bims-proned 2023-10-22 papers

bims-proned

Biomed News

on Proteostasis in neurodegeneration

Issue of 2023–10–22
eleven papers selected by
Verena Kohler, Umeå University

α-Synuclein-dependent increases in PIP5K1γ drive inositol signaling to promote neurotoxicity.
Identifying NFKB1, STAT3, and CDKN1A as Baicalein's Potential Hub Targets in Parkinson's Disease-related α-synuclein-mediated Pathways by Integrated Bioinformatics Strategies.
The interplay between α-Synuclein and NLRP3 inflammasome in Parkinson's disease.
Pathological and physiological functional cross-talks of α-synuclein and tau in the central nervous system.
Anti-amyloid potential of some phytochemicals against Aβ-peptide and α-synuclein, tau, prion, and Huntington proteins.
Clay-Polymer Nanocomposites Mediated Inhibition of Protein Aggregation: Possible Role in the Prevention of Proteinopathies.
The autophagy protein Atg9 functions in glia and contributes to parkinsonian symptoms in a Drosophila model of Parkinson's disease.
Regulatory mechanism of circular RNAs in neurodegenerative diseases.
Oligomeric and Fibrillar α-Synuclein Display Persistent Dynamics and Compressibility under Controlled Confinement.
Recent Advancements in the Treatment of Alzheimer's Disease: A Multitarget-directed Ligand Approach.
Small molecules targeting molecular chaperones for tau regulation: Achievements and challenges.

Cell Rep. 2023 Oct 13. pii: S2211-1247(23)01256-1. [Epub ahead of print]42(10): 113244

α-Synuclein-dependent increases in PIP5K1γ drive inositol signaling to promote neurotoxicity.

Jonathan D Horvath, Maria Casas, Candice Kutchukian, Sara Creus Sánchez, Melissa R Pergande, Stephanie M Cologna, Sergi Simó, Rose E Dixon, Eamonn J Dickson.

  Anomalous aggregation of α-synuclein (α-Syn) is a pathological hallmark of many degenerative synucleinopathies including Lewy body dementia (LBD) and Parkinson's disease (PD). Despite its strong link to disease, the precise molecular mechanisms that link α-Syn aggregation to neurodegeneration have yet to be elucidated. Here, we find that elevated α-Syn leads to an increase in the plasma membrane (PM) phosphoinositide PI(4,5)P2, which precipitates α-Syn aggregation and drives toxic increases in mitochondrial Ca2+ and reactive oxygen species leading to neuronal death. Upstream of this toxic signaling pathway is PIP5K1γ, whose abundance and localization is enhanced at the PM by α-Syn-dependent increases in ARF6. Selective inhibition of PIP5K1γ or knockout of ARF6 in neurons rescues α-Syn aggregation and cellular phenotypes of toxicity. Collectively, our data suggest that modulation of phosphoinositide metabolism may be a therapeutic target to slow neurodegeneration for PD and other related neurodegenerative disorders.

Keywords:  CP: Neuroscience; IP(3); PIP5K; calcium; membrane contact sites; neurodegeneration; phosphoinositide PI(4,5)P(2); α-Syn

DOI:  https://doi.org/10.1016/j.celrep.2023.113244
Curr Pharm Des. 2023 Oct 18.

Identifying NFKB1, STAT3, and CDKN1A as Baicalein's Potential Hub Targets in Parkinson's Disease-related α-synuclein-mediated Pathways by Integrated Bioinformatics Strategies.

Xingjian Li, Qiyin Deng, Yaoyun Kuang, Hengxu Mao, Meiling Yao, Changsong Lin, Xiaodong Luo, Pingyi Xu.

   BACKGROUND: The overexpression, accumulation, and cell-to-cell transmission of α-synuclein leads to the deterioration of Parkinson's disease (PD). Previous studies suggest that Baicalein (BAI) can bind to α-synuclein and inhibit α-synuclein aggregation and secretion. However, it is still unclear whether BAI can intervene with the pathogenic molecules in α-synuclein-mediated PD pathways besides targeting α-synuclein per se.
METHODS: This study aimed to systematically investigate BAI's potential targets in PD-related A53T mutant α-synuclein-mediated pathways by integrating data mining, network pharmacological analysis, and molecular docking simulation techniques.
RESULTS: The results suggest that BAI may target genes that are dysregulated in synaptic transmission, vesicle trafficking, gene transcription, protein binding, extracellular matrix formation, and kinase activity in α-synuclein-mediated pathways. NFKB1, STAT3, and CDKN1A are BAI's potential hub targets in these pathways.
CONCLUSION: Our study provides clues for future anti-PD drug development.

Keywords:  Baicalein; Parkinson’s disease; bioinformatics; neurodegenerative; pathological; α-synuclein

DOI:  https://doi.org/10.2174/0113816128259065231011114116
Biomed Pharmacother. 2023 Oct 16. pii: S0753-3322(23)01533-0. [Epub ahead of print]168 115735

The interplay between α-Synuclein and NLRP3 inflammasome in Parkinson's disease.

Qianhui Huang, Pei Yang, Yang Liu, Jianhua Ding, Ming Lu, Gang Hu.

  α-Synuclein is a member of a protein of synucleins, which is a presynaptic neuron protein. It is usually highly expressed in the brain and participates in the formation and transmission of nerve synapses. It has been reported that abnormal aggregation of α-Syn can induce the activation of NLRP3 inflammasome in microglia, increase the production of IL-1β, and aggravate neuroinflammation. Therefore, it is recognized as one of the important factors leading to neuroinflammation in Parkinson's disease. In this paper, we aimed to explore the influence of post-translational modification of α-Syn on its pathological aggregation and summarize various pathways that activate NLRP3 triggered by α-Syn and targeted therapeutic strategies, which provided new insights for further exploring the origin and targeted therapy of Parkinson's disease.

Keywords:  NLRP3; Neuroinflammation; Parkinson's disease; Pathophysiology; α-Synuclein

DOI:  https://doi.org/10.1016/j.biopha.2023.115735
Neural Regen Res. 2024 Apr;19(4): 855-862

Pathological and physiological functional cross-talks of α-synuclein and tau in the central nervous system.

Mingyue Jin, Shengming Wang, Xiaodie Gao, Zhenyou Zou, Shinji Hirotsune, Liyuan Sun.

  α-Synuclein and tau are abundant multifunctional brain proteins that are mainly expressed in the presynaptic and axonal compartments of neurons, respectively. Previous works have revealed that intracellular deposition of α-synuclein and/or tau causes many neurodegenerative disorders, including Alzheimer's disease and Parkinson's disease. Despite intense investigation, the normal physiological functions and roles of α-synuclein and tau are still unclear, owing to the fact that mice with knockout of either of these proteins do not present apparent phenotypes. Interestingly, the co-occurrence of α-synuclein and tau aggregates was found in post-mortem brains with synucleinopathies and tauopathies, some of which share similarities in clinical manifestations. Furthermore, the direct interaction of α-synuclein with tau is considered to promote the fibrillization of each of the proteins in vitro and in vivo. On the other hand, our recent findings have revealed that α-synuclein and tau are cooperatively involved in brain development in a stage-dependent manner. These findings indicate strong cross-talk between the two proteins in physiology and pathology. In this review, we provide a summary of the recent findings on the functional roles of α-synuclein and tau in the physiological conditions and pathogenesis of neurodegenerative diseases. A deep understanding of the interplay between α-synuclein and tau in physiological and pathological conditions might provide novel targets for clinical diagnosis and therapeutic strategies to treat neurodegenerative diseases.

Keywords:  alpha-synuclein; microtubule-associated protein; neurodegenerative disease; tau

DOI:  https://doi.org/10.4103/1673-5374.382231
Drug Discov Today. 2023 Oct 17. pii: S1359-6446(23)00318-5. [Epub ahead of print] 103802

Anti-amyloid potential of some phytochemicals against Aβ-peptide and α-synuclein, tau, prion, and Huntington proteins.

Jenat Pazheparambil Jerom, Soorylekshmi Madhukumar, Raveendran Harikumaran Nair, Sunilkumar Puthenpurackal Narayanan.

  Some molecules self-assemble to create complex structures through molecular self-assembly. Hydrogel preparation, tissue repair, and therapeutic drug delivery are a few applications of molecular self-assembly. However, the self-assembly of amino acids, peptides, and proteins forms amyloid fibrils, resulting in various disorders, most notably neurodegenerative ailments. Examples include the self-assembly of phenylalanine, which causes phenylketonuria; Aβ, which causes Alzheimer's disease; the tau protein, which causes both Alzheimer's and Parkinson's diseases; and α-synuclein, which causes Parkinson's illness. This review provides information related to phytochemicals of great significance that can prevent the formation of, or destabilize, amino acid, peptide, and protein self-assemblies.

Keywords:  amyloid fibrils; anti-amyloid agents; molecular self-assemblies; neurodegenerative diseases

DOI:  https://doi.org/10.1016/j.drudis.2023.103802
Protein Pept Lett. 2023 Oct 04.

Clay-Polymer Nanocomposites Mediated Inhibition of Protein Aggregation: Possible Role in the Prevention of Proteinopathies.

Romana Parveen, Sher Ali, Sadaf Fatima.

   BACKGROUND: The transformation of proteins from their native conformation into highly ordered fibrillar structures due to their misfolding and aggregation under particular conditions are described as beta-sheet enriched amyloid fibrils. The accumulation of these fibrils in different body parts is the major cause of several neurological and non-neurological conditions (proteinopathies).
OBJECTIVES: To prevent these proteinopathies, inhibition of protein aggregation is considered a promising strategy. Therefore, in this study, we synthesized montmorillonite (MMT) based poly- orthophenylenediamine (PoPD) nanocomposites (NCs) and characterized their size and morphology due to their remarkable biological properties. Further, the effect of these nanocomposites on inhibition of fibril formation was assessed.
METHODS: These nanocomposites were evaluated for their anti-amyloidogenic potential on two model proteins of amyloidopathies, i.e., human lysozyme and human serum albumin (HL & HSA), by using several biophysical methods, such as Thioflavin T (ThT) and 1-anilino-8-naphthalene sulfonate (ANS) fluorescence, congo red dye binding assay (CR). Secondary structural content was evaluated by Circular dichroism (CD) spectroscopy.
RESULTS: Results demonstrated that synthesized nanocomposites significantly inhibited fibril formation in dose-dependent manner that corresponds to their ability to arrest fibrillation. It is suggested that they may adsorb proteins to protect them against aggregation when they are subjected to aggregating conditions.
CONCLUSION: This study offers an opportunity to understand the mechanism of inhibition of fibril formation by nanocomposites, showing that they inhibit amyloid formation and amyloid diseases. Thus, the study concludes that these nanocomposites are promising candidates as therapeutic molecules for proteinopathies and are envisaged to enrich the area of personalized medicine, augmenting the human healthcare system.

Keywords:  Circular dichroism; Human serum albumin; Thioflavin T; montmorillonite.

DOI:  https://doi.org/10.2174/0109298665274059231002071951
Neural Regen Res. 2024 May;19(5): 1150-1155

The autophagy protein Atg9 functions in glia and contributes to parkinsonian symptoms in a Drosophila model of Parkinson's disease.

Shuanglong Yi, Linfang Wang, Margaret S Ho, Shiping Zhang.

  Parkinson's disease is a progressive neurodegenerative disease characterized by motor deficits, dopaminergic neuron loss, and brain accumulation of α-synuclein aggregates called Lewy bodies. Dysfunction in protein degradation pathways, such as autophagy, has been demonstrated in neurons as a critical mechanism for eliminating protein aggregates in Parkinson's disease. However, it is less well understood how protein aggregates are eliminated in glia, the other cell type in the brain. In the present study, we show that autophagy-related gene 9 (Atg9), the only transmembrane protein in the autophagy machinery, is highly expressed in Drosophila glia from adult brain. Results from immunostaining and live cell imaging analysis reveal that a portion of Atg9 localizes to the trans-Golgi network, autophagosomes, and lysosomes in glia. Atg9 is persistently in contact with these organelles. Lacking glial atg9 reduces the number of omegasomes and autophagosomes, and impairs autophagic substrate degradation. This suggests that glial Atg9 participates in the early steps of autophagy, and hence the control of autophagic degradation. Importantly, loss of glial atg9 induces parkinsonian symptoms in Drosophila including progressive loss of dopaminergic neurons, locomotion deficits, and glial activation. Our findings identify a functional role of Atg9 in glial autophagy and establish a potential link between glial autophagy and Parkinson's disease. These results may provide new insights on the underlying mechanism of Parkinson's disease.

Keywords:  Atg9; Parkinson’s disease; autophagy; glia

DOI:  https://doi.org/10.4103/1673-5374.382259
CNS Neurosci Ther. 2023 Oct 21.

Regulatory mechanism of circular RNAs in neurodegenerative diseases.

Feng Xiao, Zhi He, Siqi Wang, Jiamei Li, Xiaolan Fan, Taiming Yan, Mingyao Yang, Deying Yang.

   BACKGROUND: Neurodegenerative disease is a collective term for a category of diseases that are caused by neuronal dysfunction, such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Circular RNAs (circRNAs) are a class of non-coding RNAs without the 3' cap and 5' poly(A) and are linked by covalent bonds. CircRNAs are highly expressed in brain neurons and can regulate the pathological process of neurodegenerative diseases by affecting the levels of various deposition proteins.
AIMS: This review is aiming to suggest that the majority of circRNAs influence neurodegenerative pathologies mainly by affecting the abnormal deposition of proteins in neurodegenerative diseases.
METHODS: We systematically summarized the pathological features of neurodegenerative diseases and the regulatory mechanisms of circRNAs in various types of neurodegenerative diseases.
RESULTS: Neurodegenerative disease main features include intercellular ubiquitin-proteasome system abnormalities, changes in cytoskeletal proteins, and the continuous deposition of insoluble protein fragments and inclusion bodies in the cytoplasm or nucleus, resulting in impairment of the normal physiological processes of the neuronal system. CircRNAs have multiple mechanisms, such as acting as microRNA sponges, binding to proteins, and regulating transcription. CircRNAs, which are highly stable molecules, are expected to be potential biomarkers for the pathological detection of neurodegenerative diseases such as AD and PD.
CONCLUSIONS: In this review, we describe the regulatory roles and mechanisms of circRNAs in neurodegenerative diseases and aim to employ circRNAs as biomarkers for the diagnosis and treatment of neurodegenerative diseases.

Keywords:  biomarkers; circular RNAs; neurodegenerative diseases; pathogenesis; regulatory mechanism

DOI:  https://doi.org/10.1111/cns.14499
ACS Chem Neurosci. 2023 Oct 20.

Oligomeric and Fibrillar α-Synuclein Display Persistent Dynamics and Compressibility under Controlled Confinement.

Katie Lynn Whitcomb, Kurt Warncke.

  The roles of α-synuclein in neurotransmitter release in brain neurons and in the Parkinson's disease condition have challenged comprehensive description. To gain insight into molecular mechanistic properties that actuate α-synuclein function and dysfunction, the coupled protein and solvent dynamics of oligomer and fibril forms of human α-synuclein are examined in a low-temperature system that allows control of confinement and localization of a motionally sensitive electron paramagnetic resonance spin probe in the coupled solvent-protein regions. The rotational mobility of the spin probe resolves two distinct α-synuclein-associated solvent components for oligomers and fibrils, as for globular proteins, but with dramatically higher fluidities at each temperature, that are comparable to low-confinement, aqueous-cryosolvent mesophases. In contrast to the temperature-independent volumes of the solvent phases that surround globular and condensate-forming proteins, the higher-fluidity mesophase volume of α-synuclein oligomers and fibrils decreases with decreasing temperature, signaling a compression of this phase. This unique property and thermal hysteresis in the mobilities and component weights, together with previous high-resolution structural characterizations, suggest a model in which the dynamically disordered C-terminal domain of α-synuclein creates a compressible phase that maintains high fluidity under confinement. Robust dynamics and compressibility are fundamental molecular mechanical properties of α-synuclein oligomers and fibrils, which may contribute to dysfunction and inform about function.

Keywords:  Parkinson’s disease; electron paramagnetic resonance (EPR); intrinsically disordered protein; protein dynamics; synuclein

DOI:  https://doi.org/10.1021/acschemneuro.3c00470
Curr Med Chem. 2023 Oct 09.

Recent Advancements in the Treatment of Alzheimer's Disease: A Multitarget-directed Ligand Approach.

Sumit Kumar, Amol Mahajan, Ramesh Ambatwar, Gopal Khatik.

  Alzheimer's disease (AD) is a neurodegenerative disease and one of the leading causes of progressive dementia, affecting 50 million people worldwide. Many pathogenic processes, including amyloid β aggregation, tau hyperphosphorylation, oxidative stress, neuronal death, and deterioration of the function of cholinergic neurons, are associated with its progression. The one-compound-one-target treatment paradigm was unsuccessful in treating AD due to the multifaceted nature of Alzheimer's disease. The recent development of multitarget-directed ligand research has been explored to target the complementary pathways associated with the disease. We aimed to find the key role and progress of MTDLs in treating AD; thus, we searched for the past ten years of literature on "Pub- Med", "ScienceDirect", "ACS" and "Bentham Science" using the keywords neurodegenerative diseases, Alzheimer's disease, and multitarget-directed ligands. The literature was further filtered based on the quality of work and relevance to AD. Thus, this review highlights the current advancement and advantages of multitarget-directed ligands over traditional single-targeted drugs and recent progress in their development to treat AD.

Keywords:  Alzheimer's disease; Amyloid protein.; Brain; Dementia; Multitarget-directed ligands; Neurodegenerative diseases

DOI:  https://doi.org/10.2174/0109298673264076230921065945
Eur J Med Chem. 2023 Oct 06. pii: S0223-5234(23)00826-7. [Epub ahead of print]261 115859

Small molecules targeting molecular chaperones for tau regulation: Achievements and challenges.

Chenxi He, Jinying Gu, Danni Wang, Keran Wang, Yuxuan Wang, Qidong You, Lei Wang.

Abnormal post-translational modification of microtubule-associated protein Tau (MAPT) is a prominent pathological feature in Alzheimer's disease (AD). Previous research has focused on designing small molecules to target Tau modification, aiming to restore microtubule stability and regulate Tau levels in vivo. However, progress has been hindered, and no effective Tau-targeted drugs have been successfully marketed, which urgently requires more strategies. Heat shock proteins (HSPs), especially Hsp90 and Hsp70, have been found to play a crucial role in Tau maturation and degradation. This review explores innovative approaches using small molecules that interact with the chaperone system to regulate Tau levels. We provide a comprehensive overview of the mechanisms involving HSPs and their co-chaperones in the Tau regulation cycle. Additionally, we analyze small molecules targeting these chaperone systems to modulate Tau function. By understanding the characteristics of the molecular chaperone system and its specific impact on Tau, we aim to provide a perspective that seeks to regulate Tau levels through the manipulation of the molecular chaperone system and ultimately develop effective treatments for AD.

DOI: https://doi.org/10.1016/j.ejmech.2023.115859