Search Results (35)

The synuclein family, comprising α-, β-, and γ-synucleins, consists of highly conserved, intrinsically disordered proteins sharing substantial structural homology and exhibiting multifunctional roles in membrane interactions, vesicle trafficking, lipid homeostasis, and cellular signalling. Synucleins are enriched at presynaptic terminals, where they regulate synaptic vesicle dynamics and neurotransmission by contributing to vesicle clustering, trafficking, and the availability of vesicles for release. Aberrant expression, misfolding, and aggregation of synucleins are associated with several human diseases, particularly neurodegenerative disorders and certain cancers, highlighting their biological and clinical relevance. The primary aim of this review was to provide a focused overview of current knowledge regarding the physiological presynaptic functions of synucleins. By concentrating on this relatively underexplored aspect of synuclein biology, we sought to highlight their roles in synaptic transmission and presynaptic regulation, thereby complementing the extensive literature devoted to their pathological significance. Here, the recent findings on the contributions of α-, β-, and γ-synucleins to synaptic vesicle organization, trafficking and neurotransmitter release were summarized, and their emerging roles in maintaining presynaptic homeostasis were discussed. In addition, we consider how disruption of these physiological functions may contribute to synaptic dysfunction and the development of disease. Full article

Background/Goals: Traumatic brain injury (TBI) is increasingly recognised as an important risk factor for delayed neurodegeneration and has been implicated in the modulation of Alzheimer’s disease (AD)-related amyloid pathology. However, experimental evidence remains equivocal, suggesting that the effects of TBI on amyloidogenesis are context-dependent and influenced by factors including disease stage, injury severity, and the pre-existing neurodegenerative background. This study aimed to comprehensively assess the effects of TBI on cognitive function, synuclein-family gene expression, neuroinflammatory gene expression and amyloid plaque morphology in APPswe/PS1dE9/Blg mice. Methods: Wild-type and APP/PS1 mice were assigned to four experimental groups: WT, WT-TBI, APP/PS1 and APP/PS1-TBI. TBI was induced at 6 months of age using a controlled cortical impact device (precision impactor). Behavioural assessments were conducted at two post-injury time points to evaluate locomotor activity, object recognition memory, short-term spatial memory and spatial learning. Cortex and hippocampus samples were analysed by qRT-PCR to evaluate synuclein-family gene expression and neuroinflammation-related markers. Amyloid plaque pathology was evaluated in Congo red-stained brain sections using QuPath-based image analysis. Results: TBI did not induce a consistent increase in amyloid plaque burden in APP/PS1 mice. Instead, TBI was associated with changes in plaque-size distribution, particularly at the later post-injury time point. Behavioural assessments revealed early trauma-associated cognitive impairmen; whereas, impairments observed at later stages appeared to be driven predominantly by progression of the APP/PS1 phenotype. Gene expression analysis revealed region- and genotype-dependent alterations in synuclein-family transcripts and inflammatory markers with the most pronounced changes observed in the cortex. Conclusions: These findings indicate that TBI does not uniformly accelerate β-amyloid deposition in APP/PS1 mice with established amyloid pathology. Rather, TBI appears to modify the temporal progression and morphological characteristics of amyloid pathology while interacting with genotype-dependent transcriptional responses involving synuclein-family genes and neuroinflammatory pathways. These results highlight the complex interplay between traumatic injury and pre-existing neurodegenerative processes and warrant further studies at the protein-level and over extended follow-up periods to elucidate the underlying mechanisms. Full article

α-Synuclein (α-Syn) is a key presynaptic protein, primarily known for its role in the pathogenesis of Parkinson’s disease (PD) and other synucleinopathies, including dementia with Lewy bodies (DLB). Although much of the research has focused on the nigrostriatal dopamine (DA) pathway, there is growing recognition that the accumulation of misfolded α-Syn in the prefrontal cortex (PFC) is a critical driver of non-motor symptoms and cognitive deficits in PD and DLB. This review examines the dual role of α-Syn in the PFC circuitry, initially exploring its regulation of synaptic vesicle (SV) dynamics and recycling to maintain stable neurotransmission. We highlight its contribution to the modulation of glutamatergic (Glu) and GABAergic (γ-aminobutyric acid, GABA) synapses, which ensures the functional excitatory/inhibitory (E/I) balance of prefrontal circuits. Conversely, in PD and DLB, the transition of functional α-Syn monomers to pathological oligomers triggers a cascade of synaptic failures. We analyze how α-Syn aggregation causes pathology in dendritic spines, leads to a progressive reduction in the density of synaptic markers, and impairs cortical plasticity. Synthesizing evidence from neuroimaging studies, post-mortem human cortical samples, and animal models, this review emphasizes the PFC as a vulnerable brain region where α-Syn-mediated synaptic dysfunction translates into cognitive and emotional deficits. Deciphering these early synaptic alterations is essential for developing neuroprotective strategies that preserve cortical function in PD and DLB. Full article

The formulation of the gut–brain–microbiota axis (GBA) theory has led to new research directions that have expanded our understanding of the pathogenesis, phenotypic variability, and clinical course of Parkinson’s disease (PD). Models of PD pathogenesis, based on the Braak hypothesis, suggest a subtype of the disease in which pathological changes begin in the gut many years before the onset of brain pathology and the manifestation of motor symptoms. Gut microbiota may influence nervous system function along the GBA by influencing intestinal permeability, chronic inflammation, and α-synuclein aggregation. Accumulating evidence suggests that the gut microbiota may also regulate the synthesis and metabolism of neurotransmitters, including dopamine (DA), serotonin (5-HT), acetylcholine (ACh) and γ-aminobutyric acid (GABA), both in the gut and brain, and indirectly stimulate central nervous system activity via the vagus nerve, which receives signals from the enteric nervous system. Research on the effects of microbiota on GBA has paved the way for the identification of novel treatment strategies, including probiotics, prebiotics, synbiotics, postbiotics, antibiotics, and fecal microbiota transplantation (FMT), aimed at not only symptomatic but also disease-modifying treatment of PD. In this article, we propose a novel approach to GBA as a link between gut microbiota and gut and brain neurotransmitter metabolism in PD. We review the latest research on the gut epithelial barrier. We analyze and summarize the potential of therapeutic interventions targeting gut microbiota and their impact on neurotransmitter regulation in PD. Full article

Background: The three Synuclein family members (α-, β-, and γ-synuclein) are presynaptic proteins that regulate synaptic vesicle trafficking and thereby influence neurotransmitter release. Synucleins belong to a class of intrinsically disordered proteins and are prone to aggregation into pathological deposits, which may impair their physiological synaptic functions. Knockout (KO) mouse lines, commonly used to model synuclein depletion in the nervous system, reveal a range of phenotypes with different motor and behavioral deficits. However, given the high sequence homology and functional interplay among the three synucleins, the specific contribution of each family member to these phenotypes remains poorly understood. Objective: In this study, we conducted a comparative phenotypic analysis of γ-synuclein KO, α- and β-synuclein KO, and αβγ-synuclein KO mice. Methods: Mice were subjected to a battery of behavioral tests assessing motor activity and coordination, anxiety-like behavior, and spatial learning and memory. Synaptic vesicle proteins were analyzed in brain tissues using Western blotting. Results: We observed that knocking out γ-synuclein but not α- and β-synucleins reduces mouse lifespan and leads to sustained reduction in muscle strength implicating that γ-synuclein is essential for longevity and motor system function. Another consequence of γ-synuclein deficiency is altered anxiety-like behavior manifested as a diminished aversive response, while exploratory behavior and memory remain intact. The triple KO mice mirror γ-synuclein KO mice in some behavioral changes, including shortened lifespan, reduced muscle strength, and decreased anxiety-like behavior. However, the triple KO mice additionally exhibit hyperactivity, which is not present in the other groups. No changes in synaptic vesicle marker levels were detected, indicating that the observed motor and behavioral abnormalities are not attributable to impaired synaptic connectivity. Conclusions: Taken together, these findings demonstrate nonredundant functions of individual synuclein family members and highlight a distinct role of γ-synuclein in regulating motor performance and behavioral responses. Full article

Parkinson’s disease (PD), the second most common neurodegenerative disease, is characterized by the progressive degeneration of dopaminergic neurons in the substantia nigra pars compacta along with the aggregation of α-synuclein in Lewy bodies. Among the pathological mechanisms involved is the alteration of iron homeostasis, which promotes oxidative stress and neuronal damage. Despite therapeutic advances, today, no treatment is available to modify the course of the disease. In this study, we investigated for the first time the neuroprotective potential of bovine lactoferrin (bLf) in both its Native (Nat-) and Holo forms, using rotenone-treated N1E-115 cells to mimic PD phenotype. The results showed that the Nat-bLf was more effective than Holo-bLf in counteracting rotenone-induced cytotoxicity and neurite retraction, preserving neuronal morphology and promoting neuritogenesis, as evidenced by increased β3-Tubulin and Growth-Associated Protein-43 markers (GAP-43). Both forms of bLf preserved Tyrosine Hydroxylase (TH) levels, crucial for dopamine synthesis, reduced the DNA damage marker γ-H2Ax and prevented rotenone-induced downregulation of Divalent Metal Transporter-1 (DMT-1) and Ferroportin (Fpn), key proteins involved in iron uptake and release, thereby limiting intracellular iron accumulation. Notably, only Nat-bLf reduced the levels of α-synuclein and markers of oxidative damage. Conversely, Holo-bLf exhibited pro-oxidant effects and increased α-synuclein accumulation even in absence of rotenone. Overall, these results highlight the differential neuroprotective effects of both Nat- and Holo-form, resulting from their distinct iron saturation level and their ability to modulate protein expression, with the native form emerging as a promising candidate for therapeutic strategies to counteract PD-associated neurodegeneration. Full article

This study explores the structural transitions and aggregation behaviour of recombinant β- and γ-synucleins from five vertebrate species—Cyprinus carpio, Danio rerio, Xenopus laevis, Anolis carolinensis, and Homo sapiens—using thioflavin T fluorescence and circular dichroism spectroscopy, with and without copper ions. Although synucleins are well-conserved proteins among vertebrates, species-specific differences in amino acid composition and predicted secondary structures were observed, particularly within β-strand-forming regions. During a six-day incubation, human β-synuclein exhibited a time-dependent increase in β-sheet-rich structures, while non-mammalian β-synucleins showed limited variation. In contrast, γ-synucleins from all species displayed greater aggregation propensity, with variations in kinetics and magnitude. The presence of copper reduced the rate of aggregation in human β-synuclein, likely due to high-affinity metal-binding sites, whereas γ-synuclein aggregation was only mildly affected. Notably, copper enhanced late-phase aggregation in A. carolinensis β-synuclein. These findings suggest that sequence divergence among synuclein isoforms may underlie species-specific aggregation mechanisms and metal sensitivity. The differential aggregation behaviour observed across taxa may reflect evolutionary adaptations in synuclein function and folding propensity, with implications for understanding the molecular basis of synucleinopathies and their potential modulation by metal ions. Full article

Parkinson’s disease (PD) is a progressive neurodegenerative disorder marked by the degeneration of dopaminergic neurons in the substantia nigra, leading to decreased dopamine levels in the striatum and causing a range of motor and non-motor impairments. Although the molecular mechanisms driving PD progression remain incompletely understood, emerging evidence suggests that the buildup of nuclear DNA damage, especially DNA double-strand breaks (DDSBs), plays a key role in contributing neurodegeneration, promoting senescence and neuroinflammation. Despite the pathogenic role for DDSB in neurodegenerative disease, targeting DNA repair mechanisms in PD is largely unexplored as a therapeutic approach. Ataxia telangiectasia mutated (ATM), a key kinase in the DNA damage response (DDR), plays a crucial role in neurodegeneration. In this study, we evaluated the therapeutic potential of AZD1390, a highly selective and brain-penetrant ATM inhibitor, in reducing neuroinflammation and improving behavioral outcomes in a mouse model of α-synucleinopathy. Four-month-old C57BL/6J mice were unilaterally injected with either an empty AAV1/2 vector (control) or AAV1/2 expressing human A53T α-synuclein to the substantia nigra, followed by daily AZD1390 treatment for six weeks. In AZD1390-treated α-synuclein mice, we observed a significant reduction in the protein level of γ-H2AX, a DDSB marker, along with downregulation of senescence-associated markers, such as p53, Cdkn1a, and NF-κB, suggesting improved genomic integrity and attenuation of cellular senescence, indicating enhanced genomic stability and reduced cellular aging. AZD1390 also significantly dampened neuroinflammatory responses, evidenced by decreased expression of key pro-inflammatory cytokines and chemokines. Interestingly, mice treated with AZD1390 showed significant improvements in behavioral asymmetry and motor deficits, indicating functional recovery. Overall, these results suggest that targeting the DDR via ATM inhibition reduces genotoxic stress, suppresses neuroinflammation, and improves behavioral outcomes in a mouse model of α-synucleinopathy. These findings underscore the therapeutic potential of DDR modulation in PD and related synucleinopathy. Full article

Introduction. Previous studies have shown that probiotics have positive effects on both motor and non-motor symptoms in Parkinson’s disease (PD). Additionally, in preclinical settings, probiotics have demonstrated the ability to counteract neuronal loss and alpha-synuclein aggregation, important pathological hallmarks of PD. Notably, preliminary in vitro studies have revealed the immunomodulatory properties of probiotics. This study aims to evaluate the impact of probiotics on symptoms and peripheral cytokines levels in PD patients compared to placebo. Methods. Patients were enrolled and blindly randomized to receive either active probiotics (comprising Bifidobacterium animalis subsp. lactis BS01 LMG P-21384, Bifidobacterium longum BL03 DSM 16603, Bifidobacterium adolescentis BA02 DSM 18351, Fructo-oligosaccharides and Maltodextrin-Group A) or placebo (Maltodextrin-Group B). Clinical evaluations and plasma levels cytokines (TNF-α, IFN-γ, IL-6, and TGF-β) were also assessed at enrollment and after 12 weeks. Anti-parkinsonian therapy remained stable throughout the study. Results. Forty PD patients were recruited. After 12 weeks, Group A showed significant improvement in motor symptoms (UPDRS III: 13.89 ± 4.08 vs. 12.74 ± 4.57, p = 0.028) and non-motor symptoms (NMSS: 34.32 ± 21.41 vs. 30.11 ± 19.89, p = 0.041), with notable improvement in the gastrointestinal sub-item (3.79 ± 4.14 vs. 1.89 ± 2.54, p = 0.021). A reduction of IFN-γ levels was observed in both groups, but group A also showed a significant decrease in IL-6 and a slight increase in the anti-inflammatory cytokine TGF-β. Conclusions. Our data suggest that probiotics may modulate peripheral cytokines levels and improve clinical symptoms in PD patients. Probiotics may, therefore, represent a valuable adjunctive therapy to conventional anti-parkinsonian drugs. Full article

Accumulating evidence suggests an involvement of sphingolipids, vital components of cell membranes and regulators of cellular processes, in the pathophysiology of both Parkinson’s disease and major depressive disorder, indicating a potential common pathway in these neuropsychiatric conditions. Based on this interaction of sphingolipids and synuclein proteins, we explored the gene expression patterns of α-, β-, and γ-synuclein in a knockout mouse model deficient for acid sphingomyelinase (ASM), an enzyme catalyzing the hydrolysis of sphingomyelin to ceramide, and studied associations with behavioral parameters. Normalized Snca, Sncb, and Sncg gene expression was determined by quantitative PCR in twelve brain regions of sex-mixed homozygous (ASM−/−, n = 7) and heterozygous (ASM+/−, n = 7) ASM-deficient mice, along with wild-type controls (ASM+/+, n = 5). The expression of all three synuclein genes was brain region-specific but independent of ASM genotype, with β-synuclein showing overall higher levels and the least variation. Moreover, we discovered correlations of gene expression levels between brain regions and depression- and anxiety-like behavior and locomotor activity, such as a positive association between Snca mRNA levels and locomotion. Our results suggest that the analysis of synuclein genes could be valuable in identifying biomarkers and comprehending the common pathological mechanisms underlying various neuropsychiatric disorders. Full article

In this work, we explored the intrinsic disorder status of the three members of the synuclein family of proteins—α-, β-, and γ-synucleins—and showed that although all three human synucleins are highly disordered, the highest levels of disorder are observed in γ-synuclein. Our analysis of the peculiarities of the amino acid sequences and modeled 3D structures of the human synuclein family members revealed that the pathological mutations A30P, E46K, H50Q, A53T, and A53E associated with the early onset of Parkinson’s disease caused some increase in the local disorder propensity of human α-synuclein. A comparative sequence-based analysis of the synuclein proteins from various evolutionary distant species and evaluation of their levels of intrinsic disorder using a set of commonly used bioinformatics tools revealed that, irrespective of their origin, all members of the synuclein family analyzed in this study were predicted to be highly disordered proteins, indicating that their intrinsically disordered nature represents an evolutionary conserved and therefore functionally important feature. A detailed functional disorder analysis of the proteins in the interactomes of the human synuclein family members utilizing a set of commonly used disorder analysis tools showed that the human α-synuclein interactome has relatively higher levels of intrinsic disorder as compared with the interactomes of human β- and γ- synucleins and revealed that, relative to the β- and γ-synuclein interactomes, α-synuclein interactors are involved in a much broader spectrum of highly diversified functional pathways. Although proteins interacting with three human synucleins were characterized by highly diversified functionalities, this analysis also revealed that the interactors of three human synucleins were involved in three common functional pathways, such as the synaptic vesicle cycle, serotonergic synapse, and retrograde endocannabinoid signaling. Taken together, these observations highlight the critical importance of the intrinsic disorder of human synucleins and their interactors in various neuronal processes. Full article

Rotenone (ROT), the most significant rotenoid, which has shown anticancer activity, has also been reported to be toxic to normal cells, inducing Parkinson’s disease (PD)-like neuronal loss with aggregation of α-synuclein (α-syn). To reduce the adverse effects of ROT, its derivative, rotenoisin A (ROA), is obtained by directly irradiating a ROT solution in methanol using γ-rays, which has been reported for potential anticancer properties. However, its PD-inducing effects have not yet been researched or reported. This study sought to compare the activities of ROA and ROT on the aggregation of α-syn, apoptosis, and autophagy in SH-SY5Y cells. ROA decreased cell survival less when compared with ROT on SH-SY5Y cells at 48 h in a dose-dependent manner. ROT (0.5 and 1 μM) and ROA (4 and 5 μM) decreased the expression of tyrosine hydroxylase. Western blot analysis of the Triton X-100 insoluble fraction revealed that both ROT and ROA significantly increased the levels of oligomeric, dimeric, and monomeric phosphorylated Serine129 α-syn and total monomeric α-syn. Moreover, both compounds decreased the proportion of neuronal nuclei, the neurofilament-heavy chain, and β3-tubulin. The phosphorylation of ERK and SAPK were reduced, whereas ROA did not act on Akt. Additionally, the increased Bax/Bcl-2 ratio further activated the downstream caspases cascade. ROT promoted the LC3BII/I ratio and p62 levels; however, different ROA doses resulted in different effects on autophagy while inducing PD-like impairments in SH-SY5Y cells. Full article

Parkinson’s disease (PD) is a common neurodegenerative disorder with a complicated etiology and pathogenesis. α-Synuclein aggregation, dopaminergic (DA) neuron loss, mitochondrial injury, oxidative stress, and inflammation are involved in the process of PD. Neuroinflammation has been recognized as a key element in the initiation and progression of PD. In this review, we summarize the inflammatory response and pathogenic mechanisms of PD. Additionally, we describe the potential anti-inflammatory therapies, including nod-like receptor pyrin domain containing protein 3 (NLRP3) inflammasome inhibition, nuclear factor κB (NF-κB) inhibition, microglia inhibition, astrocyte inhibition, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibition, the peroxisome proliferator-activated receptor γ (PPARγ) agonist, targeting the mitogen-activated protein kinase (MAPK) pathway, targeting the adenosine monophosphate-activated protein kinase (AMPK)-dependent pathway, targeting α-synuclein, targeting miRNA, acupuncture, and exercise. The review focuses on inflammation and will help in designing new prevention strategies for PD. Full article