Α-synuclein Fibrils Research Articles

Synaptic Neurofilaments and GluN1-Neurofilament Light Chain Interaction in Experimental Models of α-Synucleinopathies

Introduction: Although neurofilaments are mainly expressed in large caliber myelinated axons, recent evidence supports the existence of a specific synaptic pool, where neurofilament light chain (NfL) has been proposed to stabilize NMDA receptor (NMDAR) at postsynaptic membrane through a direct interaction with the GluN1 subunit. Here, we assessed the expression and synaptic abundance of neurofilaments and their interaction with NMDAR in experimental α-synucleinopathy models. Methods: We used confocal imaging and biochemical approaches to confirm NMDAR-NfL interaction at synapses. Western blotting in purified fractions and co-immunoprecipitation assays were then performed to assess synaptic neurofilament expression and GluN1-NfL interaction in (i) α-synuclein pre-formed fibrils (α-syn PFF)-treated hippocampal neuronal cultures and (ii) mice intrastriatally injected with α-syn-PFF. Results: We identified the existence of a direct protein-protein interaction between NMDAR and NfL endogenously expressed in neurons. Our findings showed increased striatal GluN1-NfL interaction levels at early phases of α-syn PFF-treated mice compared to controls (NfL/GluN1 optical density: α-syn PFF 0.71 ± 0.04; controls 0.48 ± 0.03; t(9) = 4.67; p = 0.001). In agreement with this observation, we found that NfL levels are increased in striatal postsynaptic fractions of α-syn PFF-treated mice (normalized optical density: α-syn PFF 1.86 ± 0.14; controls 1.34 ± 0.13; t(18) = 2.70; p = 0.015). Conclusions: Our results demonstrate alterations of striatal synaptic neurofilament pool in α-synucleinopathy models and open the way to further investigations evaluating a potential role of neurofilament dysregulation in explaining glutamatergic synaptic dysfunction observed in α-synucleinopathies such as Parkinson’s disease.

Synthetic Peucedanocoumarin IV Prevents α-Synuclein Neurotoxicity in an Animal Model of Parkinson's Disease.

Pathological protein inclusion formation and propagation are the main causes of neuronal dysfunction in diverse neurodegenerative diseases; therefore, current disease-modifying therapeutic strategies have targeted this disease protein aggregation process. Recently, we reported that peucedanocoumarin III (PCiii) is a promising therapeutic compound with the ability to disaggregate α-synuclein inclusion and protect dopaminergic neurons in Parkinson’s disease (PD). Here, we found that trans-4′-acetyl-3′-tigloylkhellactone (racemic peucedanocoumarin IV [PCiv]), a structural isomer of PCiii with a higher synthetic yield presented a strong anti-aggregate activity to a degree comparable to that of PCiii. PCiv retained effective inhibitory function against β-sheet aggregate-mimic β23 cytotoxicities and potently prevented α-synucleinopathy in α-synuclein preformed fibril (PFF)-treated mice cortical neurons. In detailed pharmacokinetic profiling of PCiv, oral administration of PCiv in rats exhibited an approximately 97-min half-life and 10% bioavailability. Moreover, tissue distribution analysis revealed favorable profiles of brain penetration with a 6.4 brain-to-plasma concentration ratio. The therapeutic efficacy of PCiv was further evaluated in a sporadic PD mouse model with a combinatorial co-injection of α-synuclein preformed fibril and recombinant adeno-associated virus expressing α-synuclein. Motor dysfunctions induced in this combinatorial α-synucleinopathy PD mouse model was almost completely rescued by PCiv diet administration, and this therapeutic effect is consistent with the marked prevention of dopaminergic neuron loss and suppression of α-synuclein aggregation. Taken together, our translational study suggests that PCiv is advantageous as a therapeutic agent for neurodegenerative diseases, especially with its good synthetic yield, high brain distribution, and anti-aggregate activity. PCiv may be useful in the management of α-synuclein inclusion formation and propagation at different stages of PD.

Ascendance of Abnormal α-synuclein Fibrils Through the Vagal Nerve in Parkinson's Disease

Parkinson's disease (PD) is caused by the abnormal accumulation of α-synuclein fibrils (Lewy bodies) in the substantia nigra. The α-synuclein fibrils behave like prions. Autopsy shows that α-synucleinopathy ascends from the brain stem to the substantia nigra. In patients with PD, the α-synuclein pathology is frequently observed in the intestinal neural plexus. In animal models, injection of α-synuclein fibrils in the gastric wall or the peritoneum caused immunostaining for aggregated α-synuclein fibrils in the substantia nigra. In Finland and Sweden, truncal vagotomy, but not partial vagotomy, reduced the chance of developing PD to 50% in 35 years. Of note, not all patients with PD show ascending α-synuclein pathology in the brain and that truncal vagotomy reduced the chance of developing PD to half. Thus, α-synucleinopathy is likely to start from the intestinal neural plexus and ascends through the vagal nerve to the substantia nigra in at least 50% of patients with PD. Additionally, short-chain fatty acids (SCFA)-producing intestinal bacteria are reduced in PD. Although the underlying mechanisms are currently under investigation, the vagal nerve also senses SCFA and transmits signals to the central nervous system. This pathway is likely to be compromised by gut dysbiosis in PD.

A small molecule toll-like receptor antagonist rescues α-synuclein fibril pathology

The propagation and accumulation of pathological α-synuclein protein is thought to underlie the clinical symptoms of the neurodegenerative movement disorder Parkinson’s disease (PD). Consequently, there is significant interest in identifying the mechanisms that contribute to α-synuclein pathology, as these may inform therapeutic targets for the treatment of PD. One protein that appears to contribute to α-synuclein pathology is the innate immune pathogen recognition receptor, toll-like receptor 2 (TLR2). TLR2 is expressed on neurons, and its activation results in the accumulation of α-synuclein protein; however, the precise mechanism by which TLR2 contributes to α-synuclein pathology is unclear. Herein we demonstrate using human cell models that neuronal TLR2 activation acutely impairs the autophagy lysosomal pathway and markedly potentiates α-synuclein pathology seeded with α-synuclein preformed fibrils. Moreover, α-synuclein pathology could be ameliorated with a novel small molecule TLR2 inhibitor, including in induced pluripotent stem cell-derived neurons from a patient with PD. These results provide further insight into how TLR2 activation may promote α-synuclein pathology in PD and support that TLR2 may be a potential therapeutic target for the treatment of PD.

Direct Demonstration of Seed Size-Dependent α-Synuclein Amyloid Amplification.

The size of amyloid seeds is known to modulate their autocatalytic amplification and cellular toxicity. However, the seed size-dependent secondary nucleation mechanism, toxicity, and disease-associated biological processes mediated by α-synuclein (α-Syn) fibrils are largely unknown. Using the cellular model and in vitro reconstitution, we showed that the size of α-Syn fibril seeds dictates not only their cellular internalization and associated cell death but also the distinct mechanisms of fibril amplification pathways involved in the pathological conformational change of α-Syn. Specifically, small fibril seeds showed elongation possibly through monomer addition at the fibril termini, whereas longer fibrils template the fibril amplification by surface-mediated nucleation as demonstrated by super-resolution microscopy. The distinct mechanism of fibril amplification and cellular uptake along with toxicity suggest that breakage of fibrils into seeds of different sizes determines the underlying pathological outcome of synucleinopathies.

Effect of bacteriophage-encoded chaperonins on amyloid transformation of α-synuclein

Controversial information about the role of chaperonins in the amyloid transformation of proteins and, in particular, α-synuclein, requires a more detailed study of the observed effects due to the structure and functional state of various chaperonins. In this work, two types of phage chaperonins, the double-ring EL and the single-ring OBP, were shown to stimulate α-synuclein fibrillation in an ATP-dependent manner. Chaperonin morphology does not affect the stimulation of α-synuclein amyloid transformation. However, the ATP-dependent effect of single- and double-ring chaperonins on this process differs, which can lead to different morphology of resulting fibrils. Fibril formation seems to proceed without substrate encapsulation in the internal cavity of chaperonin, because of the structural features of phage chaperonins and their ability to function without co-chaperonins. In the absence of ATP, both chaperonins, on the contrary, completely prevent α-synuclein amyloid transformation, which provides the possibility of their use as anti-amyloid agents, in the form of incomplete molecules or mutants with suppressed ATPase activity.

Heparan sulfate proteoglycans mediate prion-like α-synuclein toxicity in Parkinson's in vivo models.

Parkinson's disease (PD) is a debilitating neurodegenerative disorder characterized by progressive motor decline and the aggregation of α-synuclein protein. Growing evidence suggests that α-synuclein aggregates may spread from neurons of the digestive tract to the central nervous system in a prion-like manner, yet the mechanisms of α-synuclein transmission and neurotoxicity remain poorly understood. Animal models that are amenable to high-throughput investigations are needed to facilitate the discovery of disease mechanisms. Here we describe the first Caenorhabditis elegans models in which feeding with α-synuclein preformed fibrils (PFFs) induces dopaminergic neurodegeneration, prion-like seeding of aggregation of human α-synuclein expressed in the host, and an associated motor decline. RNAi-mediated knockdown of the C. elegans syndecan sdn-1, or other enzymes involved in heparan sulfate proteoglycan synthesis, protected against PFF-induced α-synuclein aggregation, motor dysfunction, and dopamine neuron degeneration. This work offers new models by which to investigate gut-derived α-synuclein spreading and propagation of disease.

A sudden collapse: the disaggregation of amyloid fibres.

A hallmark of age-related neurodegenerative diseases is the presence of highly stable protein aggregates, also known as amyloid fibres. As these fibres are strongly associated with disease, it is thought that clearance of these fibres could delay or prevent disease progression. In this issue of The EMBO Journal, Beton et al unravel how the Hsc70/DNAJB1/Apg2 disaggregase machinery disassembles amyloid fibres, using α-synuclein fibrils implicated in Parkinson's Disease as a model substrate.

Genetically Encoded Aryl Alkyne for Raman Spectral Imaging of Intracellular α-Synuclein Fibrils

α-Synuclein (α-syn) is an intrinsically disordered protein involved in a group of diseases collectively termed synucleinopathies, characterized by the aggregation of α-syn to form insoluble, β-sheet-rich amyloid fibrils. Amyloid fibrils are thought to contribute to disease progression through cell-to-cell transmission, templating and propagating intracellular amyloid formation. Raman spectral imaging offers a direct characterization of protein secondary structure via the amide-I backbone vibration; however, specific detection of α-syn conformational changes against the background of other cellular components presents a challenge. Here, we demonstrate the ability to unambiguously identify cellularly internalized α-syn fibrils by coupling Raman spectral imaging with the use of a genetically encoded aryl alkyne, 4-ethynyl-l-phenylalanine (FCC), through amber codon suppression. The alkyne stretch (CC) of FCC provides a spectrally unique molecular vibration without interference from native biomolecules. Cellular uptake of FCC-α-syn fibrils formed in vitro was visualized in cultured human SH-SY5Y neuroblastoma cells by Raman spectral imaging. Fibrils appear as discrete cytosolic clusters of varying sizes, found often at the cellular periphery. Raman spectra of internalized fibrils exhibit frequency shifts and spectral narrowing relative to in vitro fibrils, highlighting the environmental sensitivity of the alkyne vibration. Interestingly, spectral analysis reveals variations in lipid and protein recruitment to these aggregates, and in some cases, secondary structural changes in the fibrils are observed. This work sets the groundwork for future Raman spectroscopic investigations using a similar approach of an evolved aminoacyl-tRNA synthetase/tRNA pair to incorporate FCC into endogenous amyloidogenic proteins to monitor their aggregation in cells.

Rapid macropinocytic transfer of α-synuclein to lysosomes.

The nervous system spread of alpha-synuclein fibrils is thought to cause Parkinson's disease (PD) and other synucleinopathies; however, the mechanisms underlying internalization and cellular spread are enigmatic. Here, we use confocal and superresolution microscopy, subcellular fractionation, and electron microscopy (EM) of immunogold-labeled α-synuclein preformed fibrils (PFFs) to demonstrate that this form of the protein undergoes rapid internalization and is targeted directly to lysosomes in as little as 2min. Uptake of PFFs is disrupted by macropinocytic inhibitors and circumvents classical endosomal pathways. Immunogold-labeled PFFs are seen at the highly curved inward edge of membrane ruffles, in newly formed macropinosomes, in multivesicular bodies and in lysosomes. While most fibrils remain in lysosomes, a portion is transferred to neighboring naive cells along with markers of exosomes. These data indicate that PFFs use a unique internalization mechanism as a component of cell-to-cell propagation.

Embelin and levodopa combination therapy for improved Parkinson's disease treatment.

Parkinson’s disease (PD), a progressive neurodegenerative disorder, affects dopaminergic neurons. Oxidative stress and gut damage play critical roles in PD pathogenesis. Inhibition of oxidative stress and gut damage can prevent neuronal death and delay PD progression. The objective of this study was to evaluate the therapeutic effect of embelin or the combination with levodopa (LD) in a rotenone-induced PD mouse model. At the end of experimentation, the mice were sacrificed and the midbrain was used to evaluate various biochemical parameters, such as nitric oxide, peroxynitrite, urea, and lipid peroxidation. In the substantia nigra (midbrain), tyrosine hydroxylase (TH) expression was examined by immunohistochemistry, and Nurr1 expression was evaluated by western blotting. Gut histopathology was evaluated on tissue sections stained with hematoxylin and eosin. In silico molecular docking studies of embelin and α-synuclein (α-syn) fibrils were also performed. Embelin alone or in combination with LD ameliorated oxidative stress and gut damage. TH and Nurr1 protein levels were also significantly restored. Docking studies confirmed the affinity of embelin toward α-syn. Taken together, embelin could be a promising drug for the treatment of PD, especially when combined with LD.

Gut Microbiota: A Novel Therapeutic Target for Parkinson's Disease.

Parkinson’s disease (PD) is the second most common neurodegenerative disease characterized by motor dysfunction. Growing evidence has demonstrated that gut dysbiosis is involved in the occurrence, development and progression of PD. Numerous clinical trials have identified the characteristics of the changed gut microbiota profiles, and preclinical studies in PD animal models have indicated that gut dysbiosis can influence the progression and onset of PD via increasing intestinal permeability, aggravating neuroinflammation, aggregating abnormal levels of α-synuclein fibrils, increasing oxidative stress, and decreasing neurotransmitter production. The gut microbiota can be considered promising diagnostic and therapeutic targets for PD, which can be regulated by probiotics, psychobiotics, prebiotics, synbiotics, postbiotics, fecal microbiota transplantation, diet modifications, and Chinese medicine. This review summarizes the recent studies in PD-associated gut microbiota profiles and functions, the potential roles, and mechanisms of gut microbiota in PD, and gut microbiota-targeted interventions for PD. Deciphering the underlying roles and mechanisms of the PD-associated gut microbiota will help interpret the pathogenesis of PD from new perspectives and elucidate novel therapeutic strategies for PD.

Bis-chalcone polyphenols with potential preventive and therapeutic effects on PD: Design, synthesis and in vitro disaggregation activity against α-synuclein oligomers and fibrils

α-Syn fibrils, which are neurotoxic, play a key role in the development of PD. Maintaining α-Syn proteostasis by suitable molecule ligands is an effective approach to prevent aggregation. Disintegrating the existed oligomers and fibrils into individual α-Syn by small molecular compounds is a more efficient way to treat PD. This work designed and synthesized two series of bis-chalcone polyphenol compounds, which possess a sheet-like conjugated skeleton with stronger H-bonding, π-stacking, and hydrophobic interaction with α-Syn protein residues. Some compounds have shown high α-Syn aggregation inhibitory activities in vitro with IC50 down to 0.64 μM. The inhibition goes throughout the aggregation process from the lag to the stationary phase by stabilizing α-Syn proteostasis conformation and preventing β-sheets aggregation, especially in the lag phase. In addition, the inhibitors present good disintegration abilities against the existed α-Syn oligomers and fibrils. The preliminary mechanism studies suggest that the inhibitors could quickly and randomly bind to the specific site closed to the β-sheet domain in the fibril, resulting in unstable and collapse of the protein fibril and yielding a complex system with aggregates of different sizes and monomers. The inhibitors, which could penetrate the blood-brain barrier, are expected to develop into the drug candidates for PD targeting α-Syn aggregation.

Structural Insights of Fe3+ Induced α-synuclein Fibrillation in Parkinson’s Disease

Amyloid aggregation of α-synuclein (α-syn) in Lewy bodies (LBs) is the pathological hallmark of Parkinson’s disease (PD). Iron, especially Fe3+, is accumulated in substantia nigra of PD patients and co-deposited with α-syn in LBs. However, how Fe3+ modulates α-syn fibrillation at molecular level remains unclear. In this study, we found that Fe3+ can promote α-syn fibrillation at low concentration while inhibit its fibrillation at high concentration. NMR titration study shows poor interaction between α-syn monomer and Fe3+. Instead, we found that Fe3+ binds to α-syn fibrils. By using cryo-electron microscopy (cryo-EM), we further determined the atomic structure of α-syn fibril in complex with Fe3+ at the resolution of 2.7 Å. Strikingly, two extra electron densities adjacent to His50 and Glu57 were observed as putative binding sites of Fe3+ and water molecules, suggesting that Fe3+ binds to the negative cleft of the fibril and stabilizes the fibril structure for promoting α-syn aggregation. Further mutagenesis study shows mutation of His50 abolishes the Fe3+-facilitated fibrillation of α-syn. Our work illuminates the structural basis of the interaction of Fe3+ and α-syn in both monomeric and fibrillar forms, and sheds light on understanding the pathological role of Fe3+ in α-syn aggregation in PD.

α-Synuclein fibrils explore actin-mediated macropinocytosis for cellular entry into model neuroblastoma neurons.

Alpha-synuclein (α-Syn), an intrinsically disordered protein (IDP), is associated with neurodegenerative disorders, including Parkinson's disease (PD or other α-synucleinopathies. Recent investigations propose the transmission of α-Syn protein fibrils, in a prion-like manner, by entering proximal cells to seed further fibrillization in PD. Despite the recent advances, the mechanisms by which extracellular protein aggregates internalize into the cells remain poorly understood. Using a simple cell-based model of human neuroblastoma-derived differentiated neurons, we present the cellular internalization of α-Syn PFF to check cellular uptake and recycling kinetics along with the standard endocytic markers Transferrin (Tf) marking clathrin-mediated endocytosis (CME) and Galectin3 (Gal3) marking clathrin-independent endocytosis (CIE). Specific inhibition of endocytic pathways using chemical inhibitors reveals no significant involvement of CME, CIE and caveolae-mediated endocytosis (CvME). A substantial reduction in cellular uptake was observed after perturbation of actin polymerization and treatment with macropinosomes inhibitor. Our results show that α-Syn PFF mainly internalizes into the SH-SY5Y cells and differentiated neurons via the macropinocytosis pathway. The elucidation of the molecular and cellular mechanism involved in the α-Syn PFF internalization will help improve the understanding of α-synucleinopathies including PD, and further design specific inhibitors for the same.

Quiescent Elongation of α-Synuclein Pre-form Fibrils Under Different Solution Conditions.

The intracellular aggregation of α-synuclein in neurons/glia is considered to be a key step in the pathogenesis of synucleinopathy [including Parkinson’s disease (PD), dementia with Lewy body (DLB), multiple system atrophy (MSA), etc.]. Increasing evidence indicates that the initial pathological α-synuclein aggregates can replicate themselves and propagate in a “seeding” manner to multiple areas of the brain and even to peripheral tissue, which makes it the most important biomarker for the diagnosis of synucleinopathies in recent years. The amplification and propagation capabilities of α-synuclein aggregates are very similar to those of prion-like diseases, which are based on the inherent self-recruitment capabilities of existing misfolded proteins. In vitro, the rapid recruitment process can be reproduced in a simplified model by adding a small amount of α-synuclein pre-formed fibrils to the monomer solution as fibril seeds, which may partially reveal the properties of α-synuclein aggregates. In this study, we explored the elongation rate of α-synuclein pre-formed fibrils under a quiescent incubation condition (rather than shaking/agitating). By using the ThT fluorescence assay, we compared and quantified the elongation fluorescence curves to explore the factors that affect fibril elongation. These factors include proteins’ concentration, temperature, NaCl strength, SDS, temperature pretreatment, and so on. Our work further describes the elongation of α-synuclein fibrils under quiescent incubation conditions. This may have important implications for the in vitro amplification and preservation of α-synuclein aggregates to further understand the prion-like transmission mechanism of PD.

Analysis of hemisphere-dependent effects of unilateral intrastriatal injection of α-synuclein pre-formed fibrils on mitochondrial protein levels, dynamics, and function

Genetic and neuropathological evidence strongly implicates aberrant forms of α-synuclein in neurodegeneration. Antibodies specific for α-synuclein phosphorylated at serine 129 (pS129) are selective for the pathological protein aggregates that are characteristic of Parkinson’s disease (PD) and other synucleinopathies, such as dementia with Lewy bodies (DLB) and multiple system atrophy (MSA). Although the etiology of most synucleinopathies remains uncertain, a large body of evidence points to mitochondrial dysfunction. The recent development of animal models based on intracranial injection of α-synuclein pre-formed fibrils (PFFs) has provided a valuable experimental system in which to study the spread and neurotoxicity of α-synuclein aggregates, yet the effects of PFF-induced protein aggregates on mitochondrial function and dynamics have not been rigorously examined in vivo. To help fill this knowledge gap, we injected the striatum of mice unilaterally with well-characterized small length (< 30 nm) PFFs or monomeric α-synuclein control and measured the distribution and extent of pS129 α-synuclein-immunoreactive aggregates, the loss of tyrosine hydroxylase-immunoreactive neurons in the substantia nigra, the abundance of mitochondrial proteins, and the activity of mitochondrial respiratory chain components at 3 months and 6 months post injection. Intrastriatal injection of small length PFFs, but not monomeric α-synuclein control, induced robust pS129 α-synuclein immunoreactive inclusions in the cortex, ventral midbrain, and striatum, as well as in rarely reported brain regions, such as the hippocampus, as early as 3 months post injection. Significant loss of nigral tyrosine hydroxylase-immunoreactive neurons was observed in the PFF-injected hemisphere at 3 months and 6 months post injection. The unilateral striatal injection of small length PFFs also caused hemisphere-dependent and treatment-dependent changes in the cortical levels of mitochondrial proteins such as VDAC1, COX-IV, and DRP-1, as well as functional changes in mitochondrial complex I activity in the contralateral striatum. Together, these data demonstrate that intrastriatal injection of mice with small length PFFs induces extensive bilateral protein aggregates, significant unilateral nigral cell loss, and altered contralateral levels of mitochondrial proteins and respiratory chain activity. Our data suggest this animal model may be useful for studying the role of mitochondrial dysfunction in α-synucleinopathies, for studying the hemisphere-dependent effects of α-synuclein aggregates, and for testing neuroprotective therapies that target mitochondrial dysfunction and protein aggregation.

A breakdown in microglial metabolic reprogramming causes internalization dysfunction of α-synuclein in a mouse model of Parkinson’s disease

BackgroundThe α-synuclein released by neurons activates microglia, which then engulfs α-synuclein for degradation via autophagy. Reactive microglia are a major pathological feature of Parkinson’s disease (PD), although the exact role of microglia in the pathogenesis of PD remains unclear. Transient receptor potential vanilloid type 1 (TRPV1) channels are nonselective cation channel protein that have been proposed as neuroprotective targets in neurodegenerative diseases.MethodsUsing metabolic profiling, microglia energy metabolism was measured including oxidative phosphorylation and aerobic glycolysis. The mRFP-GFP-tagged LC3 reporter was introduced to characterize the role of TRPV1 in microglial autophagy. α-synuclein preformed fibril (PFF) TRPV1flox/flox; Cx3cr1Cre mouse model of sporadic PD were employed to study the capacity of TRPV1 activation to attenuate neurodegeneration process.ResultsWe found that acute exposure to PFF caused microglial activation as a result of metabolic reprogramming from oxidative phosphorylation to aerobic glycolysis via the AKT–mTOR–HIF-1α pathway. Activated microglia eventually reached a state of chronic PFF-tolerance, accompanied by broad defects in energy metabolism. We showed that metabolic boosting by treatment with the TRPV1 agonist capsaicin rescued metabolic impairments in PFF-tolerant microglia and also defects in mitophagy caused by disruption of the AKT–mTOR–HIF-1α pathway. Capsaicin attenuated phosphorylation of α-synuclein in primary neurons by boosting phagocytosis in PFF-tolerant microglia in vitro. Finally, we found that behavioral deficits and loss of dopaminergic neurons were accelerated in the PFF TRPV1flox/flox; Cx3cr1Cre mouse model of sporadic PD. We identified defects in energy metabolism, mitophagy and phagocytosis of PFF in microglia from the substantia nigra pars compacta of TRPV1flox/flox; Cx3cr1Cre mice.ConclusionThe findings suggest that modulating microglial metabolism might be a new therapeutic strategy for PD.

Tau accelerates α-synuclein aggregation and spreading in Parkinson’s disease

The aggregation and prion-like propagation of α-synuclein are involved in the pathogenesis of Parkinson's disease. However, the underlying mechanisms regulating the assembly and spreading of α-synuclein fibrils remain poorly understood. Tau co-deposits with α-synuclein in the brains of Parkinson's disease patients, suggesting a pathological interplay between them. Here we show that tau interacts with α-synuclein and accelerates its aggregation. Compared with pure α-synuclein fibrils, the tau-modified α-synuclein fibrils show enhanced seeding activity, inducing mitochondrial dysfunction, synaptic impairment and neurotoxicity in vitro. Injection of the tau-modified α-synuclein fibrils into the striatum of mice induces more severe α-synuclein pathology, motor dysfunction and cognitive impairment when compared with the mice injected with pure α-synuclein fibrils. Knockout of tau attenuates the propagation of α-synuclein pathology and Parkinson's disease-like symptoms both in mice injected with α-syn fibrils and α-syn A53T transgenic mice. In conclusion, tau facilitates α-synuclein aggregation and propagation in Parkinson's disease.

Hybrids of polyphenolic acids and xanthone, the potential preventive and therapeutic effects on PD: Design, synthesis, in vitro anti-aggregation of α-synuclein, and disaggregation against the existed α-synuclein oligomer and fibril

The misfolding and aggregation of α-Syn are the central mechanism linking and facilitating the other pathological mechanisms of PD. Maintaining α-Syn proteostasis by suitable inhibitors is an effective means to prevent PD. Disintegrating the neurotoxic oligomers and fibrils into the normal functional α-Syn by inhibitors is a more efficient way for PD treatment. This work synthesized two series hybrids of polyphenolic acids and xanthone. The hybrids possess a sheet-like conjugated skeleton and higher binding energies with α-Syn residues. Some compounds present well α-Syn aggregation inhibitory activities in vitro (IC50 down to 2.58 μM). The inhibitory action goes throughout the aggregation process from lag to the stationary phase by stabilizing α-Syn proteostasis conformation and preventing β-sheets aggregation. The candidate compounds with appropriate LogP values (2.02–3.11) present good disintegration abilities against the existed α-Syn oligomers and fibrils. The preliminary mechanism studies suggest that the inhibitors could quickly and randomly bind to the specific site closed to the β-sheet domain in the fibril, resulting in unstable and collapse of the protein fibril, yielding a complex system with aggregates of different sizes and monomers.