Biophysical Journal, Journal Year: 2024, Volume and Issue: 123(12), P. 1610 - 1619
Published: May 3, 2024
Language: Английский
Trends in Neurosciences, Journal Year: 2022, Volume and Issue: 46(2), P. 153 - 166
Published: Dec. 23, 2022
Language: Английский
Citations
97
Brain, Journal Year: 2023, Volume and Issue: 146(9), P. 3587 - 3597
Published: May 15, 2023
The critical role of alpha-synuclein in Parkinson's disease represents a pivotal discovery. Some progress has been made over recent years identifying disease-modifying therapies for that target alpha-synuclein. However, these treatments have not yet shown clear efficacy slowing the progression this disease. Several explanations exist issue. pathogenesis is complex and fully clarified heterogeneity disease, with diverse genetic susceptibility risk factors different clinical courses, adds further complexity. Thus, deep understanding physiological pathophysiological functions crucial. In review, we first describe cellular animal models developed to study pathological roles protein, including transgenic techniques, use viral vectors intracerebral injections fibrils. We then provide evidence tools are crucial modelling pathogenesis, causing protein misfolding aggregation, synaptic dysfunction, brain plasticity impairment cell-to-cell spreading species. particular, focus on possibility dissecting pre- postsynaptic effects both conditions. Finally, show how vulnerability specific neuronal cell types may facilitate systemic dysfunctions leading multiple network alterations. These functional alterations underlie motor non-motor manifestations occur before overt neurodegeneration. now understand therapeutic targeting patients requires caution, since exerts important functions. Moreover, interactions other molecules induce synergistic detrimental effects. only might be enough. Combined should considered future.
Language: Английский
Citations
62
International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(6), P. 5914 - 5914
Published: March 21, 2023
Alpha-Synuclein (α-Syn) is one of the most important molecules involved in pathogenesis Parkinson’s disease and related disorders, synucleinopathies, but also several other neurodegenerative disorders with a more elusive role. This review analyzes activities α-Syn, different conformational states, monomeric, oligomeric fibrils, relation to neuronal dysfunction. The damage induced by α-Syn various conformers will be analyzed its capacity spread intracellular aggregation seeds prion-like mechanism. In view prominent role inflammation virtually all activity illustrated considering influence on glial reactivity. We others have described interaction between general cerebral dysfunctional α-Syn. Differences microglia astrocyte activation been observed when vivo presence oligomers has combined lasting peripheral inflammatory effect. reactivity was amplified, while astrocytes were damaged double stimulus, opening new perspectives for control synucleinopathies. Starting from our studies experimental models, we extended perspective find useful pointers orient future research potential therapeutic strategies disorders.
Language: Английский
Citations
57
Current Opinion in Neurobiology, Journal Year: 2024, Volume and Issue: 85, P. 102841 - 102841
Published: Feb. 1, 2024
Language: Английский
Citations
26
Pharmacology & Therapeutics, Journal Year: 2025, Volume and Issue: unknown, P. 108797 - 108797
Published: Jan. 1, 2025
The traditional model of protein structure determined by the amino acid sequence is today seriously challenged fact that approximately half human proteome made up proteins do not have a stable 3D structure, either partially or in totality. These proteins, called intrinsically disordered (IDPs), are involved numerous physiological functions and associated with severe pathologies, e.g. Alzheimer, Parkinson, Creutzfeldt-Jakob, amyotrophic lateral sclerosis (ALS), type 2 diabetes. Targeting these challenging for two reasons: i) we need to preserve their functions, ii) drug design molecular docking possible due lack reliable starting conditions. Faced this challenge, solutions proposed artificial intelligence (AI) such as AlphaFold clearly unsuitable. Instead, suggest an innovative approach consisting mimicking, short synthetic peptides, conformational flexibility IDPs. which call adaptive derived from domains IDPs become structured after interacting ligand. Adaptive peptides designed aim selectively antagonizing harmful effects IDPs, without targeting them directly but through selected ligands, affecting properties. This"target target, arrow" strategy promised open new route discovery currently undruggable proteins.
Language: Английский
Citations
2
International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(3), P. 2477 - 2477
Published: Jan. 27, 2023
Synucleinopathies are a set of devastating neurodegenerative diseases that share pathologic accumulation the protein α-synuclein (α-syn). This causes neuronal death resulting in irreversible dementia, deteriorating motor symptoms, and cognitive decline. While etiology these conditions remains largely unknown, microglia, resident immune cells central nervous system (CNS), have been consistently implicated pathogenesis synucleinopathies. Microglia generally believed to be neuroprotective early stages α-syn contribute further neurodegeneration chronic disease states. molecular mechanisms by which microglia achieve this role still being investigated, here we highlight major findings date. In review, describe how structural varieties inherently disordered result varied microglial receptor-mediated interactions. We also summarize receptors enable cellular recognition uptake α-syn. Lastly, review downstream effects processing within including spread other brain regions neuroinflammation Understanding mechanism interactions with is vital conceptualizing targets for novel therapeutic interventions. addition, given significant diversity pathophysiology synucleinopathies, such gauging all potential pathways state.
Language: Английский
Citations
33
Biochimica et Biophysica Acta (BBA) - General Subjects, Journal Year: 2025, Volume and Issue: unknown, P. 130772 - 130772
Published: Feb. 1, 2025
Language: Английский
Citations
1
npj Parkinson s Disease, Journal Year: 2025, Volume and Issue: 11(1)
Published: March 4, 2025
Based on the prevailing α-synuclein "gain-of-function" hypothesis, reducing levels and removing its aggregates is a current focus of disease-modifying therapies for Parkinson's disease. Emerging evidence "loss-of-function" suggests that it may be necessary to replenish monomeric levels. We propose personalized comprehensive approach different subgroups based whether likely contribute disease pathogenesis through "gain-of-function", "loss-of-function", or both mechanisms.
Language: Английский
Citations
1
Results in Engineering, Journal Year: 2024, Volume and Issue: 24, P. 102790 - 102790
Published: Sept. 5, 2024
Language: Английский
Citations
6
Journal of Neuroscience Research, Journal Year: 2024, Volume and Issue: 102(2)
Published: Feb. 1, 2024
Abstract Synapses serve as the points of communication between neurons, consisting primarily three components: presynaptic membrane, synaptic cleft, and postsynaptic membrane. They transmit signals through release reception neurotransmitters. Synaptic plasticity, ability synapses to undergo structural functional changes, is influenced by proteins such growth‐associated proteins, vesicle density neurotrophic growth factors. Furthermore, maintaining plasticity consumes more than half brain's energy, with a significant portion this energy originating from ATP generated mitochondrial metabolism. Consequently, quantity, distribution, transport, function mitochondria impact stability brain metabolism, thereby participating in regulation fundamental processes including neuronal differentiation, neurite outgrowth, synapse formation, neurotransmitter release. This article provides comprehensive overview associated common factors two, well relationship metabolism plasticity.
Language: Английский
Citations
5