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STUDY OBJECTIVES: To determine any correlation between serum alpha-synuclein (α-syn) concentrations and restless legs syndrome (RLS), and to explore the impact of intravenous iron supplementation on serum α-syn levels. METHODS: We collected clinical data on 113 RLS patients in whom serum α-syn levels were quantified using an ELISA kit and compared to a group of 45 age matched controls. A subset of 9 RLS patients who received intravenous (IV) iron underwent pre- and post-treatment blood sampling to assess α-syn and ferritin response. RESULTS: Family history of RLS was reported by 62.8% of patients, and current dopaminergic augmentation was observed in 31.0%. Low serum ferritin levels below 75 µg/L were seen in 39.8%. Serum α-syn levels were found to be significantly decreased in RLS patients (mean: 7.7 ng/ml) compared to controls (mean: 10.7 ng/ml,), p<0.05. Stratification based on sex, age and age of onset, did not reveal significant differences in α-syn levels. In 9 RLS patients who received IV iron treatment, a linear correlation between fold change in α-syn and ferritin was observed (R: 0.7, p <0.05). The temporal relation between serum α-syn and IV iron treatment showed a gradual decline of α-syn and ferritin by time correlation (p = 0.023, R: -0.739). CONCLUSION: In our study of 113 RLS subjects, serum α-syn levels were decreased in RLS patients compared to healthy controls and increased in the 9 patients who received IV iron treatment in correlation with ferritin. This correlation could suggest a mechanism for reduced dopamine transmission in RLS.

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Parkinson's disease (PD) is a multifactorial, chronic, and progressive neurodegenerative disorder inducing movement alterations as a result of the loss of dopaminergic (DAergic) neurons of the pars compacta in the substantia nigra and protein aggregates of alpha synuclein (α-Syn). Although its etiopathology agent has not yet been clearly established, environmental and genetic factors have been suggested as the major contributors to the disease. Mutations in the glucosidase beta acid 1 (GBA1) gene, which encodes the lysosomal glucosylceramidase (GCase) enzyme, are one of the major genetic risks for PD. We found that the GBA1 K198E fibroblasts but not WT fibroblasts showed reduced catalytic activity of heterozygous mutant GCase by -70% but its expression levels increased by 3.68-fold; increased the acidification of autophagy vacuoles (e.g., autophagosomes, lysosomes, and autolysosomes) by +1600%; augmented the expression of autophagosome protein Beclin-1 (+133%) and LC3-II (+750%), and lysosomal-autophagosome fusion protein LAMP-2 (+107%); increased the accumulation of lysosomes (+400%); decreased the mitochondrial membrane potential (∆Ψm) by -19% but the expression of Parkin protein remained unperturbed; increased the oxidized DJ-1Cys106-SOH by +900%, as evidence of oxidative stress; increased phosphorylated LRRK2 at Ser935 (+1050%) along with phosphorylated α-synuclein (α-Syn) at pathological residue Ser129 (+1200%); increased the executer apoptotic protein caspase 3 (cleaved caspase 3) by +733%. Although exposure of WT fibroblasts to environmental neutoxin rotenone (ROT, 1 µM) exacerbated the autophagy-lysosomal system, oxidative stress, and apoptosis markers, ROT moderately increased those markers in GBA1 K198E fibroblasts. We concluded that the K198E mutation endogenously primes skin fibroblasts toward autophagy dysfunction, OS, and apoptosis. Our findings suggest that the GBA1 K198E fibroblasts are biochemically and molecularly equivalent to the response of WT GBA1 fibroblasts exposed to ROT.

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Introduction: Increasing evidence suggests that air pollution has a significant impact on the development of synucleinopathies, but the potential neurobiological mechanisms are unknown. We aimed to explore the associations of air pollution (including ozone [O3], nitrogen dioxide [NO2], and particulate matter [PM2.5]) with CSF α-syn levels in urban older adults. Methods: We included 933 urban participants from the Chinese Alzheimer's Biomarker and LifestylE study. The 5-year average levels of air pollution exposure were estimated in the areas of residence. Multivariate linear regression was conducted to detect the correlation of air pollution with CSF α-syn levels. Subgroup analyses by age, gender, season, and history of coronary heart disease (CHD) were performed. Moreover, restricted cubic spline (RCS) models were applied to explore the potential nonlinear relationships. Results: We found a significant correlation of CSF α-syn level with PM2.5 in urban participants. Specifically, multiple linear regression showed a significant negative association between PM2.5 and CSF α-syn level (p = 0.029), which was more significant in female, midlife, non-CHD, and cold season subgroups. Besides, RCS models showed that O3 had an inverse J-shaped association with CSF α-syn levels in urban participants (p for nonlinearity = 0.040), and the harmful effect possibly appeared when O3 was above 37.9 ppb. Discussion: Long-term exposure to air pollution was associated with lower CSF α-syn levels, which may offer a new direction for exploring and preventing synucleinopathies.

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Loss of select neuronal populations such as midbrain dopamine (DA) neurons is a pathological hallmark of Parkinson's disease (PD). The small neuronal protein α-synuclein has been related both genetically and neuropathologically to PD, yet how and if it contributes to selective vulnerability remains elusive. Here, we describe the generation of a novel adeno-associated viral vector (AAV) for Cre-dependent overexpression of wild-type human α-synuclein. Our strategy allows us to restrict α-synuclein to select neuronal populations and hence investigate the cell-autonomous effects of elevated α-synuclein in genetically-defined cell types. Since DA neurons in the substantia nigra pars compacta (SNc) are particularly vulnerable in PD, we investigated in more detail the effects of increased α-synuclein in these cells. AAV-mediated overexpression of wildtype human α-synuclein in SNc DA neurons increased the levels of α-synuclein within these cells and augmented phosphorylation of α-synuclein at serine-129, which is considered a pathological feature of PD and other synucleinopathies. However, despite abundant α-synuclein overexpression and hyperphosphorylation we did not observe any dopaminergic neurodegeneration up to 90 days post virus infusion. In contrast, we noticed that overexpression of α-synuclein resulted in increased locomotor activity and elevated striatal DA levels suggesting that α-synuclein enhanced dopaminergic activity. We therefore conclude that cell-autonomous effects of elevated α-synuclein are not sufficient to trigger acute dopaminergic neurodegeneration.

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INTRODUCTION: Alpha-synuclein (αSyn) is believed to play a central role in the pathogenesis of Parkinson's disease (PD). Cerebrospinal fluid (CSF) total αSyn were significantly lower in PD patients, whereas the aggregates were higher, and this phenomenon was further exacerbated with longer disease duration. However, whether CSF αSyn can be the cause and/or a consequence in PD is not fully elucidated. METHOD: We administered 2 ng or 200 ng αSyn preformed fibrils (PFFs) by intracerebroventricular injection for consecutive 7 days in C57BL/6 mice. The olfactory function was assessed by the olfactory discrimination test and buried food-seeking test. The locomotor function was assessed by the rotarod test, pole test, open field test and CatWalk gait analysis. Phosphorylated αSyn at serine 129 was detected by the immunohistochemistry staining. Iron levels was determined by Perl's-diaminobenzidine iron staining and synchrotron-based X-ray fluorescence. RESULTS: The mice did not exhibit any diffuse synucleinopathy in the brain for up to 30 weeks, although αSyn PFFs induced aggregation in SH-SY5Y cells and in the substantia nigra and striatum of mice with stereotactic injection. No impairment of motor behaviors or olfactory functions were observed, although there was a temporary motor enhancement at 1 week. We then demonstrated iron levels were comparable in certain brain regions, suggesting there was no iron deposition/redistribution occurred. CONCLUSION: The intraventricular injection of αSyn PFFs does not induce synucleinopathy or behavioral symptoms. These findings have implications that CSF αSyn aggregates may not necessarily contribute to the onset or progression in PD.

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Parkinson's disease (PD) is typically a sporadic late-onset disorder, which has made it difficult to model in mice. Several transgenic mouse models bearing mutations in SNCA, which encodes alpha-Synuclein (α-Syn), have been made, but these lines do not express SNCA in a physiologically accurate spatiotemporal pattern, which limits the ability of the mice to recapitulate the features of human PD. Here, we generated knock-in mice bearing the G51D SNCA mutation. After establishing that their motor symptoms begin at 9 mo of age, we then sought earlier pathologies. We assessed the phosphorylation at Serine 129 of α-Syn in different tissues and detected phospho-α-Syn in the olfactory bulb and enteric nervous system at 3 mo of age. Olfactory deficit and impaired gut transit followed at 6 mo, preceding motor symptoms. The SncaG51D mice thus parallel the progression of human PD and will enable us to study PD pathogenesis and test future therapies.

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Alpha-synuclein (αSyn) forms pathologic aggregates in Parkinson's disease (PD) and is implicated in mechanisms underlying neurodegeneration. While pathologic αSyn has been extensively studied, there is currently no method to evaluate αSyn within the brains of living patients. Patients with PD are often treated with deep brain stimulation (DBS) surgery in which surgical instruments are in direct contact with neuronal tissue; herein, we describe a method by which tissue is collected from DBS surgical instruments in PD and essential tremor (ET) patients and demonstrate that αSyn is detected. 24 patients undergoing DBS surgery for PD (17 patients) or ET (7 patients) were enrolled; from patient samples, 81.2 ± 44.8 µg of protein (n = 15), on average, was collected from surgical instruments. Light microscopy revealed axons, capillaries, and blood cells as the primary components of purified tissue (n = 3). ELISA assay further confirmed the presence of neuronal and glial tissue in DBS samples (n = 4). Further analysis was conducted using western blot, demonstrating that multiple αSyn antibodies are reactive in PD (n = 5) and ET (n = 3) samples; truncated αSyn (1-125 αSyn) was significantly increased in PD (n = 5) compared to ET (n = 3), in which αSyn misfolding is not expected (0.64 ± 0.25 vs. 0.25 ± 0.12, P = 0.046), thus showing that multiple forms of αSyn can be detected from living PD patients with this method.

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The aggregation of the protein α-synuclein into amyloid deposits is associated with multiple neurological disorders, including Parkinson's disease. Soluble amyloid oligomers are reported to exhibit higher toxicity than insoluble amyloid fibrils, with dimers being the smallest toxic oligomer. Small molecule drugs, such as fasudil, have shown potential in targeting α-synuclein aggregation and reducing its toxicity. In this study, we use atomistic molecular dynamics simulations to demonstrate how fasudil affects the earliest stage of aggregation, namely dimerization. Our results show that the presence of fasudil reduces the propensity for intermolecular contact formation between protein chains. Consistent with previous reports, our analysis confirms that fasudil predominantly interacts with the negatively charged C-terminal region of α-synuclein. However, we also observe transient interactions with residues in the charged N-terminal and hydrophobic NAC regions. Our simulations indicate that while fasudil prominently interacts with the C-terminal region, it is the transient interactions with residues in the N-terminal and NAC regions that effectively block the formation of intermolecular contacts between protein chains and prevent early dimerization of this disordered protein.

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BACKGROUND: The term rapidly progressive dementia (RPD) with Lewy bodies (rpDLB) is used for DLB patients who develop a rapidly progressive neurological syndrome and have reduced survival. Here, we characterise the clinical, neuropathological, and molecular characteristics of a large rpDLB neuropathological series. METHODS: We included all RPD patients with a disease duration < 4 years submitted to our prion disease referral centre between 2003 and 2022 who showed Lewy body pathology (LBP) in limbic or neocortical stages as primary neuropathological diagnosis, had no systemic condition justifying the rapid deterioration and were previously neurologically unimpaired. Clinical features were retrieved and compared with Creutzfeldt-Jakob disease (CJD) and rapidly progressive Alzheimer's disease (rpAD) cohorts. Neuropathological and genetic (whole exome sequencing, APOE genotyping, and C9orf72 repeat expansion analysis) characteristics of rpDLB patients were systematically investigated. We scored semi-quantitatively the LBP load and performed a α-synuclein (αSyn) RT-QuIC seeding amplification assay (SAA) on cerebrospinal fluid (CSF) and tenfold serially diluted brain homogenates from different brain areas in rpDLB patients and typical long-lasting Lewy body disease (LBD) with dementia patients as control group. RESULTS: RpDLB patients were older (p = 0.047) and presented more cognitive fluctuations (p = 0.005), visual hallucinations (p = 0.020), neuropsychiatric symptoms (p = 0.006) and seizures (p = 0.032), and fewer cerebellar (p < 0.001) and visual (p = 0.004) signs than CJD ones. Delirium onset was more common than in both CJD (p < 0.001) and rpAD (p = 0.008). Atypical LBD signs (pyramidal, myoclonus, akinetic mutism) were common. All tested patients were positive by CSF αSyn SAA. Concomitant pathologies were common, with only four cases showing relatively "pure" LBP. LBP load and αSyn seeding activity measured through αSyn RT-QuIC SAA were not significantly different between rpDLB patients and typical LBD. We found a likely pathogenic variant in GBA in one patient. CONCLUSIONS: Our results indicate that: 1) rpDLB exhibits a distinct clinical signature (2) CSF αSyn SAA is a reliable diagnostic test; 3) rpDLB is a heterogeneous neuropathological entity that can be underlain by both widespread pure LBP, or multiple copathologies 4) rpDLB is likely not sustained by distinct αSyn conformational strains; 5) genetic defects may, at least occasionally, contribute to the poor prognosis in these patients.

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We probed the mechanism by which the Parkinson's disease-associated protein α-synuclein (α-syn)/SNCA promotes the pathogenesis and progression of melanoma. We found that the human melanoma cell line SK-MEL-28 in which SNCA is knocked out (SNCA-KO) has low levels of tetraspanin CD81, which is a cell-surface protein that promotes invasion, migration, and immune suppression. Analyzing data from the Cancer Genome Atlas, we show that SNCA and CD81 mRNA levels are positively correlated in melanoma; melanoma survival is inversely related to the levels of SNCA and CD81; and SNCA/CD81 are inversely related to the expression of key cytokine genes (IL12A, IL12B, IFN, IFNG, PRF1 and GZMB) for immune activation and immune cell-mediated killing of melanoma cells. We propose that high levels of α-syn and CD81 in melanoma and in immune cells drive invasion and migration and in parallel cause an immunosuppressive microenvironment; these contributing factors lead to aggressive melanomas.

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Alpha-synuclein oligomers play a crucial role in the early diagnosis of Parkinson's disease (PD). In this study, a mercaptoundecanoic acid (MUA)-capped gold nanorod (GNR)-coated and chitosan (CH)-immobilized fiber optic probe has shown considerable sensitivity of its detection. The proposed U-shaped fiber optic biosensor based on localized surface plasmon resonance (LSPR) was applied to detect α-syn oligomer (OA) biomarker. By analyzing OA concentrations, the biosensor achieved a limit of detection of (LOD) 11 pM within the concentration range of 10-100 pM and the sensitivity value was found as 502.69 Δλ/RIU. Upon analysis of the CV% (coefficient of variation) and accuracy/recovery values, it is revealed that the sensor successfully fulfilled the criteria for success, displaying accuracy/recovery values within the range of 80%-120% and CV% values below 20%. This sensor presents significant advantages, including high sensitivity, specificity, and ability to detect very low concentrations of OA. In conclusion, the suggested U-shaped fiber optic biosensor has the potential to be valuable in the early detection of PD from a clinical perspective.

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Alpha-synuclein (α-syn) aggregation plays a critical role in the pathogenicity of Parkinson's Disease (PD). This study aims to evaluate the aggregation propensity of α-syn fragment peptides designed using the variability found in humans and animals. Thioflavin T (ThT) and transmission electron microscopy (TEM) were used to validate the formation of fibrils to identify important amino acid residues. Human α-syn fragments 51-75, 37-61, 62-86, 76-100, and 116-140 demonstrate a significantly higher tendency to aggregate compared to fragments 1-25, 26-50, and 91-115. All species analyzed of the α-syn 37-61 and 62-86 regions were shown to form fibrils on both ThT and TEM. The α-syn 37-61 and 62-86 fragment regions exhibited a high susceptibility to aggregation, with fibril formation observed in all species. The A53T mutation in several α-syn 37-61 fragments may enhance their propensity for aggregation, suggesting a correlation between this mutation and the capacity for fibril formation. Furthermore, the presence of the non-amyloid-ß component (NAC) region, specifically in α-syn 62-86, was consistently observed in several fragments that displayed fibril formation, indicating a potential correlation between the NAC region and the process of fibril formation in α-syn. Finally, the combination of a high quantity of valine and a low quantity of acidic amino acids in these fragments may serve as indicators of α-syn fibril formation.

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To date, the molecular mechanisms of the common neurodegenerative disorder Parkinson's disease (PD) are unknown and, as a result, there is no neuroprotective therapy that may stop or slow down the process of neuronal cell death. The aim of the current study was to evaluate the prospects of using the mTOR molecule as a potential target for PD therapy due to the dose-dependent effect of mTOR kinase activity inhibition on cellular parameters associated with, PD pathogenesis. The study used peripheral blood monocyte-derived macrophages and SH-SY5Y neuroblastoma cell line. As a result, we have for the first time showed that inhibition of mTOR by Torin1 only at a concentration of 100 nM affects the level of the lysosomal enzyme glucocerebrosidase (GCase), encoded by the GBA1 gene. Mutations in GBA1 are considered a high-risk factor for PD development. This concentration led a decrease in pathological phosphorylated alpha-synuclein (Ser129), an increase in its stable tetrameric form with no changes in the lysosomal enzyme activities and concentrations of lysosphingolipids. Our findings suggest that inhibition of the mTOR protein kinase could be a promising approach for developing therapies for PD, particularly for GBA1-associated PD.

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Protein liquid-liquid phase separation (LLPS) is a rapidly emerging field of study on biomolecular condensate formation. In recent years, this phenomenon has been implicated in the process of amyloid fibril formation, serving as an intermediate step between the native protein transition into their aggregated state. The formation of fibrils via LLPS has been demonstrated for a number of proteins related to neurodegenerative disorders, as well as other amyloidoses. Despite the surge in amyloid-related LLPS studies, the influence of protein condensate formation on the end-point fibril characteristics is still far from fully understood. In this work, we compare alpha-synuclein aggregation under different conditions, which promote or negate its LLPS and examine the differences between the formed aggregates. We show that alpha-synuclein phase separation generates a wide variety of assemblies with distinct secondary structures and morphologies. The LLPS-induced structures also possess higher levels of toxicity to cells, indicating that biomolecular condensate formation may be a critical step in the appearance of disease-related fibril variants.

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Parkinson's disease (PD) is a prevalent neurodegenerative disease marked by dopaminergic neuronal loss and misfolded alpha-synuclein (α-syn) accumulation, which results in both motor and cognitive symptoms. Its occurrence grows with age, with a larger prevalence among males. Despite substantial study, effective medicines to reduce or stop the progression of diseases remain elusive. Interest has grown in examining dietary components, such as caffeine present in coffee, for potential medicinal effects. Epidemiological studies imply a lower incidence of PD with coffee drinking, attributable to caffeine's neuroprotective abilities. Beyond caffeine, coffee constituent like chlorogenic acid and cafestol have anti-Parkinsonian benefits. Moreover, coffee use has been related with variations in gut microbiota composition, which may reduce intestinal inflammation and prevent protein misfolding in enteric nerves, perhaps through the microbiota-gut-brain axis. This review gives a summary of the neuroprotective effects of coffee, investigating both its motor and non-motor advantages in individuals with PD as well as in experimental models of PD. We reviewed some bioactive constituents of coffee, their respective interactions with misfolded α-syn accumulation, and its emerging mechanisms associated to the gut microbiome.

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Aggregation of alpha-Synuclein (αSyn) has been connected to several neurodegenerative diseases, such as Parkinson's disease (PD), dementia with Lewy Bodies (DLB), and multiple system atrophy (MSA), that are collected under the umbrella term synucleinopathies. The membrane binding abilities of αSyn to negatively charged phospholipids have been well described and are connected to putative physiological functions of αSyn. Consequently, αSyn-related neurodegeneration has been increasingly connected to changes in lipid metabolism and membrane lipid composition. Indeed, αSyn aggregation has been shown to be triggered by the presence of membranes in vitro, and some genetic risk factors for PD and DLB are associated with genes coding for proteins directly involved in lipid metabolism. At the same time, αSyn aggregation itself can cause alterations of cellular lipid composition and brain samples of patients also show altered lipid compositions. Thus, it is likely that there is a reciprocal influence between cellular lipid composition and αSyn aggregation, which can be further affected by environmental or genetic factors and ageing. Little is known about lipid changes during physiological ageing and regional differences of the lipid composition of the aged brain. In this review, we aim to summarise our current understanding of lipid changes in connection to αSyn and discuss open questions that need to be answered to further our knowledge of αSyn related neurodegeneration.

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Parkinson's disease (PD) is a degenerative neurological disorder resulting from the death of dopaminergic neurons, which, in turn, results in impaired motor and cognitive functions. Early diagnosis is important in achieving a good prognosis for PD. Currently, the only approved way to diagnose PD is through medical history, current symptoms, and neurological examination. This, however, can only happen after PD progresses far enough in patients. Biomarkers in cerebrospinal fluid (CSF) and blood plasma, however, may provide insight into the early progress of PD and potentially concurrent dementia, which can also aid in the development of novel treatments. Specifically, this systematic review explores alpha-synuclein (α-syn) and tubulin-associated unit (Tau) proteins and analyzes their potential roles as biomarkers while also touching on nilotinib and immunotherapy as potential treatment options. PubMed, PubMed Central (PMC), Medline, and Cochrane Library serve as the databases for relevant literature, upon which eligibility criteria and quality checks - Assessment of Multiple Systematic Review (AMSTAR) tool, Newcastle-Ottawa Quality Assessment Scale, Cochrane risk-of-bias assessment 2 (RoB2), and Scale for the Assessment of Narrative Review (SANRA) - were applied. The remaining literature examines the various aspects of PD and Parkinson's disease dementia (PDD) and associated biomarkers. From 10 studies, 2,361 participants, both PD patients and healthy controls (HCs), were assessed and compared. Various assessment scales, such as the Unified Parkinson's Disease Rating Scale part III (UPDRS III), were used to ascertain the severity or progression of PD in patients while also seeking a noticeable correlation with α-syn and total Tau (t-Tau). The lack of standardized clinical testing has led to conflicting reports. Thus, while the articles generally agree on the potential efficacy of α-syn and Tau protein analysis in the diagnosis, prognosis, and treatment of PD and PDD, they also argue for further testing and trials.

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Parkinson's disease (PD) is a common multisystem neurodegenerative disorder affecting 1% of the population over the age of 60 years. The main neuropathological features of PD are the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the presence of alpha synuclein (αSyn)-rich Lewy bodies both manifesting with classical motor signs. αSyn has emerged as a key protein in PD pathology as it can spread through synaptic networks to reach several anatomical regions of the body contributing to the appearance of non-motor symptoms (NMS) considered prevalent among individuals prior to PD diagnosis and persisting throughout the patient's life. NMS mainly includes loss of taste and smell, constipation, psychiatric disorders, dementia, impaired rapid eye movement (REM) sleep, urogenital dysfunction, and cardiovascular impairment. This review summarizes the more recent findings on the impact of αSyn deposits on several prodromal NMS and emphasizes the importance of early detection of αSyn toxic species in biofluids and peripheral biopsies as prospective biomarkers in PD.

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The retina is increasingly recognised as a potential source of biomarkers for neurodegenerative diseases. Hallmark protein aggregates in the retinal neuronal tissue could be imaged through light non-invasively. Post-mortem studies have already shown the presence of specific hallmark proteins in Alzheimer's disease, primary tauopathies, synucleinopathies and frontotemporal lobar degeneration. This study aims to assess proteinopathy in a post-mortem cohort with different neurodegenerative diseases and assess the presence of the primary pathology in the retina. Post-mortem eyes were collected in collaboration with the Netherlands Brain Bank from donors with Alzheimer's disease (n = 17), primary tauopathies (n = 8), synucleinopathies (n = 27), frontotemporal lobar degeneration (n = 8), mixed pathology (n = 11), other neurodegenerative diseases (n = 6), and cognitively normal controls (n = 25). Multiple cross sections of the retina and optic nerve tissue were immunostained using antibodies against pTau Ser202/Thr205 (AT8), amyloid-beta (4G8), alpha-synuclein (LB509), pTDP-43 Ser409/410 and p62-lck ligand (p62) and were assessed for the presence of aggregates and inclusions. pTau pathology was observed as a diffuse signal in Alzheimer's disease, primary tauopathies and controls with Alzheimer's disease neuropathological changes. Amyloid-beta was observed in the vessel wall and as cytoplasmic granular deposits in all groups. Alpha-synuclein pathology was observed as Lewy neurites in the retina in synucleinopathies associated with Lewy pathology and as oligodendroglial cytoplasmic inclusions in the optic nerve in multiple system atrophy. Anti-pTDP-43 generally showed typical neuronal cytoplasmic inclusion bodies in cases with frontotemporal lobar degeneration with TDP-43 and also in cases with later stages of limbic-associated TDP-43 encephalopathy. P62 showed inclusion bodies similar to those seen with anti-pTDP-43. Furthermore, pTau and alpha-synuclein pathology were significantly associated with increasing Braak stages for neurofibrillary tangles and Lewy bodies, respectively. Mixed pathology cases in this cohort consisted of cases (n = 6) with high Braak LB stages (> 4) and low or moderate AD pathology, high AD pathology (n = 1, Braak NFT 6, Thal phase 5) with moderate LB pathology, or a combination of low/moderate scores for different pathology scores in the brain (n = 4). There were no cases with advanced co-pathologies. In seven cases with Braak LB ≥ 4, LB pathology was observed in the retina, while tau pathology in the retina in the mixed pathology group (n = 11) could not be observed. From this study, we conclude that the retina reflects the presence of the major hallmark proteins associated with neurodegenerative diseases. Although low or moderate levels of copathology were found in the brains of most cases, the retina primarily manifested protein aggregates associated with the main neurodegenerative disease. These findings indicate that with appropriate retinal imaging techniques, retinal biomarkers have the potential to become highly accurate indicators for diagnosing the major neurodegenerative diseases of the brain.

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Parkinson's disease is one of the vital neurodegenerative ailments attributed to a rise in Alpha-synuclein proteins leading to the advancement of motor and cognitive deterioration. Interestingly, in PD lncRNAs, miRNAs and siRNAs are also key regulators of SNCA and alpha-synuclein aggregation. This review will focus on the roles of these three types of small RNAs in trebling the development of PD through regulating SNCA expression or alpha-synuclein protein mediating the RNA from acting. Parkinson's disease is defined by the build-up of alpha-synuclein protein resulting predominantly from the elevated expression level of the SNCA gene. Non-coding RNAs have gained broad appeal as fundamental modulators of gene expression and protein aggregation dynamics, with significant implications on the aetiology of PD. LncRNAs modulate SNCA transcription and edit epigenetic modifications, while miRNA target mRNA is involved in the stability and translation of count alpha-synuclein. Considering all these data, siRNAs can achieve the precise gene silencing effect that directly induces the downregulation of SNCA mRNA. This review also summarizes some recent reports about the interaction between these ncRNAs with the SNCA gene and alpha-synuclein protein, each through its independent in addition to synergistic mechanisms. This review highlights the possibility of therapeutic interventions to perturb SNCA expression to prevent alpha-synuclein aggregation via targeting ncRNAs that might be spun off novel drug development for PD.

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