Alpha-synuclein pathological deposition alters functional homeostasis and connectivity of striatal dopaminergic synapses and results in microglia activation, pathology spreading, muscle stiffness, whole brain atrophy and metabolic changes before producing frank nigral neuron deafferentation

Published: May 9, 2025

The progressive accumulation of α-synuclein (α-Syn) aggregates is believed to contribute Parkinson’s disease (PD) pathogenesis. Nevertheless, the earliest pre-degenerative molecular, functional, neuroinflammatory and metabolic changes associated with α-Syn-pathology deposition still need be disclosed staged. Here, we investigated these events in a transgenic mouse model early prodromal PD expressing C-terminally truncated human (1-120 amino acids) α-Syn under guidance rat tyrosine hydroxylase (TH) promoter by using two-photon confocal microscopy, functional behavioural studies, longitudinal Magnetic Resonance Imaging (MRI) Positron Emission Tomography plus Computed (PET-CT) followed conventional or radiomic analysis. We found that before onset frank dopaminergic striatal fibres deafferentation, mice exhibited significant alterations synapse homeostasis connectivity, accompanied other widespread brain changes. In particular, observed early, transient increase Vesicular Monoamine Transporter 2 (VMAT2) dopamine transporter (DAT), turnover, depolarization-dependent release loss DAT inhibition-related facilitation. These occurred absence deficits were signs stiffness without motility impairment. PET-CT confirmed but binding dorsal striatum, raise neuroinflammation marker [¹⁸F]-VC701 as corroborated Ionized calcium-binding adaptor molecule 1 (Iba1) immunolabeling. MRI studies evidenced atrophy volume reduction different areas mice. Radiomic-based analysis [¹⁸F]-FDG-PET-CT revealed increasing texture supportive throughout brain. Finally, also pathology diffusion non-catecholaminergic neurons motor cortex. Our findings indicate drives unexpected molecular connectivity at synapses parallel spreading, neuroinflammation, leading explicit nigrostriatal deafferentation

Language: Английский

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Nanoplatforms Targeting Intrinsically Disordered Protein Aggregation for Translational Neuroscience Applications

Nanomaterials, Journal Year: 2025, Volume and Issue: 15(10), P. 704 - 704

Published: May 8, 2025

Intrinsically disordered proteins (IDPs), such as tau, beta-amyloid (Aβ), and alpha-synuclein (αSyn), are prone to misfolding, resulting in pathological aggregation propagation that drive neurodegenerative diseases, including Alzheimer’s disease (AD), frontotemporal dementia (FTD), Parkinson’s (PD). Misfolded IDPs aggregate into oligomers fibrils, exacerbating progression by disrupting cellular functions the central nervous system, triggering neuroinflammation neurodegeneration. Furthermore, aggregated exhibit prion-like behavior, acting seeds released extracellular space, taken up neighboring cells, have a propagating pathology across different regions of brain. Conventional inhibitors, small molecules, peptides, antibodies, face challenges stability blood–brain barrier penetration, limiting their efficacy. In recent years, nanotechnology-based strategies, multifunctional nanoplatforms or nanoparticles, emerged promising tools address these challenges. These leverage tailored designs prevent remodel reduce associated neurotoxicity. This review discusses advances designed target Aβ, αSyn aggregation, with focus on roles reducing We examine critical aspects nanoplatform design, choice material backbone targeting moieties, which influence interactions IDPs. also highlight key mechanisms interaction between inhibit redirect cascade towards nontoxic, off-pathway species, disrupt fibrillar structures soluble forms. further outline future directions for enhancing IDP clearance, achieving spatiotemporal control, improving cell-specific targeting. nanomedicine strategies offer compelling paths forward developing more effective targeted therapies diseases.

Language: Английский

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Role of Specific Autoantibodies in Neurodegenerative Diseases: Pathogenic Antibodies or Promising Biomarkers for Diagnosis

Antibodies, Journal Year: 2023, Volume and Issue: 12(4), P. 81 - 81

Published: Dec. 8, 2023

Neurodegenerative diseases (NDDs) affect millions of people worldwide. They develop due to the pathological accumulation and aggregation various misfolded proteins, axonal synaptic loss dysfunction, inflammation, cytoskeletal abnormalities, defects in DNA RNA, neuronal death. This leads activation immune responses release antibodies against them. Recently, it has become clear that autoantibodies (Aabs) can contribute demyelination, loss, brain cognitive dysfunction. significantly changed understanding participation humoral autoimmunity neurodegenerative disorders. It is crucial understand how neuroinflammation involved neurodegeneration, aid improving diagnostic therapeutic value Aabs future. review aims provide data on system's role NDDs, pathogenic some specific molecules associated with most common their potential as biomarkers for monitoring diagnosing NDDs. suggested autoimmune aspects NDDs will facilitate early diagnosis help elucidate previously unknown pathobiology these diseases.

Language: Английский

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Abnormal α-Synuclein Aggregates Cause Synaptic- and Microcircuit-Specific Deficits in the Retinal Rod Pathway

American Journal Of Pathology, Journal Year: 2024, Volume and Issue: 194(5), P. 796 - 809

Published: Feb. 21, 2024

Language: Английский

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Parkinson’s disease-associated mutations in α-synuclein alters its lipid-bound state

Biophysical Journal, Journal Year: 2024, Volume and Issue: 123(12), P. 1610 - 1619

Published: May 3, 2024

Language: Английский

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