Lipid Membranes Influence the Ability of Small Molecules To Inhibit Huntingtin Fibrillization

Beasley, Maryssa; Stonebraker, Alyssa R.; Hasan, Iraj; Kapp, Kathryn L; Liang, Barry J.; Agarwal, Garima; Groover, Sharon E.; Sedighi, Faezeh; Legleiter, Justin

doi:10.1021/acs.biochem.9b00739

Cited by 30 publications

(44 citation statements)

References 85 publications

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“…In a study by Beasley et al, the authors analyzed if the presence of lipid vesicles changed the ability of EGCG or curcumin to modify aggregated htt and affect htt and lipid linkage. They observed that, regardless of the interaction with membrane environment, EGCG prevented htt fibril formation if lipid vesicles were present, inhibiting amyloid formation [ 51 ]; this shows that EGCG is a potential drug candidate for HD treatment and of other conditions involving altered protein aggregation linked to amyloid deposition. A recent study in Drosophila models show that EGCG improves neurodegeneration caused by mutant htt [ 53 ].…”

Section: Resultsmentioning

confidence: 99%

Therapeutic Effects of Catechins in Less Common Neurological and Neurodegenerative Disorders

et al. 2021

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In recent years, neurological and neurodegenerative disorders research has focused on altered molecular mechanisms in search of potential pharmacological targets, e.g., imbalances in mechanisms of response to oxidative stress, inflammation, apoptosis, autophagy, proliferation, differentiation, migration, and neuronal plasticity, which occur in less common neurological and neurodegenerative pathologies (Huntington disease, multiple sclerosis, fetal alcohol spectrum disorders, and Down syndrome). Here, we assess the effects of different catechins (particularly of epigalocatechin-3-gallate, EGCG) on these disorders, as well as their use in attenuating age-related cognitive decline in healthy individuals. Antioxidant and free radical scavenging properties of EGCG -due to their phenolic hydroxyl groups-, as well as its immunomodulatory, neuritogenic, and autophagic characteristics, makes this catechin a promising tool against neuroinflammation and microglia activation, common in these pathologies. Although EGCG promotes the inhibition of protein aggregation in experimental Huntington disease studies and improves the clinical severity in multiple sclerosis in animal models, its efficacy in humans remains controversial. EGCG may normalize DYRK1A (involved in neural plasticity) overproduction in Down syndrome, improving behavioral and neural phenotypes. In neurological pathologies caused by environmental agents, such as FASD, EGCG enhances antioxidant defense and regulates placental angiogenesis and neurodevelopmental processes. As demonstrated in animal models, catechins attenuate age-related cognitive decline, which results in improvements in long-term outcomes and working memory, reduction of hippocampal neuroinflammation, and enhancement of neuronal plasticity; however, further studies are needed. Catechins are valuable compounds for treating and preventing certain neurodegenerative and neurological diseases of genetic and environmental origin. However, the use of different doses of green tea extracts and EGCG makes it difficult to reach consistent conclusions for different populations.

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Section: Resultsmentioning

confidence: 99%

Therapeutic Effects of Catechins in Less Common Neurological and Neurodegenerative Disorders

et al. 2021

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“…Despite the scarcity of in vivo demonstrations, curcumin was reported to impair the misfolding of huntingtin protein, in analogy with the well-established effect on β-amyloid (289,(291)(292)(293)(294)(295).…”

Section: Huntington Diseasementioning

confidence: 97%

The pharmacological basis of the curcumin nutraceutical uses: an update

Canistro¹,

Chiavaroli²,

Cicia³

et al. 2021

Pharm Adv

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Curcumin is the major phytoconstituent found in the rhizomes of Curcuma longa L. Preparations derived from the rhizome of the plant, referred as turmeric, have been used for centuries in the traditional Indian system of medicine. The recent literature has shown curcumin as one of the most interesting pleiotropic nutraceuticals capable of interacting with different molecular targets involved in chronic diseases. The present review summarizes and critically discusses the very recent literature published between 2018 and 2021. We focused on the preclinical pharmacological actions of curcumin in relation to its possible clinical application in several pathophysiological states and disturbances including inflammation and pain, as well as metabolic, cardiovascular, dermatological, and central nervous system diseases. The most relevant molecular targets of curcumin, such as transcription factors, pro-inflammatory mediators, enzymes, and protein kinase as well as pharmacokinetics in humans are also reviewed.

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“…PFs are formed from proteins implicated in other neurodegenerative diseases, including tauopathy [66], Parkinson's disease [67,68], familial amyloid polyneuropathy [69], and Huntington's disease [70], indicating a common mechanism. Similar to Aβ, tau and α-synuclein (αS) also form PFs with annular, pore-like structures, thereby exerting membrane permeabilization activity [66,67].…”

Section: Pfs Are Present In Other Neurodegenerative Diseasesmentioning

confidence: 99%

Protofibrils of Amyloid-β are Important Targets of a Disease-Modifying Approach for Alzheimer’s Disease

Ono

Tsuji

2020

IJMS

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Worldwide, Alzheimer’s disease (AD) is the most common age-related neurodegenerative disease and is characterized by unique pathological hallmarks in the brain, including plaques composed of amyloid β-protein (Aβ) and neurofibrillary tangles of tau protein. Genetic studies, biochemical data, and animal models have suggested that Aβ is responsible for the pathogenesis of AD (i.e., the amyloid hypothesis). Indeed, Aβ molecules tend to aggregate, forming oligomers, protofibrils, and mature fibrils. However, while these Aβ species form amyloid plaques of the type implicated in AD neurodegeneration, recent clinical trials designed to reduce the production of Aβ and/or the plaque burden have not demonstrated clinical efficacy. In addition, recent studies using synthetic Aβ peptides, cell culture models, Arctic transgenic mice, and human samples of AD brain tissues have suggested that the pre-fibrillar forms of Aβ, particularly Aβ protofibrils, may be the most critical species, compared with extracellular fibrillar forms. We recently reported that protofibrils of Aβ1-42 disturbed membrane integrity by inducing reactive oxygen species generation and lipid peroxidation, resulting in decreased membrane fluidity, intracellular calcium dysregulation, depolarization, and synaptic toxicity. Therefore, the therapeutic reduction of protofibrils may prevent the progression of AD by ameliorating neuronal damage and cognitive dysfunction through multiple mechanisms.

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Lipid Membranes Influence the Ability of Small Molecules To Inhibit Huntingtin Fibrillization

Cited by 30 publications

References 85 publications

Therapeutic Effects of Catechins in Less Common Neurological and Neurodegenerative Disorders

Therapeutic Effects of Catechins in Less Common Neurological and Neurodegenerative Disorders

The pharmacological basis of the curcumin nutraceutical uses: an update

Protofibrils of Amyloid-β are Important Targets of a Disease-Modifying Approach for Alzheimer’s Disease

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