Alpha Synuclein: Neurodegeneration and Inflammation

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(6), С. 5914 - 5914

Опубликована: Март 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.

Язык: Английский

---

Targeting synapse function and loss for treatment of neurodegenerative diseases

Nature Reviews Drug Discovery, Год журнала: 2023, Номер 23(1), С. 23 - 42

Опубликована: Ноя. 27, 2023

Язык: Английский

---

Recent advances in nanotechnology for Parkinson’s disease: diagnosis, treatment, and future perspectives

Frontiers in Medicine, Год журнала: 2025, Номер 12

Опубликована: Янв. 22, 2025

Parkinson’s disease is a progressive neurodegenerative that destroys substantia nigra dopaminergic neurons, causing tremors, bradykinesia, rigidity, and postural instability. Current treatment approaches primarily focus on symptom management, employing pharmacological, non-pharmacological, surgical methods. However, these treatments often result in fluctuating symptoms, side effects, progression. Here, the authors have reviewed emerging field of nanomedicine as promising path for treatment, emphasizing its potential to overcome limitations traditional therapies. Nanomedicine utilizes nanoparticles targeted drug delivery, leveraging their small size high surface area volume ratio cross blood-brain barrier deliver therapeutic agents directly affected brain regions. Various nanoparticles, including lipid-based, polymeric, metallic, carbon-based, shown treatment. Additionally, nanocarrier systems like liposomes, nanogels, dendrimers, solid lipid offer controlled sustained release agents, enhancing bioavailability reducing effects. This review provides insights into pathophysiology disease, highlighting mechanisms neurodegeneration, role alpha-synuclein, disruption pathways. It further discusses application gene therapy conjunction with interventions.

Язык: Английский

---

Pathogenesis of Parkinson’s Disease

Neurologic Clinics, Год журнала: 2025, Номер unknown

Опубликована: Янв. 1, 2025

Язык: Английский

---

Ultrasound-Assisted CRISPRi-Exosome for Epigenetic Modification of α-Synuclein Gene in a Mouse Model of Parkinson’s Disease

ACS Nano, Год журнала: 2024, Номер 18(11), С. 7837 - 7851

Опубликована: Март 4, 2024

Currently, there is a lack of effective treatment for Parkinson's disease (PD). In PD patients, aberrant methylation SNCA (α-synuclein gene) has been reported and may be potential therapeutic target. this study, we established an epigenetic regulation platform based on exosomal CRISPR intervention system. With the assist focused ultrasound (FUS) opening blood-brain barrier, engineered exosomes carrying RVG (rabies viral glycoprotein) targeting peptide, sgRNA (single guide RNA), dCas9-DNMT3A (named RVG-CRISPRi-Exo) were efficiently delivered into brain lesions induced specific SNCA. vivo, FUS combined with RVG-CRISPRi-Exo significantly improved motor performance, balance coordination, neurosensitivity in mice, greatly down-regulated elevation α-synuclein (α-syn) caused by modeling, rescued cell apoptosis, alleviated progression mice. [18F]-FP-DTBZ imaging suggested that synaptic function nigrostriatal pathway could restored, which was conducive to control behavior Pyrosequencing results showed methylate CpG at sites SNCA, fine-tuned editing achieved good effects model vitro, transcripts α-syn expression relieved neuronal damage. Collectively, our findings provide proof-of-principle development targeted nanodelivery insights diseases.

Язык: Английский

---

Interplay of α-synuclein with Lipid Membranes: Cooperative Adsorption, Membrane Remodeling and Coaggregation

JACS Au, Год журнала: 2024, Номер 4(4), С. 1250 - 1262

Опубликована: Март 19, 2024

α-Synuclein is a small neuronal protein enriched at presynaptic termini. It hypothesized to play role in neurotransmitter release and synaptic vesicle cycling, while the formation of α-synuclein amyloid fibrils associated with several neurodegenerative diseases, most notably Parkinson's Disease. The molecular mechanisms both physiological pathological functions remain be fully understood, but cases, interactions membranes an important role. In this Perspective, we discuss aspects lipid including cooperative adsorption, membrane remodeling fibril presence membranes. We highlight coupling between different phenomena their interplay context α-synuclein.

Язык: Английский

---

Automated procedure to detect subtle motor alterations in the balance beam test in a mouse model of early Parkinson’s disease

Scientific Reports, Год журнала: 2024, Номер 14(1)

Опубликована: Янв. 9, 2024

Parkinson's disease (PD) is the most common motor neurodegenerative disorder, characterised by aggregated α-synuclein (α-syn) constituting Lewy bodies. We aimed to investigate temporal changes in impairments a PD mouse model induced overexpression of α-syn with conventional manual analysis balance beam test and novel approach using machine learning algorithms automate behavioural analysis. combined automated animal tracking markerless pose estimation DeepLabCut, classification Simple Behavior Analysis. Our procedure was able detect subtle deficits performances that could not assess. The revealed time-course significant differences for "walking" behaviour mean interval between each bout, median event bout duration classifier probability occurrence male mice, even though no statistically loss tyrosine hydroxylase nigrostriatal system found either sex. These findings are valuable early detection impairment models. provide user-friendly, step-by-step guide assessment test, which aims be replicable without any computational programming knowledge.

Язык: Английский

---

Identification of novel phenolic inhibitors from traditional Chinese medicine against toxic α-synuclein aggregation via regulating phase separation

International Journal of Biological Macromolecules, Год журнала: 2025, Номер 297, С. 139875 - 139875

Опубликована: Янв. 14, 2025

Язык: Английский

---

α-synuclein and tau: interactions, cross-seeding, and the redefinition of synucleinopathies as complex proteinopathies

Frontiers in Neuroscience, Год журнала: 2025, Номер 19

Опубликована: Март 27, 2025

Neurodegenerative diseases are characterized by protein aggregation and overlapping pathologies, challenging traditional classifications highlighting shared underlying mechanisms. Parkinson’s disease related synucleinopathies, including Lewy body dementia multiple system atrophy, highlight the interplay between α-synuclein tau, two key proteins implicated in these disorders. Recent studies reveal that tau co-aggregate, interact synergistically, propagate via prion-like mechanisms, exacerbating neuronal dysfunction. This review examines physiological roles pathological transitions of α-synuclein, emphasizing their microtubule dynamics, synaptic regulation, structural heterogeneity aggregates. Evidence from post-mortem brains, transgenic models, proteomic analyses underscores significance soluble oligomers as primary neurotoxic species explores diverse molecular composition bodies glial cytoplasmic inclusions. The co-localization influenced genetic factors post-translational modifications, offers insights into mechanisms across synucleinopathies tauopathies. These findings advocate for integrated therapeutic strategies targeting cross-seeding proteostatic disruption while preserving roles. By framing neurodegeneration a collapse networks rather than isolated proteinopathies, this work proposes paradigm shift toward understanding treating complex neurodegenerative

Язык: Английский

---

Live-cell quantification reveals viscoelastic regulation of synapsin condensates by α-synuclein

Science Advances, Год журнала: 2025, Номер 11(16)

Опубликована: Апрель 18, 2025

Synapsin and α-synuclein represent a growing list of condensate-forming proteins where the material states condensates are directly linked to cellular functions (e.g., neurotransmission) pathology neurodegeneration). However, quantifying condensate properties in living systems has been substantial challenge. Here, we develop micropipette aspiration whole-cell patch-clamp (MAPAC), platform that allows direct quantification live cells. We find 10,000-fold variations viscoelasticity synapsin condensates, regulated by partitioning α-synuclein, marker for synucleinopathies. Through vitro reconstitutions, identify multiple molecular factors distinctly regulate viscosity, interfacial tension, maturation confirming roles α-synuclein. Overall, our study provides unprecedented quantitative insights into neuronal reveals crucial role regulating viscoelasticity. Furthermore, envision MAPAC applicable broad range vivo.

Язык: Английский

---