Liquid–liquid phase separation in Alzheimer’s disease

Fu, Qinggang; Zhang, Bixiang; Chen, Xiaoping; Chu, Liang

doi:10.1007/s00109-023-02407-3

Cited by 8 publications

(3 citation statements)

References 183 publications

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“…The main driving force for both homotypic and heterotypic LLPSs of tau appears to be electrostatic interactions that can be modulated by post-translational modifications (PTMs). Phosphorylation and acetylation have been demonstrated to exert a regulatory effect on LLPS [ 58 , 59 , 60 , 61 ]. In neurodegenerative diseases, aberrant post-translational modifications of tau protein result in the loss of normal regulatory functions, which negatively impact the normal functioning of neurons and contribute to the onset and progression of neurological disorders.…”

Section: Post-translational Modifications Of Tau Proteinmentioning

confidence: 99%

Role of Tau Protein in Neurodegenerative Diseases and Development of Its Targeted Drugs: A Literature Review

Yang,

Zhi,

Wang

2024

Molecules

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Tau protein is a microtubule-associated protein that is widely distributed in the central nervous system and maintains and regulates neuronal morphology and function. Tau protein aggregates abnormally and forms neurofibrillary tangles in neurodegenerative diseases, disrupting the structure and function of neurons and leading to neuronal death, which triggers the initiation and progression of neurological disorders. The aggregation of tau protein in neurodegenerative diseases is associated with post-translational modifications, which may affect the hydrophilicity, spatial conformation, and stability of tau protein, promoting tau protein aggregation and the formation of neurofibrillary tangles. Therefore, studying the role of tau protein in neurodegenerative diseases and the mechanism of aberrant aggregation is important for understanding the mechanism of neurodegenerative diseases and finding therapeutic approaches. This review describes the possible mechanisms by which tau protein promotes neurodegenerative diseases, the post-translational modifications of tau protein and associated influencing factors, and the current status of drug discovery and development related to tau protein, which may contribute to the development of new therapeutic approaches to alleviate or treat neurodegenerative diseases.

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Section: Post-translational Modifications Of Tau Proteinmentioning

confidence: 99%

Role of Tau Protein in Neurodegenerative Diseases and Development of Its Targeted Drugs: A Literature Review

Yang,

Zhi,

Wang

2024

Molecules

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“…This is because intrinsically disordered domain-containing proteins are naturally susceptible to aggregation ( Ayyadevara et al, 2022 ), and also to metal ion-included LLPS ( Sołtys et al, 2023 ). In particular, copper and zinc can induce LLPS as seen in AD with both Aβ and Tau undergoing LLPS in response to metal ion-induced stress ( Fu et al, 2024 ). In PD α-Synuclein also undergoes LLPS via copper exposure ( Ray et al, 2020 ).…”

Section: Metal Ions Llps and Co-aggregation Of Als Proteinsmentioning

confidence: 99%

Copper toxicity and deficiency: the vicious cycle at the core of protein aggregation in ALS

Min,

Sarlus,

Harris

2024

Front. Mol. Neurosci.

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The pathophysiology of ALS involves many signs of a disruption in copper homeostasis, with both excess free levels and functional deficiency likely occurring simultaneously. This is crucial, as many important physiological functions are performed by cuproenzymes. While it is unsurprising that many ALS symptoms are related to signs of copper deficiency, resulting in vascular, antioxidant system and mitochondrial oxidative respiration deficiencies, there are also signs of copper toxicity such as ROS generation and enhanced protein aggregation. We discuss how copper also plays a key role in proteostasis and interacts either directly or indirectly with many of the key aggregate-prone proteins implicated in ALS, such as TDP-43, C9ORF72, SOD1 and FUS as well as the effect of their aggregation on copper homeostasis. We suggest that loss of cuproprotein function is at the core of ALS pathology, a condition that is driven by a combination of unbound copper and ROS that can either initiate and/or accelerate protein aggregation. This could trigger a positive feedback cycle whereby protein aggregates trigger the aggregation of other proteins in a chain reaction that eventually captures elements of the proteostatic mechanisms in place to counteract them. The end result is an abundance of aggregated non-functional cuproproteins and chaperones alongside depleted intracellular copper stores, resulting in a general lack of cuproenzyme function. We then discuss the possible aetiology of ALS and illustrate how strong risk factors including environmental toxins such as BMAA and heavy metals can functionally behave to promote protein aggregation and disturb copper metabolism that likely drives this vicious cycle in sporadic ALS. From this synthesis, we propose restoration of copper balance using copper delivery agents in combination with chaperones/chaperone mimetics, perhaps in conjunction with the neuroprotective amino acid serine, as a promising strategy in the treatment of this incurable disease.

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“…The pathological hallmark of neurodegenerative disorders such as amyotrophic lateral sclerosis, Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, and frontotemporal dementia is protein aggregates. The accumulation of misfolded and aggregated proteins, such as TAR DNA-binding protein-43 (TDP-43), fused in sarcoma (FUS), α-synuclein, tau, amyloid-β (Aβ), and mutant huntingtin protein (mHTT), leads to neuronal dysfunction and ultimately neuronal death. − …”

Section: Introductionmentioning

confidence: 99%

Photoreversible Aggregation of the Biliprotein Containing the First and Second GAF Domains of a Cyanobacteriochrome All2699 in Nostoc sp. PCC7120

Zhan,

Zhao,

et al. 2024

Biochemistry

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As plant photoreceptors, phytochromes are capable of detecting red light and far-red light, thereby governing plant growth. All2699 is a photoreceptor found in Nostoc sp. PCC7120 that specifically responds to red light and far-red light. All2699g1g2 is a truncated protein carrying the first and second GAF (cGMP phosphodiesterase/adenylyl cyclase/FhlA) domains of All2699. In this study, we found that, upon exposure to red light, the protein underwent aggregation, resulting in the formation of protein aggregates. Conversely, under far-red light irradiation, these protein aggregates dissociated. We delved into the factors that impact the aggregation of All2699g1g2, focusing on the protein structure. Our findings showed that the GAF2 domain contains a low-complexity (LC) loop region, which plays a crucial role in mediating protein aggregation. Specifically, phenylalanine at position 239 within the LC loop region was identified as a key site for the aggregation process. Furthermore, our research revealed that various factors, including irradiation time, temperature, concentration, NaCl concentration, and pH value, can impact the aggregation of All2699g1g2. The aggregation led to variations in Pfr concentration depending on temperature, NaCl concentration, and pH value. In contrast, ΔLC did not aggregate and therefore lacked responses to these factors. Consequently, the LC loop region of All2699g1g2 extended and enhanced sensory properties.

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Liquid–liquid phase separation in Alzheimer’s disease

Cited by 8 publications

References 183 publications

Role of Tau Protein in Neurodegenerative Diseases and Development of Its Targeted Drugs: A Literature Review

Role of Tau Protein in Neurodegenerative Diseases and Development of Its Targeted Drugs: A Literature Review

Copper toxicity and deficiency: the vicious cycle at the core of protein aggregation in ALS

Photoreversible Aggregation of the Biliprotein Containing the First and Second GAF Domains of a Cyanobacteriochrome All2699 in Nostoc sp. PCC7120

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