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Background The in vivo detection of phosphorylated‐α‐synuclein (pS129‐α‐syn) via immunofluorescence in cutaneous nerve fibers has emerged as a promising biomarker for diagnosing synucleinopathies, including Parkinson's disease, dementia with Lewy bodies and multiple system atrophy (MSA). However, the variability in biopsy protocols, particularly regarding the choice and number of anatomical sites, limits standardisation and clinical applicability. Objective To evaluate the diagnostic accuracy of different biopsy site combinations for pS129‐α‐syn detection in a large cohort of patients with confirmed synucleinopathies, to identify a sampling strategy that ensures high sensitivity while reducing patient burden, promoting methodological standardisation and clinical applicability. Methods In this 10‐year retrospective study, data from 227 patients with Lewy Body Diseases (LBD) (n = 194) or MSA (n = 33), who were identified as positive based on the three anatomical sites (two samples from each site: the cervical region (CE), thigh (TH) and distal leg (LEG)) skin biopsies protocol, were analysed. Diagnostic sensitivity was calculated for each site and combination, stratified by sex and disease duration. Results The results showed that the CE + LEG combination yielded the highest diagnostic sensitivity in both the LBD (97.68%) and MSA (100%) cohorts, independent of sex and duration. The TH site offered minimal additional diagnostic value when combined with CE and LEG. Conclusions CE + LEG dual‐site skin biopsy provides high diagnostic accuracy for both LBD and MSA, making it a less invasive yet effective alternative to the tri‐site protocols (six samples). The distinct deposition patterns observed between disease subtypes warrant further investigation to enhance the biomarker's diagnostic and pathophysiological relevance. This study evaluated the diagnostic accuracy of different skin biopsy site combinations for in vivo detection of phosphorylated‐α‐synuclein, aiming to identify a standardised and less invasive sampling strategy. In a 10‐year retrospective cohort of 227 patients with Lewy body diseases or multiple system atrophy, the cervical plus distal leg combination showed the highest diagnostic sensitivity (97.7% and 100%, respectively). Sampling from the thigh provided minimal additional diagnostic benefit, supporting a dual‐site protocol as an effective alternative approach.

The cell‐to‐cell transfer of α‐synuclein (α‐Syn) greatly contributes to Parkinson's disease (PD) pathogenesis and underlies the spread of α‐Syn pathology. During this process, extracellular α‐Syn can activate microglia and neuroinflammation, which plays an important role in PD. However, the effect of extracellular α‐Syn on microglia autophagy is poorly understood. In the present study, we reported that extracellular α‐Syn inhibited the autophagy initiation, as indicated by LC3‐II reduction and p62 protein elevation in BV2 and cultured primary microglia. The in vitro findings were verified in microglia‐enriched population isolated from α‐Syn‐overexpressing mice induced by adeno‐associated virus (AAV2/9)‐encoded wildtype human α‐Syn injection into the substantia nigra (SN). Mechanistically, α‐Syn led to microglial autophagic impairment through activating toll‐like receptor 4 (Tlr4) and its downstream p38 and Akt‐mTOR signaling because Tlr4 knockout and inhibition of p38, Akt as well as mTOR prevented α‐Syn‐induced autophagy inhibition. Moreover, inhibition of Akt reversed the mTOR activation but failed to affect p38 phosphorylation triggered by α‐Syn. Functionally, the in vivo evidence showed that lysozyme 2 Cre (Lyz2cre)‐mediated depletion of autophagy‐related gene 5 (Atg5) in microglia aggravated the neuroinflammation and dopaminergic neuron losses in the SN and exacerbated the locomotor deficit in α‐Syn‐overexpressing mice. Taken together, the results suggest that extracellular α‐Syn, via Tlr4‐dependent p38 and Akt‐mTOR signaling cascades, disrupts microglial autophagy activity which synergistically contributes to neuroinflammation and PD development. Autophagy‐dependent and independent machinery synergistically contribute to hα‐Syn‐caused neuroinflammation in PD. The basal autophagy activity restricts microglia inflammation. Extracellular hα‐Syn interacts with and activates Tlr4, resulting in inflammatory responses, as well as autophagy suppression in microglia via Tlr4‐dependent p38 and Akt/mTOR signaling cascades. This impairs the inhibitory effect of autophagy on inflammation, and thus aggravating hα‐Syn‐induced inflammatory responses.

There are currently no pharmacological treatments available that completely halt or reverse the progression of Parkinson’s Disease (PD). Hence, there is an unmet need for neuroprotective therapies. Lewy bodies are a neuropathological hallmark of PD and contain aggregated α-synuclein (α-syn) which is thought to be neurotoxic and therefore a suitable target for therapeutic interventions. To investigate this further, a systematic review was undertaken to evaluate whether anti-α-syn therapies are effective at preventing PD progression in preclinical in vivo models of PD and via current human clinical trials. An electronic literature search was performed using MEDLINE and EMBASE (Ovid), PubMed, the Web of Science Core Collection, and Cochrane databases to collate clinical evidence that investigated the targeting of α-syn. Novel preclinical anti-α-syn therapeutics provided a significant reduction of α-syn aggregations. Biochemical and immunohistochemical analysis of rodent brain tissue demonstrated that treatments reduced α-syn-associated pathology and rescued dopaminergic neuronal loss. Some of the clinical studies did not provide endpoints since they had not yet been completed or were terminated before completion. Completed clinical trials displayed significant tolerability and efficacy at reducing α-syn in patients with PD with minimal adverse effects. Collectively, this review highlights the capacity of anti-α-syn therapies to reduce the accumulation of α-syn in both preclinical and clinical trials. Hence, there is potential and optimism to target α-syn with further clinical trials to restrict dopaminergic neuronal loss and PD progression and/or provide prophylactic protection to avoid the onset of α-syn-induced PD.

BACKGROUND Most Alzheimer's disease (AD) cases show mixed pathology, with α‐synuclein (αSyn) aggregates present in a substantial proportion. The cerebrospinal fluid (CSF) α‐synuclein seed amplification assay (αS‐SAA) enables in vivo detection of pathogenic αSyn aggregates, but its clinical significance remains unclear. METHODS We prospectively evaluated 108 individuals with mild cognitive impairment or mild dementia due to suspected AD undergoing lumbar puncture for anti‐amyloid therapy (ATT) eligibility. CSF AD biomarkers and αS‐SAA were analyzed alongside cognitive, olfactory, and rapid eye movement sleep behavior disorder (RBD) assessments. RESULTS Of 65 participants with biomarker‐confirmed AD, 21 (32.3%) were αS‐SAA positive. Positivity was linked to older age at testing and self‐reported olfactory impairment (P = 0.004), but not other demographic or cognitive features. Within the αS‐SAA–positive group, RBD presence correlated with faster seeding kinetics. CONCLUSIONS αS‐SAA positivity is common in early AD and associated with olfactory dysfunction. Longitudinal follow‐up is required to test if assay status predicts response to ATTs. Highlights α‐synuclein (αS) co‐pathology was detected in 32% of early Alzheimer's disease (AD) cases. α‐synuclein seed amplification assay (αS‐SAA) positivity was associated with self‐reported olfactory impairment. Rapid eye movement sleep behavior disorder was linked to faster αs seeding kinetics. Findings support biological heterogeneity in early biomarker‐confirmed AD. αS‐SAA may inform patient stratification for amyloid‐targeting therapies.

While the initial pathology of Parkinson’s disease and other α‐synucleinopathies is often confined to circumscribed brain regions, it can spread and progressively affect adjacent and distant brain locales. This process may be controlled by cellular receptors of α‐synuclein fibrils, one of which was proposed to be the LAG3 immune checkpoint molecule. Here, we analysed the expression pattern of LAG3 in human and mouse brains. Using a variety of methods and model systems, we found no evidence for LAG3 expression by neurons. While we confirmed that LAG3 interacts with α‐synuclein fibrils, the specificity of this interaction appears limited. Moreover, overexpression of LAG3 in cultured human neural cells did not cause any worsening of α‐synuclein pathology ex vivo . The overall survival of A53T α‐synuclein transgenic mice was unaffected by LAG3 depletion, and the seeded induction of α‐synuclein lesions in hippocampal slice cultures was unaffected by LAG3 knockout. These data suggest that the proposed role of LAG3 in the spreading of α‐synucleinopathies is not universally valid. SYNOPSIS This study re‐evaluated the role of neuronal lymphocyte‐activation gene 3 (LAG3) in modulating the spreading of α‐synucleinopathies. The expression of LAG3 in neurons could not be validated, using genomic and proteomic approaches. The binding of α‐synuclein fibrils to LAG3 appeared to be limited regarding its specificity and affinity. Overexpression of LAG3 in human neurons did not lead to an increased deposition of α‐synuclein aggregates ex vivo . The genetic ablation of LAG3 did not lead to a prolonged survival of mice expressing human A53T α‐synuclein. The absence of LAG3 did not influence the deposition of α‐synuclein inclusions in organotypic slice cultures. Graphical Abstract This study re‐evaluated the role of neuronal lymphocyte‐activation gene 3 (LAG3) in modulating the spreading of α‐synucleinopathies.

Parkinson’s disease (PD) is the second most common neurodegenerative disorder of the elderly, presenting primarily with symptoms of motor impairment. The disease is diagnosed most commonly by clinical examination with a great degree of accuracy in specialized centers. However, in some cases, non-classical presentations occur when it may be difficult to distinguish the disease from other types of degenerative or non-degenerative movement disorders with overlapping symptoms. The diagnostic difficulty may also arise in patients at the early stage of PD. Thus, a biomarker could help clinicians circumvent such problems and help them monitor the improvement in disease pathology during anti-parkinsonian drug trials. This review first provides a brief overview of PD, emphasizing, in the process, the important role of α-synuclein in the pathogenesis of the disease. Various attempts made by the researchers to develop imaging, genetic, and various biochemical biomarkers for PD are then briefly reviewed to point out the absence of a definitive biomarker for this disorder. In view of the overwhelming importance of α-synuclein in the pathogenesis, a detailed analysis is then made of various studies to establish the biomarker potential of this protein in PD; these studies measured total α-synuclein, oligomeric, and post-translationally modified forms of α-synuclein in cerebrospinal fluid, blood (plasma, serum, erythrocytes, and circulating neuron-specific extracellular vesicles) and saliva in combination with certain other proteins. Multiple studies also examined the accumulation of α-synuclein in various forms in PD in the neural elements in the gut, submandibular glands, skin, and the retina. The measurements of the levels of certain forms of α-synuclein in some of these body fluids or their components or peripheral tissues hold a significant promise in establishing α-synuclein as a definitive biomarker for PD. However, many methodological issues related to detection and quantification of α-synuclein have to be resolved, and larger cross-sectional and follow-up studies with controls and patients of PD, parkinsonian disorders, and non-parkinsonian movement disorders are to be undertaken.

Epigenetic deregulation of α‐synuclein plays a key role in Parkinson’s disease (PD). Analysis of the SNCA promoter using the ENCODE database revealed the presence of important histone post‐translational modifications (PTMs) including transcription‐promoting marks, H3K4me3 and H3K27ac, and repressive mark, H3K27me3. We investigated these histone marks in post‐mortem brains of controls and PD patients and observed that only H3K4me3 was significantly elevated at the SNCA promoter of the substantia nigra (SN) of PD patients both in punch biopsy and in NeuN‐positive neuronal nuclei samples. To understand the importance of H3K4me3 in regulation of α‐synuclein, we developed CRISPR/dCas9‐based locus‐specific H3K4me3 demethylating system where the catalytic domain of JARID1A was recruited to the SNCA promoter. This CRISPR/dCas9 SunTag‐JARID1A significantly reduced H3K4me3 at SNCA promoter and concomitantly decreased α‐synuclein both in the neuronal cell line SH‐SY5Y and idiopathic PD‐iPSC derived dopaminergic neurons. In sum, this study indicates that α‐synuclein expression in PD is controlled by SNCA ’s histone PTMs and modulation of the histone landscape of SNCA can reduce α‐synuclein expression. Synopsis Histone posttranslational modifications play a major role in the regulation of α‐synuclein expression in Parkinson’s disease (PD). Locus‐specific editing of H3K4me3 at the SNCA promoter reverts the deregulated expression of α‐synuclein in neurons in the context of PD. α‐synuclein expression is controlled by epigenetic regulation. H3K4me3 is heavily enriched at the SNCA promoter in PD patient brains. Locus‐specific editing of H3K4me3 reduces neuronal α‐synuclein expression in PD. Graphical Abstract Histone posttranslational modifications play a major role in the regulation of α‐synuclein expression in Parkinson’s disease (PD). Locus‐specific editing of H3K4me3 at the SNCA promoter reverts the deregulated expression of α‐synuclein in neurons in the context of PD.

α-Synuclein (α-Syn) aggregation, proceeding fromoligomers to fibrils, is one central hallmark of neurodegeneration in synucleinopathies. α-Syn oligomers are toxic by triggering neurodegenerative processes in in vitro and in vivo models. However, the precise contribution of α-Syn oligomers to neurite pathology in human neurons and the underlying mechanisms remain unclear. Here, we demonstrate the formation of oligomeric α-Syn intermediates and reduced axonal mitochondrial transport in human neurons derived from induced pluripotent stem cells (iPSC) from a Parkinson’s disease patient carrying an α-Syn gene duplication. We further show that increased levels of α-Syn oligomers disrupt axonal integrity in human neurons. We apply an α-Syn oligomerization model by expressing α-Syn oligomer-forming mutants (E46K and E57K) and wild-type α-Syn in human iPSC-derived neurons. Pronounced α-Syn oligomerization led to impaired anterograde axonal transport of mitochondria, which can be restored by the inhibition of α-Syn oligomer formation. Furthermore, α-Syn oligomers were associated with a subcellular relocation of transport-regulating proteins Miro1, KLC1, and Tau as well as reduced ATP levels, underlying axonal transport deficits. Consequently, reduced axonal density and structural synaptic degeneration were observed in human neurons in the presence of high levels of α-Syn oligomers. Together, increased dosage of α-Syn resulting in α-Syn oligomerization causes axonal transport disruption and energy deficits, leading to synapse loss in human neurons. This study identifies α-Syn oligomers as the critical species triggering early axonal dysfunction in synucleinopathies.

The presence of protein inclusions, called Lewy bodies (LBs) and Lewy neurites (LNs), in the brain is the main feature of Parkinson’s disease (PD). Recent evidence that the prion-like propagation of α-synuclein (α-syn), as a major component of LBs and LNs, plays an important role in the progression of PD has gained much attention, although the molecular mechanism remains unclear. In this study, we evaluated whether neuronal ApoE regulates the cell-to-cell transmission of α-syn and explored its molecular mechanism using in vitro and in vivo model systems. We demonstrate that neuronal ApoE deficiency attenuates both α-syn uptake and release by downregulating LRP-1 and LDLR expression and enhancing chaperone-mediated autophagy activity, respectively, thereby contributing to α-syn propagation. In addition, we observed that α-syn propagation was attenuated in ApoE knockout mice injected with pre-formed mouse α-syn fibrils. This study will help our understanding of the molecular mechanisms underlying α-syn propagation.

Parkinson’s disease (PD) is characterized by the accumulation of misfolded and aggregated α-synuclein (α-syn) into intraneuronal inclusions named Lewy bodies (LBs). Although it is widely believed that α-syn plays a central role in the pathogenesis of PD, the processes that govern α-syn fibrillization and LB formation remain poorly understood. In this work, we sought to dissect the spatiotemporal events involved in the biogenesis of the LBs at the genetic, molecular, biochemical, structural, and cellular levels. Toward this goal, we further developed a seeding-based model of α-syn fibrillization to generate a neuronal model that reproduces the key events leading to LB formation, including seeding, fibrillization, and the formation of inclusions that recapitulate many of the biochemical, structural, and organizational features of bona fide LBs. Using an integrative omics, biochemical and imaging approach, we dissected the molecular events associated with the different stages of LB formation and their contribution to neuronal dysfunction and degeneration. In addition, we demonstrate that LB formation involves a complex interplay between α-syn fibrillization, posttranslational modifications, and interactions between α-syn aggregates and membranous organelles, including mitochondria, the autophagosome, and endolysosome. Finally, we show that the process of LB formation, rather than simply fibril formation, is one of the major drivers of neurodegeneration through disruption of cellular functions and inducing mitochondria damage and deficits, and synaptic dysfunctions. We believe that this model represents a powerful platform to further investigate the mechanisms of LB formation and clearance and to screen and evaluate therapeutics targeting α-syn aggregation and LB formation.