Metabolic Syndrome?

International Journal of Molecular Sciences ◽

10.3390/ijms21062005 ◽

2020 ◽

Vol 21 (6) ◽

pp. 2005 ◽

Cited By ~ 2

Author(s):

Grazia Rutigliano ◽

Lavinia Bandini ◽

Simona Sestito ◽

Grazia Chiellini

Keyword(s):

Neurodegenerative Disorders ◽

Energy Homeostasis ◽

Functional Relationship ◽

Large Body ◽

Molecular Targets ◽

Experimental Models ◽

Metabolic Disturbances ◽

Pharmacological Agents ◽

Mediated Effects ◽

Trace Amine

In the two decades since its discovery, a large body of evidence has amassed to highlight the potential of 3-iodothyronamine (T1AM) as an antiobesity drug, whose pleiotropic signaling actions profoundly impact energy metabolism. In the present review, we recapitulate the most relevant properties of T1AM, including its structural and functional relationship to thyroid hormone, its endogenous levels, molecular targets, as well as its genomic and non-genomic effects on metabolism elicited in experimental models after exogenous administration. The physiological and pathophysiological relevance of T1AM in the regulation of energy homeostasis and metabolism is also discussed, along with its potential therapeutic applications in metabolic disturbances. Finally, we examine a number of T1AM analogs that have been recently developed with the aim of designing novel pharmacological agents for the treatment of interlinked diseases, such as metabolic and neurodegenerative disorders, as well as additional synthetic tools that can be exploited to further explore T1AM-dependent mechanisms and the physiological roles of trace amine-associated receptor 1 (TAAR1)-mediated effects.

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Screening The Efficacy of Melatonin On Neurodegeneration Mediated By ER Stress, Inflammation And Oxidative Damage

10.21203/rs.3.rs-769141/v1 ◽

2021 ◽

Author(s):

Fathima Hajee Basha ◽

S. Hemalatha

Keyword(s):

Circadian Rhythm ◽

Oxidative Damage ◽

Er Stress ◽

Neurodegenerative Disorders ◽

Structural Integrity ◽

Molecular Targets ◽

Therapeutic Strategies ◽

Functional Abilities ◽

Mitochondrial Defects ◽

Upr Pathway

Abstract Neurodegeneration may be defined as a clinical condition wherein neurons gradually lose their structural integrity, viability, functional abilities and the damage inflicted upon the neurons is often irreversible. The number of elderly patients suffering from Neurodegenerative disorders is expected to rise tremendously over the next couple of years. Thus, there is an urgent need to delve into and study the underlying cause and mechanisms, so that we may be able to develop more effective therapeutic strategies and drugs and better understand the origin and progression of the disease.The various mechanisms that have been observed to contribute to neurodegeneration include aggregation and accumulation of misfolded proteins, impaired autophagy, oxidative damage, neuroinflammation, mitochondrial defects, increased SUMOylation of proteins, impaired UPR pathways, disruption of axonal transport.Melatonin, a neurohormone is involved in a variety of functions including scavenging free radicals, synchronizing the circadian rhythm, mitigating immune response.Melatonin has shown to modulate the UPR pathway ,antioxidant pathway through Nrf2 and inflammatory pathway through NFκB. The study aims to determine the efficacy of melatonin on neurodegeneration mediated by ER stress, inflammation and oxidative damage through in silico approaches. The molecular targets chosen were ATF6, XBP1, PERK, Nrf2, NFκB and they were docked against melatonin. Additionally various physiochemical analysis such as ADME were also carried out to determine its drug ability. The findings were that melatonin not only shows excellent interactions with the targets but also possess drug-like physicochemical properties that makes it a valuable choice for the treatment of neurodegenerative disorders.

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Insights into amyloid disease from fly models

Essays in Biochemistry ◽

10.1042/bse0560069 ◽

2014 ◽

Vol 56 ◽

pp. 69-83 ◽

Cited By ~ 1

Author(s):

Ko-Fan Chen ◽

Damian C. Crowther

Keyword(s):

Drosophila Melanogaster ◽

Neurodegenerative Disorders ◽

Amyloid Β ◽

Amyloid Β Peptide ◽

Disease Pathogenesis ◽

Amyloid Aggregates ◽

Aβ Amyloid ◽

Polypeptide Chains ◽

Amyloid Diseases

The formation of amyloid aggregates is a feature of most, if not all, polypeptide chains. In vivo modelling of this process has been undertaken in the fruitfly Drosophila melanogaster with remarkable success. Models of both neurological and systemic amyloid diseases have been generated and have informed our understanding of disease pathogenesis in two main ways. First, the toxic amyloid species have been at least partially characterized, for example in the case of the Aβ (amyloid β-peptide) associated with Alzheimer's disease. Secondly, the genetic underpinning of model disease-linked phenotypes has been characterized for a number of neurodegenerative disorders. The current challenge is to integrate our understanding of disease-linked processes in the fly with our growing knowledge of human disease, for the benefit of patients.

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Inflammageing in the cardiovascular system: mechanisms, emerging targets, and novel therapeutic strategies

Clinical Science ◽

10.1042/cs20191213 ◽

2020 ◽

Vol 134 (17) ◽

pp. 2243-2262

Author(s):

Danlin Liu ◽

Gavin Richardson ◽

Fehmi M. Benli ◽

Catherine Park ◽

João V. de Souza ◽

...

Keyword(s):

Cardiovascular Diseases ◽

Cardiovascular System ◽

Nlrp3 Inflammasome ◽

Molecular Mechanisms ◽

Molecular Targets ◽

Therapeutic Interventions ◽

Low Grade ◽

Cardiovascular Research ◽

Inflammatory Processes ◽

Ach Receptors

Abstract In the elderly population, pathological inflammation has been associated with ageing-associated diseases. The term ‘inflammageing’, which was used for the first time by Franceschi and co-workers in 2000, is associated with the chronic, low-grade, subclinical inflammatory processes coupled to biological ageing. The source of these inflammatory processes is debated. The senescence-associated secretory phenotype (SASP) has been proposed as the main origin of inflammageing. The SASP is characterised by the release of inflammatory cytokines, elevated activation of the NLRP3 inflammasome, altered regulation of acetylcholine (ACh) nicotinic receptors, and abnormal NAD+ metabolism. Therefore, SASP may be ‘druggable’ by small molecule therapeutics targeting those emerging molecular targets. It has been shown that inflammageing is a hallmark of various cardiovascular diseases, including atherosclerosis, hypertension, and adverse cardiac remodelling. Therefore, the pathomechanism involving SASP activation via the NLRP3 inflammasome; modulation of NLRP3 via α7 nicotinic ACh receptors; and modulation by senolytics targeting other proteins have gained a lot of interest within cardiovascular research and drug development communities. In this review, which offers a unique view from both clinical and preclinical target-based drug discovery perspectives, we have focused on cardiovascular inflammageing and its molecular mechanisms. We have outlined the mechanistic links between inflammageing, SASP, interleukin (IL)-1β, NLRP3 inflammasome, nicotinic ACh receptors, and molecular targets of senolytic drugs in the context of cardiovascular diseases. We have addressed the ‘druggability’ of NLRP3 and nicotinic α7 receptors by small molecules, as these proteins represent novel and exciting targets for therapeutic interventions targeting inflammageing in the cardiovascular system and beyond.

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