Redox Imbalance in Neurological Disorders in Adults and Children DOI Creative Commons
Federica Rey, Clarissa Berardo, Erika Maghraby

et al.

Antioxidants, Journal Year: 2023, Volume and Issue: 12(4), P. 965 - 965

Published: April 20, 2023

Oxygen is a central molecule for numerous metabolic and cytophysiological processes, and, indeed, its imbalance can lead to pathological consequences. In the human body, brain an aerobic organ this reason, it very sensitive oxygen equilibrium. The consequences of are especially devastating when occurring in organ. Indeed, hypoxia, hyperoxia, protein misfolding, mitochondria dysfunction, alterations heme metabolism neuroinflammation. Consequently, these dysfunctions cause neurological alterations, both pediatric life adult ages. These disorders share common pathways, most which consequent redox imbalance. review, we will focus on present neurodegenerative (specifically Alzheimer’s disease, Parkinson’s disease amyotrophic lateral sclerosis) (X-adrenoleukodystrophies, spinal muscular atrophy, mucopolysaccharidoses Pelizaeus–Merzbacher Disease), highlighting their underlining dysfunction identifying potential therapeutic strategies.

Language: Английский

Mechanisms and pathology of protein misfolding and aggregation DOI
Nikolaos Louros, Joost Schymkowitz, Frédéric Rousseau

et al.

Nature Reviews Molecular Cell Biology, Journal Year: 2023, Volume and Issue: 24(12), P. 912 - 933

Published: Sept. 8, 2023

Language: Английский

Citations

122
Misfolded protein oligomers: mechanisms of formation, cytotoxic effects, and pharmacological approaches against protein misfolding diseases DOI Creative Commons
Dillon J. Rinauro, Fabrizio Chiti, Michele Vendruscolo

et al.

Molecular Neurodegeneration, Journal Year: 2024, Volume and Issue: 19(1)

Published: Feb. 20, 2024

The conversion of native peptides and proteins into amyloid aggregates is a hallmark over 50 human disorders, including Alzheimer's Parkinson's diseases. Increasing evidence implicates misfolded protein oligomers produced during the formation process as primary cytotoxic agents in many these devastating conditions. In this review, we analyze processes by which are formed, their structures, physicochemical properties, population dynamics, mechanisms cytotoxicity. We then focus on drug discovery strategies that target ability to disrupt cell physiology trigger degenerative processes.

Language: Английский

Citations

51
O-GlcNAc forces an α-synuclein amyloid strain with notably diminished seeding and pathology DOI Creative Commons
Aaron T. Balana, Anne‐Laure Mahul‐Mellier, Binh A. Nguyen

et al.

Nature Chemical Biology, Journal Year: 2024, Volume and Issue: 20(5), P. 646 - 655

Published: Feb. 12, 2024

Abstract Amyloid-forming proteins such α-synuclein and tau, which are implicated in Alzheimer’s Parkinson’s disease, can form different fibril structures or strains with distinct toxic properties, seeding activities pathology. Understanding the determinants contributing to formation of amyloid features could open new avenues for developing disease-specific diagnostics therapies. Here we report that O-GlcNAc modification monomers results core structure, as revealed by cryogenic electron microscopy, diminished activity seeding-based neuronal rodent models disease. Although mechanisms underpinning neutralization O-GlcNAc-modified fibrils remain unclear, our vitro mechanistic studies indicate heat shock interactions inhibit their activity, suggesting may alter interactome ways lead reduce vivo. Our show posttranslational modifications, modification, key pathogenicity.

Language: Английский

Citations

32
Dysbiosis of the gut microbiota and its effect on α-synuclein and prion protein misfolding: consequences for neurodegeneration DOI Creative Commons

Nasir Uddin Mahbub,

Md Minarul Islam, Seong‐Tshool Hong

et al.

Frontiers in Cellular and Infection Microbiology, Journal Year: 2024, Volume and Issue: 14

Published: Feb. 16, 2024

Abnormal behavior of α-synuclein and prion proteins is the hallmark Parkinson’s disease (PD) illnesses, respectively, being complex neurological disorders. A primary cause protein aggregation, brain injury, cognitive loss in illnesses misfolding normal cellular (PrP C ) into an infectious form Sc ). Aggregation causes disruptions processes (PD), leading to dopamine-producing neurons motor symptoms. Alteration composition or activity gut microbes may weaken intestinal barrier make it possible for prions go from brain. The gut-brain axis linked neuroinflammation; metabolites produced by microbiota affect aggregation α-synuclein, regulate inflammation immunological responses, influence course neurotoxicity proteins, even if their targets are distinct proteins. This thorough analysis explores interactions that exist between neurodegenerative particularly involvement microbiota, a collection bacteria, archaea, fungi, viruses etc., various becoming increasingly recognized. microbiome influences neuroinflammation, neurotransmitter synthesis, mitochondrial function, integrity through axis, which contributes development progression disease. review delves molecular mechanisms underlie these relationships, emphasizing effects microbial such as bacterial lipopolysaccharides (LPS), short-chain fatty acids (SCFAs) regulating functioning. Additionally, looks at how environmental dietary decisions whether they could be risk factors illnesses. study concludes highlighting critical role plays It also provides promising direction future research treatment approaches. People afflicted difficult ailments find hope new preventive therapeutic approaches diseases better understood.

Language: Английский

Citations

19
Targeted degradation of ⍺-synuclein aggregates in Parkinson’s disease using the AUTOTAC technology DOI Creative Commons
Jihoon Lee, Ki Woon Sung, Eun-Jin Bae

et al.

Molecular Neurodegeneration, Journal Year: 2023, Volume and Issue: 18(1)

Published: June 24, 2023

There are currently no disease-modifying therapeutics for Parkinson's disease (PD). Although extensive efforts were undertaken to develop therapeutic approaches delay the symptoms of PD, untreated α-synuclein (α-syn) aggregates cause cellular toxicity and stimulate further progression. PROTAC (Proteolysis-Targeting Chimera) has drawn attention as a modality target α-syn. However, PROTACs have yet shown selectively degrade α-syn mainly owing limited capacity proteasome aggregates, necessitating development novel fundamentally eliminate aggregates.We employed AUTOTAC (Autophagy-Targeting Chimera), macroautophagy-based targeted protein degradation (TPD) platform developed in our earlier studies. A series chemicals was synthesized chimeras that bind both p62/SQSTM1/Sequestosome-1, an autophagic receptor. The efficacy Autotacs evaluated phagophores subsequently lysosomes hydrolysis via p62-dependent macroautophagy. engagement monitored by oligomerization localization p62 markers. rescue PD characterized cultured cells mice. PK/PD (pharmacokinetics/pharmacodynamics) profiles investigated oral drug PD.ATC161 induced selective at DC50 ~ 100 nM. No apparent observed with monomeric ATC161 mediated targeting binding ZZ domain accelerating self-polymerization. These p62-cargo complexes delivered membranes lysosomal degradation. In models, exhibited reduce cell-to-cell transmission from damages DNA mitochondria. mice established injecting preformed fibrils (PFFs) into brain striata stereotaxic surgery, administration 10 mg/kg reduced their propagation. also mitigated associated glial inflammatory response improved muscle strength locomotive activity.AUTOTAC provides drugs PD. ATC161, excellent profiles, induces vitro vivo. We suggest is degrades pathogenic

Language: Английский

Citations

42
Development of Small Molecules Targeting α-Synuclein Aggregation: A Promising Strategy to Treat Parkinson’s Disease DOI Creative Commons
Samuel Peña‐Díaz, Javier García‐Pardo, Salvador Ventura

et al.

Pharmaceutics, Journal Year: 2023, Volume and Issue: 15(3), P. 839 - 839

Published: March 3, 2023

Parkinson’s disease, the second most common neurodegenerative disorder worldwide, is characterized by accumulation of protein deposits in dopaminergic neurons. These are primarily composed aggregated forms α-Synuclein (α-Syn). Despite extensive research on this only symptomatic treatments currently available. However, recent years, several compounds, mainly an aromatic character, targeting α-Syn self-assembly and amyloid formation have been identified. discovered different approaches, chemically diverse exhibit a plethora mechanisms action. This work aims to provide historical overview physiopathology molecular aspects associated with disease current trends small compound development target aggregation. Although these molecules still under development, they constitute important step toward discovering effective anti-aggregational therapies for disease.

Language: Английский

Citations

29
Exploring the Aggregation Propensity of PHF6 Peptide Segments of the Tau Protein Using Ion Mobility Mass Spectrometry Techniques DOI Creative Commons
Iuliia Stroganova,

Hannah Willenberg,

Thaleia Tente

et al.

Analytical Chemistry, Journal Year: 2024, Volume and Issue: 96(13), P. 5115 - 5124

Published: March 22, 2024

Peptide and protein aggregation involves the formation of oligomeric species, but complex interplay between oligomers different conformations sizes complicates their structural elucidation. Using ion mobility mass spectrometry (IM-MS), we aim to reveal these early steps for Ac-PHF6-NH2 peptide segment from tau protein, thereby distinguishing species gaining an understanding pathway. An important factor that is often neglected, which can alter propensity peptides, terminal capping groups. Here, demonstrate use IM-MS probe stages aggregate Ac-PHF6-NH2, Ac-PHF6, PHF6-NH2, uncapped PHF6 segments. The four segments confirmed using thioflavin T fluorescence assays transmission electron microscopy. A novel approach based on post-IM fragmentation quadrupole selection TIMS-Qq-ToF (trapped mobility) spectrometer was developed enhance oligomer assignment, especially higher-order aggregates. This pushes limits IM identification isobaric whose signatures appear closer each other with increasing size, provides new insights into interpretation data. In addition, TIMS collision cross section values are compared traveling wave (TWIMS) data evaluate potential instrumental bias in trapped results. two platforms principles have configurations, providing us valuable insight preservation weakly bound biomolecular complexes such as

Language: Английский

Citations

8
Inhibition of fibril formation by polyphenols: molecular mechanisms, challenges, and prospective solutions DOI
Shilpa Sharma, Shashank Deep

Chemical Communications, Journal Year: 2024, Volume and Issue: 60(53), P. 6717 - 6727

Published: Jan. 1, 2024

Modulation of the aggregation pathway by polyphenols through interactions with various species generated during aggregation.

Language: Английский

Citations

8
Misfolded alpha‐synuclein in amyotrophic lateral sclerosis: Implications for diagnosis and treatment DOI Creative Commons
Richard Smith, Hanna Hovren, Robert Bowser

et al.

European Journal of Neurology, Journal Year: 2024, Volume and Issue: 31(4)

Published: Jan. 25, 2024

Alpha-synuclein (α-Syn) oligomers and fibrils have been shown to augment the aggregation of TAR DNA-binding Protein 43 (TDP-43) monomers in vitro, supporting idea that TDP-43 proteinopathies such as ALS may be modulated by presence toxic forms α-Syn. Recently, parkinsonian features were reported a study European patients Lewy bodies demonstrated pathologically similar series patients. Based on these other considerations, we sought determine whether seed-competent α-Syn can identified spinal fluid with including familial, sporadic, Guamanian disease.

Language: Английский

Citations

7
The Role of α-Synuclein in Etiology of Neurodegenerative Diseases DOI Open Access

Daria Krawczuk,

Magdalena Groblewska,

Jan Mroczko

et al.

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(17), P. 9197 - 9197

Published: Aug. 24, 2024

A presynaptic protein called α-synuclein plays a crucial role in synaptic function and neurotransmitter release. However, its misfolding aggregation have been implicated variety of neurodegenerative diseases, particularly Parkinson’s disease, dementia with Lewy bodies, multiple system atrophy. Emerging evidence suggests that interacts various cellular pathways, including mitochondrial dysfunction, oxidative stress, neuroinflammation, which contributes to neuronal cell death. Moreover, has involved the propagation processes through prion-like mechanisms, where misfolded proteins induce similar conformational changes neighboring neurons. Understanding multifaced roles neurodegeneration not only aids acquiring more knowledge about pathophysiology these diseases but also highlights potential biomarkers therapeutic targets for intervention alpha-synucleinopathies. In this review, we provide summary mechanisms by processes, focusing on misfolding, oligomerization, formation insoluble fibrils form characteristic bodies. Furthermore, compare value species diagnosing differentiating selected diseases.

Language: Английский

Citations

7