Search Results (181)

Parkinson’s disease (PD) is a progressive, multisystemic α-synucleinopathy, recognized as the second most prevalent neurodegenerative disorder globally. Its neuropathology is characterized by the degeneration of dopaminergic neurons, particularly in the substantia nigra pars compacta (SNpc), and the intraneuronal accumulation of α-synuclein-forming Lewy bodies. Oxidative stress is a key contributor to PD pathogenesis. Thioredoxin-interacting protein (TXNIP) is a crucial regulator of cellular redox balance, inhibiting the antioxidant function of thioredoxin. This pilot study aimed to investigate the protein expression and localization of TXNIP in the SNpc of PD patients compared to healthy controls. We performed immunohistochemical analyses on 12 post-mortem human brain sections (formalin-fixed, paraffin-embedded) from six subjects with PD and six healthy controls. The study was performed on PD subjects with Braak stage 6. Our findings revealed that in control samples, TXNIP protein was distinctly and closely associated with neuromelanin (NM) pigment within the cytoplasm of SNpc dopaminergic neurons. Conversely, in PD samples, there was a markedly weak cytoplasmic expression of TXNIP, and critically, this association with NM pigment was absent. Furthermore, PD samples exhibited a significant reduction in both dopaminergic neurons and NM content, consistent with advanced disease. These findings, which mirror previous transcriptomic data showing TXNIP gene under-expression in the same subjects, suggest that altered TXNIP expression and localization in SNpc dopaminergic neurons are features of late-stage PD, potentially reflecting neuronal dysfunction and loss. Full article

Alpha-Synuclein (α-Syn) is a presynaptic neuronal protein implicated in the pathogenesis of Parkinson’s disease (PD) and other synucleinopathies, primarily through its aggregation into insoluble fibrils. The extended α-Syn half-life necessitates treatment durations that are incompatible with efficient high-throughput drug screening, can risk compound stability or cause cellular toxicity. To address this, we inserted a PEST sequence, a motif known to promote rapid protein degradation, at the C-terminus of the SNCA gene using CRISPR/Cas9 to create a novel cell line with reduced α-Syn half-life. This modification accelerates α-Syn turnover, providing a robust model for studying α-Syn dynamics and offering a platform that is applicable to other long-lived proteins. Our results demonstrate a six-fold reduction in α-Syn half-life, enabling the rapid detection of changes in protein levels and facilitating the identification of molecules that modulate α-Syn production and degradation pathways. Using inhibitors of the proteasome, transcription, and translation further validated the model’s utility in examining various mechanisms that impact protein levels. This novel cell line represents a significant advancement for studying α-Syn dynamics and offers promising avenues to develop therapeutics for α-synucleinopathies. Future research should focus on validating this model in diverse experimental settings and exploring its potential in high-throughput screening applications. Full article

ATP13A2 is a lysosomal polyamine transporter with loss of function mutations linked to multiple neurodegenerative disorders including Parkinson’s disease (PD). Knockout of ATP13A2 in mice leads to age-related sensorimotor impairments and in the brain lipofuscinosis, gliosis, and modest alpha-synuclein (αSyn) pathology. However, few studies have included ATP13A2 heterozygous mice as a comparison. In the present study, the effect of reduced or complete loss of ATP13A2 function on behavior, αSyn, gliosis, dopamine, and polyamines were determined in mice. Male and female ATP13A2 wildtype (WT), heterozygous (Het), and knockout (KO) mice were assessed behaviorally at 3, 12, and 18 months of age. In the brain, αSyn, phosphorylated αSyn, and GFAP were measured in the prefrontal cortex, striatum, ventral midbrain, and cerebellum. Polyamine and neurotransmitter analyses were performed in the same brain regions. Similar to previous studies, KO mice developed motor impairments and widespread gliosis in the brain. In addition, polyamine content was altered in Het and KO mice. In contrast, Het mice showed impairments in cognitive function and an age-related increase in αSyn in the brain. These results indicate potentially different pathological mechanisms when ATP13A2 is reduced compared to when it is knocked out and may have important implications for disease modification in synucleinopathies including PD. Full article

Pathological aggregation of α-synuclein (αS) is implicated in the pathogenesis of Parkinson’s disease (PD) and other α-synucleinopathies. The current view is that neuron-to-neuron spreading of αS pathology contributes to the progression of α-synucleinopathy. We used an A53T mutant human αS transgenic mouse model (TgA53T) to examine whether the site of pathogenic αS inoculation affects the pattern of neuropathology and whether soluble and insoluble fractions derived from crude pathogenic tissue lysates exhibit differential capacities to initiate αS pathology. To test whether the inoculation site impacts the ultimate spatial/temporal patterns of αS pathology, αS preformed fibrils (PFFs), or brain homogenates from TgA53T mice with α-synucleinopathy, were injected into the cortex/striatum, brainstem, or skeletal muscle. In all cases, inoculation of pathogenic αS induced end-stage motor dysfunction within ~100 days post-inoculation (dpi). Significantly, irrespective of the inoculation sites, the ultimate distribution of the αS pathology was like that seen in normally aged TgA53T mice at end-stage, indicating that the intrinsic neuronal vulnerability is a significant determinant in the induction of αS pathology, even when initiated by inoculation of pathogenic αS. Temporal analysis of brainstem-injected TgA53T mice show that initial αS pathology was seen by 30 days post-inoculation and inflammatory changes occur at later stages. In addition, we show that both highly soluble (S150) and insoluble (P150) fractions from end-stage TgA53T mice can seed de novo αS pathology in vivo. Moreover, the endoplasmic reticulum (ER)-enriched fraction from the TgA53T mice were highly pathogenic as the ER fraction induced αS pathology faster than other fractions when injected unilaterally into TgA53T mice. Our results suggest that multiple αS species from the brain can initiate the development of progressive αS pathology. 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

Neurodegenerative diseases (NDDs) that are characterized by the accumulation of alpha-synuclein (α-syn) aggregates in both neurons and the non-neuronal cells of the brain are called synucleinopathies. The most common synucleinopathies includes Parkinson’s disease (PD), Parkinson’s disease dementia (PDD), multiple system atrophy (MSA), and dementia with Lewy bodies (DLB). Significant progress has been made in the development of positron emission tomography (PET) radiotracers for synucleinopathies, yielding several α-syn tracers that have entered clinical studies. However, selective α-syn imaging still faces inherent challenges. This review provides a comprehensive overview of the progress in α-syn PET radiotracers from three angles: Alzheimer’s disease (AD)-derived scaffolds, representative compound scaffolds and analogs, and the identification of α-syn tracers through high-throughput screening (HTS). We discuss the characteristics, advantages, and limitations of the tracers for preclinical and clinical application. Finally, future directions in the development of radioligands for proteinopathies are discussed. There is no clinical available PET radiotracer for imaging α-syn aggregates, but these advances have laid a key foundation for non-invasive α-syn imaging and early diagnosis of synucleinopathies. Full article

Parkinson’s disease and related synucleinopathies, including dementia with Lewy bodies and multiple system atrophy, are characterised by the pathological aggregation of the α-synuclein (aSyn) protein in neuronal and glial cells, leading to cellular dysfunction and neurodegeneration. This review synthesizes knowledge of aSyn biology, including its structure, aggregation mechanisms, cellular interactions, and systemic influences. We highlight the structural diversity of aSyn aggregates, ranging from oligomers to fibrils, their strain-like properties, and their prion-like propagation. While the role of prion-like mechanisms in disease progression remains a topic of ongoing debate, these processes may contribute to the clinical heterogeneity of synucleinopathies. Dysregulation of protein clearance pathways, including chaperone-mediated autophagy and the ubiquitin–proteasome system, exacerbates aSyn accumulation, while post-translational modifications influence its toxicity and aggregation propensity. Emerging evidence suggests that immune responses and alterations in the gut microbiome are key modulators of aSyn pathology, linking peripheral processes—particularly those of intestinal origin—to central neurodegeneration. Advances in biomarker development, such as cerebrospinal fluid assays, post-translationally modified aSyn, and real-time quaking-induced conversion technology, hold promise for early diagnosis and disease monitoring. Furthermore, positron emission tomography imaging and conformation-specific antibodies offer innovative tools for visualising and targeting aSyn pathology in vivo. Despite significant progress, challenges remain in accurately modelling human synucleinopathies, as existing animal and cellular models capture only specific aspects of the disease. This review underscores the need for more reliable aSyn biomarkers to facilitate the development of effective treatments. Achieving this goal requires an interdisciplinary approach integrating genetic, epigenetic, and environmental insights. Full article

This study investigated the therapeutic potential of the nuclear retinoid X receptor (RXR) in mitigating the progression of alpha-synucleinopathies (αSNPs), particularly in Parkinson’s disease (PD). PD-like pathology in mice was successfully induced through the co-delivery of AAV expressing human α-synuclein (αS) and αS preformed fibrils (PFFs) into the substantia nigra pars compacta (SNpc). Significant increases in Lewy body (LB)-like inclusions, loss of tyrosine hydroxylase-positive (TH+) neurons, and reductions in dopamine (DA) levels in the striatum were observed. Additionally, diminished levels of PPARα and NURR1—proteins essential for neuronal survival—along with elevated expression of IBA1 and GFAP, markers of microglial activation and astrocytic gliosis, respectively, are associated with the pathogenesis of Parkinson’s disease. AAV-mediated overexpression of human RXRα demonstrated preservation of TH+ neurons, prevention of DA decline, and attenuation of αS accumulation. Furthermore, RXR-treated PD brains showed a reduced number of GFAP+ and Iba1+ cells, decreased GFAP+ and IBA1+ immunoreactivity, and fewer and less widespread LB-like aggregates. RXR overexpression also enhanced the production of PPARα and NURR1. These findings suggest that RXRα upregulation promotes neuroprotection by mitigating αSNPs and chronic neuroinflammation, a major contributor to PD progression. This research underscores the therapeutic potential of targeting nuclear receptors, such as RXR, in neurodegenerative diseases like PD. Full article

Lewy Body Disease (LBD) and Multiple System Atrophy (MSA) are synucleinopathies with distinct prognoses and neuropathologies, however, with overlapping clinical symptoms. Different disease characteristics are proposed to be determined by distinct conformations of alpha-synuclein (α-Syn) aggregates, which can self-propagate and spread between cells via a prion-like mechanism. The goal of this study is to investigate whether α-syn aggregates amplified from brain and CSF samples of LBD and MSA patients using the Seed Amplification Assay (SAA) maintain α-Syn seeding properties similar to those of α-syn aggregates derived from patients’ brains. To address this, SAA-amplified and un-amplified α-Syn aggregates from LBD and MSA patients’ brains, as well as SAA-amplified α-Syn aggregates from LBD and MSA patients’ CSF samples, were used to treat synuclein biosensor cells, and induced intracellular α-Syn inclusions were analyzed by confocal microscopy. Our data indicate that induced α-Syn aggregates from LBD and MSA patients’ brains have similar seeding properties and morphological characteristics in the α-Syn biosensor cells as those amplified from LBD and MSA patients’ brains, as well as those amplified from LBD and MSA patients’ CSF samples. In this study, we demonstrated that, regardless of the source of aggregates, the seeds from LBD and MSA produce cellular accumulation of α-Syn with distinct morphologies, confirming the presence of different conformational strains of α-Syn in LBD and MSA and allowing us to differentiate synucleinopathies based on the morphology of aggregates and seeding properties. Full article

Rapid eye movement (REM) sleep behavior disorder (RBD) is a parasomnia characterized by loss of muscle atonia and abnormal behaviors occurring during REM sleep. Idiopathic RBD (iRBD) is recognized as the strongest prodromal hallmark of α-synucleinopathies, with an established conversion rate to a neurodegenerative condition that reaches up to 96.6% at 15 years of follow-up. Moreover, RBD-converters display a more severe clinical trajectory compared to those that do not present with RBD. However, the extent to which iRBD represents a distinct genetic entity or an early manifestation of neurodegeneration remains unclear. To address this, we applied Genomic Structural Equation Modeling (GenomicSEM) using a GWAS-by-subtraction approach to disentangle the genetic architecture of iRBD from the shared genomic liability across α-synucleinopathies. Our findings highlight the SNCA locus as a key genetic regulator of iRBD susceptibility. While iRBD exhibits a partially distinct genetic signature, residual genomic overlap with neurodegenerative traits suggests that its genetic architecture exists along a continuum of α-synucleinopathy risk. In this scenario, the associations with neuroanatomical correlates may serve as early indicators of a trajectory toward future neurodegeneration. These findings provide a framework for identifying biomarkers that could aid in disease stratification and risk prediction, potentially improving early intervention strategies. Full article

Alpha-synuclein has been associated with neurodegeneration, especially in Parkinson’s disease (PD). This study aimed to review clinical, biochemical, and neuroimaging markers and management of prodromal synucleinopathies. The prodromal state of synucleinopathies can be better understood with PD pathophysiology, and it can be separated into premotor and pre-diagnostic phases. The incidence of PD in patients with prodromal phase symptoms ranges from 0.07 to 14.30, and the most frequently studied pathology is the REM behavioral disorder (RBD). Neuroimaging markers are related to dopamine denervation, brain perfusion changes, gross anatomy changes, and peripheral abnormalities. α-synuclein assays (SAA) in CSF revealed high sensitivity (up to 97%) and high specificity (up to 92%); in the last decade, there was the development of other matrices (blood, skin, and olfactory mucosa) for obtaining quantitative and qualitative α-synuclein. Other biomarkers are neurofilament light chain, DOPA decarboxylase, and multiplexed mass spectrometry assay. Regarding genetic counseling in α-synucleinopathies, it is an important topic in clinical practice to discuss with patients with high-risk individuals and should involve basic principles of autonomy, beneficence, and non-maleficence. Some of the themes that should be reviewed are the involvement of physical activity, diet (including alcohol, coffee, and vitamin supplementation), smoking, sleep, and stress in the pathophysiology of synucleinopathies. The number of trials related to prodromal symptoms is still scarce, and the number of studies evaluating intervention is even lower. Full article

Background/Objectives: Multiple system atrophy (MSA) presents a challenging diagnosis due to its clinical overlap with other neurodegenerative disorders, especially other α-synucleinopathies. The main purpose of this systematic review and meta-analysis was to assess neurofilament light chain (NfL) differences in the CSF and blood of patients with MSA versus the healthy control group (HC), patients with Parkinson’s disease (PD) and patients with Lewy body dementia (LBD). Secondarily, the diagnostic metrics of CSF and circulating NfL in MSA versus HC, PD, LBD, progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) were discussed. Methods: MEDLINE and EMBASE were thoroughly searched for relevant case-control studies. Standardized mean differences (SMDs) were calculated separately for CSF and blood NfL per comparison. Statistical heterogeneity was assessed based on the Q and I^2 statistics. Results: Twenty-five relevant studies were retrieved. Quantitative syntheses revealed elevated CSF and circulating NfL levels in individuals with MSA versus HC [SMD = 1.80 (95%CI = 1.66, 1.94) and SMD = 2.00 (95%CI = 1.36, 2.63), respectively] versus PD [SMD = 1.65 (95%CI = 1.26, 2.03) and SMD = 1.63 (95%CI = 0.84, 2.43), respectively] as well as versus LBD [SMD = 1.17, (95%CI = 0.71, 1.63) and SMD = 0.65 (95%CI = 0.30, 1.00), respectively]. Diagnostic accuracy was outstanding for CSF and blood NfL in MSA versus HC and PD, and it was moderate in MSA versus LBD. On the other hand, it was suboptimal in MSA vs. PSP and CBD. Conclusions: Both CSF and circulating NfL levels are elevated in MSA compared to HC, PD and LBD. To achieve optimal diagnostic properties, further work is required in the standardization of processes and the establishment of reference NfL intervals and/or thresholds. Full article

Multiple system atrophy (MSA), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD) are the most common atypical parkinsonism (AP) syndromes. They are clinically characterized by varying combinations of levodopa-poorly responsive parkinsonism, motor, cerebellar, and other signs. They are associated with a wide spectrum of non-motor symptoms, including prominent cognitive impairment such as global cognitive deficits, memory, executive, attentional, visuospatial, language, and non-verbal reasoning dysfunctions. Within the APs, their cognitive functioning is distributed along a continuum from MSA with the least impaired cognitive profile (similar to Parkinson’s disease) to PSP and CBD with the greatest decline in global cognitive and executive domains. Although their pathological hallmarks are different—MSA α-synucleinopathy, CBD, and PSP 4-repeat tauopathies—cognitive dysfunctions in APs show both overlaps and dissimilarities. They are often preceding and anticipate motor dysfunctions, finally contributing to reduced quality of life of patients and caregivers. The present paper will review the current evidence of the prevalence and type of cognitive impairment in these AP syndromes, their neuroimaging, pathogenic backgrounds, and current management options based on extensive literature research. Cognitive dysfunctions in APs are due to disruption of prefronto-subcortical and striato-thalamo-cortical circuitries and multiple essential brain networks. This supports the concept that they are brain network disorders due to complex pathogenic mechanisms related to the basic proteinopathies that are still poorly understood. Therefore, the pathophysiology and pathogenesis of cognitive impairment in APs deserve further elucidation as a basis for early diagnosis and adequate treatment of these debilitating comorbidities. Full article

(1) Background: Parkinson’s disease (PD) is characterized by the pathological accumulation of α-synuclein (α-syn) containing Lewy bodies (LBs) and Lewy neurites (LNs) within neurons. Growing evidence indicates that α-syn may propagate throughout the nervous system in a manner similar to prion-like transmission. Extracellular vesicles (EVs) may contribute to this pathway. We and others have reported that ATP13A2/PARK9 deficiency results in decreased EVs while its overexpression leads to increased EV generation. For analyzing EV-mediated α-syn secretion in neighboring neurons, we planned to alter Atp13a2 levels in vivo. (2) Methods: Three months after inoculating mouse α-syn fibrils into the striatum of Atp13a2-null and wild-type mice, we stained brain sections with anti-phosphorylated α-syn antibodies and then quantified LBs/LNs. We also examined the effect of increased levels of ATP13A2 by injecting lentivirus carrying human ATP13A2. Finally, we used cultured astrocytes and microglia for α-syn uptake and release, which were mediated by EVs. (3) Results: While LBs/LNs were formed in the entire brains, no significant difference was observed in LB/LN formation between Atp13a2-deficient and wild-type mice. Interestingly, the overexpression of ATP13A2 led to decreased LB/LN formation in the entire brains. Microglia and astrocytes released EVs more than neurons. EVs released from microglia and astrocytes contained more α-syn PFFs than those from neurons. (4) Conclusions: These results suggest that enhanced EV secretion by increased ATP13A2 levels attenuate the spreading of α-syn in brains, suggesting a protective role of ATP13A2 in α-synucleinopathies Full article

Background/Objectives: ¹²³Iodo-metaiodobenzylguanidine single photon emission computed tomography/computed tomography (¹²³I-MIBG SPECT/CT) is used to evaluate the cardiac sympathetic nervous system in cardiac diseases such as arrhythmogenic right ventricular cardiomyopathy (ARVC) and α-synucleinopathies such as Parkinson’s diseases. A common feature of these diseases is denervation. We aimed to compare quantitative and semi-quantitative cardiac sympathetic innervation using ¹²³I-MIBG imaging of ARVC and α-synucleinopathies. Methods: Cardiac innervation was assessed using ¹²³I-MIBG SPECT/CT in 20 patients diagnosed with definite ARVC and 8 patients with clinically diagnosed α-synucleinopathies. Heart-to-mediastinum-ratio (H/M-ratio), as semi-quantitative, was evaluated. Additionally, standardized uptake value (SUV), as quantitative, was measured as SUV_median, SUV_max, and SUV_peak in the left ventricle (LV), the right ventricle (RV), and in the global heart, based on a CT scan following quantitative image reconstruction. Results: The quantification of ¹²³I-MIBG uptake in the LV, the RV, and the global heart was feasible in patients suffering from α-synucleinopathies. SUV_median, and SUV_peak demonstrated a significant difference between ARVC and α-synucleinopathies across all regions, with the α-synucleinopathy group showing a lower uptake. In addition, the H/M ratio showed significantly lower uptake in patients with α-synucleinopathies than in patients with ARVC. Conclusions: Patients with α-synucleinopathies demonstrate significantly lower cardiac innervation in semi-quantitative and quantitative examinations than ARVC patients. The comparison of semi-quantitative and quantitative examinations suggests that quantitative examination offers an advantage. Quantitative analysis can be performed separately for the LV, RV, and global heart. However, analyzing the LV or RV does not provide additional benefit over analyzing the global heart in distinguishing between α-synucleinopathies and ARVC. Considering the different clinical manifestations of these two diseases, the absolute SUV values should not be generalized across different pathologies, and disease-specific ranges should be used instead. Full article