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Lancet (London, England) Jan 2024Parkinson's disease is a progressive neurodegenerative condition associated with the deposition of aggregated α-synuclein. Insights into the pathogenesis of Parkinson's... (Review)
Review
Parkinson's disease is a progressive neurodegenerative condition associated with the deposition of aggregated α-synuclein. Insights into the pathogenesis of Parkinson's disease have been derived from genetics and molecular pathology. Biochemical studies, investigation of transplanted neurons in patients with Parkinson's disease, and cell and animal model studies suggest that abnormal aggregation of α-synuclein and spreading of pathology between the gut, brainstem, and higher brain regions probably underlie the development and progression of Parkinson's disease. At a cellular level, abnormal mitochondrial, lysosomal, and endosomal function can be identified in both monogenic and sporadic Parkinson's disease, suggesting multiple potential treatment approaches. Recent work has also highlighted maladaptive immune and inflammatory responses, possibly triggered in the gut, that accelerate the pathogenesis of Parkinson's disease. Although there are currently no disease-modifying treatments for Parkinson's disease, we now have a solid basis for the development of rational neuroprotective therapies that we hope will halt the progression of this disabling neurological condition.
Topics: Animals; Humans; Parkinson Disease; alpha-Synuclein; Brain; Models, Animal; Neurons
PubMed: 38245249
DOI: 10.1016/S0140-6736(23)01478-2 -
Neuron Aug 2023The circadian clock protein BMAL1 modulates glial activation and amyloid-beta deposition in mice. However, the effects of BMAL1 on other aspects of neurodegenerative...
The circadian clock protein BMAL1 modulates glial activation and amyloid-beta deposition in mice. However, the effects of BMAL1 on other aspects of neurodegenerative pathology are unknown. Here, we show that global post-natal deletion of Bmal1 in mouse tauopathy or alpha-synucleinopathy models unexpectedly suppresses both tau and alpha-synuclein (αSyn) aggregation and related pathology. Astrocyte-specific Bmal1 deletion is sufficient to prevent both αSyn and tau pathology in vivo and induces astrocyte activation and the expression of Bag3, a chaperone critical for macroautophagy. Astrocyte Bmal1 deletion enhances phagocytosis of αSyn and tau in a Bag3-dependent manner, and astrocyte Bag3 overexpression is sufficient to mitigate αSyn spreading in vivo. In humans, BAG3 is increased in patients with AD and is highly expressed in disease-associated astrocytes (DAAs). Our results suggest that early activation of astrocytes via Bmal1 deletion induces Bag3 to protect against tau and αSyn pathologies, providing new insights into astrocyte-specific therapies for neurodegeneration.
Topics: Animals; Humans; Mice; Adaptor Proteins, Signal Transducing; alpha-Synuclein; Amyloid beta-Peptides; Apoptosis Regulatory Proteins; ARNTL Transcription Factors; Astrocytes; Synucleinopathies; tau Proteins; Tauopathies
PubMed: 37315555
DOI: 10.1016/j.neuron.2023.05.006 -
Science Advances Nov 2023Recent studies have identified increasing levels of nanoplastic pollution in the environment. Here, we find that anionic nanoplastic contaminants potently precipitate...
Recent studies have identified increasing levels of nanoplastic pollution in the environment. Here, we find that anionic nanoplastic contaminants potently precipitate the formation and propagation of α-synuclein protein fibrils through a high-affinity interaction with the amphipathic and non-amyloid component (NAC) domains in α-synuclein. Nanoplastics can internalize in neurons through clathrin-dependent endocytosis, causing a mild lysosomal impairment that slows the degradation of aggregated α-synuclein. In mice, nanoplastics combine with α-synuclein fibrils to exacerbate the spread of α-synuclein pathology across interconnected vulnerable brain regions, including the strong induction of α-synuclein inclusions in dopaminergic neurons in the substantia nigra. These results highlight a potential link for further exploration between nanoplastic pollution and α-synuclein aggregation associated with Parkinson's disease and related dementias.
Topics: Mice; Animals; alpha-Synuclein; Parkinson Disease; Microplastics; Inclusion Bodies; Dopaminergic Neurons
PubMed: 37976362
DOI: 10.1126/sciadv.adi8716 -
Brain : a Journal of Neurology Jan 2024Parkinson's disease is clinically known for the loss of dopaminergic neurons in the substantia nigra pars compacta and accumulation of intraneuronal cytoplasmic...
Parkinson's disease is clinically known for the loss of dopaminergic neurons in the substantia nigra pars compacta and accumulation of intraneuronal cytoplasmic inclusions rich in alpha-synuclein called 'Lewy bodies' and 'Lewy neurites'. Together with dementia with Lewy bodies and multiple system atrophy, Parkinson's disease is part of a group of disorders called synucleinopathies. Currently, diagnosis of synucleinopathies is based on the clinical assessment which often takes place in advanced disease stages. While the causal role of alpha-synuclein aggregates in these disorders is still debatable, measuring the levels, types or seeding properties of different alpha-synuclein species hold great promise as biomarkers. Recent studies indicate significant differences in peptide, protein and RNA levels in blood samples from patients with Parkinson's disease. Seed amplification assays using CSF, blood, skin biopsy, olfactory swab samples show great promise for detecting synucleinopathies and even for discriminating between different synucleinopathies. Interestingly, small extracellular vesicles, such as exosomes, display differences in their cargoes in Parkinson's disease patients versus controls. In this update, we focus on alpha-synuclein aggregation and possible sources of disease-related species released in extracellular vesicles, which promise to revolutionize the diagnosis and the monitoring of disease progression.
Topics: Humans; alpha-Synuclein; Synucleinopathies; Parkinson Disease; Exosomes; Biomarkers
PubMed: 37526295
DOI: 10.1093/brain/awad260 -
Translational Neurodegeneration Aug 2023The accumulation of α-synuclein (α-syn), an essential step in PD development and progression, is observed not only in neurons but also in glia, including astrocytes....
BACKGROUND
The accumulation of α-synuclein (α-syn), an essential step in PD development and progression, is observed not only in neurons but also in glia, including astrocytes. The mechanisms regulating astrocytic α-syn level and aggregation remain unclear. More recently, it has been demonstrated that a part of α-syn spreading occurs through extracellular vesicles (EVs), although it is unknown whether this process is involved in astrocytes of PD. It is known, however, that EVs derived from the central nervous system exist in the blood and are extensively explored as biomarkers for PD and other neurodegenerative disorders.
METHODS
Primary astrocytes were transfected with A53T α-syn plasmid or exposed to α-syn aggregates. The level of astrocyte-derived EVs (AEVs) was assessed by nanoparticle tracking analysis and immunofluorescence. The lysosomal function was evaluated by Cathepsin assays, immunofluorescence for levels of Lamp1 and Lamp2, and LysoTracker Red staining. The Apogee assays were optimized to measure the GLT-1 AEVs in clinical cohorts of 106 PD, 47 multiple system atrophy (MSA), and 103 healthy control (HC) to test the potential of plasma AEVs as a biomarker to differentiate PD from other forms of parkinsonism.
RESULTS
The number of AEVs significantly increased in primary astrocytes with α-syn deposition. The mechanism of increased AEVs was partially attributed to lysosomal dysfunction. The number of α-syn-carrying AEVs was significantly higher in patients with PD than in HC and MSA. The integrative model combining AEVs with total and aggregated α-syn exhibited efficient diagnostic power in differentiating PD from HC with an AUC of 0.915, and from MSA with an AUC of 0.877.
CONCLUSIONS
Pathological α-syn deposition could increase the astrocytic secretion of EVs, possibly through α-syn-induced lysosomal dysfunction. The α-syn-containing AEVs in the peripheral blood may be an effective biomarker for clinical diagnosis or differential diagnosis of PD.
Topics: Humans; alpha-Synuclein; Astrocytes; Parkinson Disease; Multiple System Atrophy; Extracellular Vesicles
PubMed: 37620916
DOI: 10.1186/s40035-023-00372-y -
Brain : a Journal of Neurology Sep 2023The critical role of alpha-synuclein in Parkinson's disease represents a pivotal discovery. Some progress has been made over recent years in identifying... (Review)
Review
The critical role of alpha-synuclein in Parkinson's disease represents a pivotal discovery. Some progress has been made over recent years in identifying disease-modifying therapies for Parkinson's disease that target alpha-synuclein. However, these treatments have not yet shown clear efficacy in slowing the progression of this disease. Several explanations exist for this issue. The pathogenesis of Parkinson's disease is complex and not yet fully clarified and the heterogeneity of the disease, with diverse genetic susceptibility and risk factors and different clinical courses, adds further complexity. Thus, a deep understanding of alpha-synuclein physiological and pathophysiological functions is crucial. In this review, we first describe the cellular and animal models developed over recent years to study the physiological and pathological roles of this protein, including transgenic techniques, use of viral vectors and intracerebral injections of alpha-synuclein fibrils. We then provide evidence that these tools are crucial for modelling Parkinson's disease pathogenesis, causing protein misfolding and aggregation, synaptic dysfunction, brain plasticity impairment and cell-to-cell spreading of alpha-synuclein species. In particular, we focus on the possibility of dissecting the pre- and postsynaptic effects of alpha-synuclein in both physiological and pathological conditions. Finally, we show how vulnerability of specific neuronal cell types may facilitate systemic dysfunctions leading to multiple network alterations. These functional alterations underlie diverse motor and non-motor manifestations of Parkinson's disease that occur before overt neurodegeneration. However, we now understand that therapeutic targeting of alpha-synuclein in Parkinson's disease patients requires caution, since this protein exerts important physiological synaptic functions. Moreover, the interactions of alpha-synuclein with other molecules may induce synergistic detrimental effects. Thus, targeting only alpha-synuclein might not be enough. Combined therapies should be considered in the future.
Topics: Animals; alpha-Synuclein; Animals, Genetically Modified; Disease Models, Animal; Neurons; Parkinson Disease; Humans
PubMed: 37183455
DOI: 10.1093/brain/awad150 -
Cell Stem Cell Jul 2023Human induced pluripotent stem cells (hiPSCs) offer advantages for disease modeling and drug discovery. However, recreating innate cellular pathologies, particularly in...
Human induced pluripotent stem cells (hiPSCs) offer advantages for disease modeling and drug discovery. However, recreating innate cellular pathologies, particularly in late-onset neurodegenerative diseases with accumulated protein aggregates including Parkinson's disease (PD), has been challenging. To overcome this barrier, we developed an optogenetics-assisted α-synuclein (α-syn) aggregation induction system (OASIS) that rapidly induces α-syn aggregates and toxicity in PD hiPSC-midbrain dopaminergic neurons and midbrain organoids. Our OASIS-based primary compound screening with SH-SY5Y cells identified 5 candidates that were secondarily validated with OASIS PD hiPSC-midbrain dopaminergic neurons and midbrain organoids, leading us to finally select BAG956. Furthermore, BAG956 significantly reverses characteristic PD phenotypes in α-syn preformed fibril models in vitro and in vivo by promoting autophagic clearance of pathological α-syn aggregates. Following the FDA Modernization Act 2.0's emphasis on alternative non-animal testing methods, our OASIS can serve as an animal-free preclinical test model (newly termed "nonclinical test") for the synucleinopathy drug development.
Topics: Humans; alpha-Synuclein; Dopaminergic Neurons; Induced Pluripotent Stem Cells; Neuroblastoma; Optogenetics; Parkinson Disease
PubMed: 37339636
DOI: 10.1016/j.stem.2023.05.015 -
Science Translational Medicine Nov 2023Pathologic α-synuclein plays an important role in the pathogenesis of α-synucleinopathies such as Parkinson's disease (PD). Disruption of proteostasis is thought to be...
Pathologic α-synuclein plays an important role in the pathogenesis of α-synucleinopathies such as Parkinson's disease (PD). Disruption of proteostasis is thought to be central to pathologic α-synuclein toxicity; however, the molecular mechanism of this deregulation is poorly understood. Complementary proteomic approaches in cellular and animal models of PD were used to identify and characterize the pathologic α-synuclein interactome. We report that the highest biological processes that interacted with pathologic α-synuclein in mice included RNA processing and translation initiation. Regulation of catabolic processes that include autophagy were also identified. Pathologic α-synuclein was found to bind with the tuberous sclerosis protein 2 (TSC2) and to trigger the activation of the mammalian target of rapamycin (mTOR) complex 1 (mTORC1), which augmented mRNA translation and protein synthesis, leading to neurodegeneration. Genetic and pharmacologic inhibition of mTOR and protein synthesis rescued the dopamine neuron loss, behavioral deficits, and aberrant biochemical signaling in the α-synuclein preformed fibril mouse model and transgenic models of pathologic α-synuclein-induced degeneration. Pathologic α-synuclein furthermore led to a destabilization of the TSC1-TSC2 complex, which plays an important role in mTORC1 activity. Constitutive overexpression of TSC2 rescued motor deficits and neuropathology in α-synuclein flies. Biochemical examination of PD postmortem brain tissues also suggested deregulated mTORC1 signaling. These findings establish a connection between mRNA translation deregulation and mTORC1 pathway activation that is induced by pathologic α-synuclein in cellular and animal models of PD.
Topics: Animals; Mice; alpha-Synuclein; Disease Models, Animal; Mammals; Mechanistic Target of Rapamycin Complex 1; Parkinson Disease; Proteomics; TOR Serine-Threonine Kinases
PubMed: 38019930
DOI: 10.1126/scitranslmed.add0499 -
Neuron Dec 2023Phosphorylation of α-synuclein at the serine-129 site (α-syn Ser129P) is an established pathologic hallmark of synucleinopathies and a therapeutic target. In...
Phosphorylation of α-synuclein at the serine-129 site (α-syn Ser129P) is an established pathologic hallmark of synucleinopathies and a therapeutic target. In physiologic states, only a fraction of α-syn is phosphorylated at this site, and most studies have focused on the pathologic roles of this post-translational modification. We found that unlike wild-type (WT) α-syn, which is widely expressed throughout the brain, the overall pattern of α-syn Ser129P is restricted, suggesting intrinsic regulation. Surprisingly, preventing Ser129P blocked activity-dependent synaptic attenuation by α-syn-thought to reflect its normal function. Exploring mechanisms, we found that neuronal activity augments Ser129P, which is a trigger for protein-protein interactions that are necessary for mediating α-syn function at the synapse. AlphaFold2-driven modeling and membrane-binding simulations suggest a scenario where Ser129P induces conformational changes that facilitate interactions with binding partners. Our experiments offer a new conceptual platform for investigating the role of Ser129 in synucleinopathies, with implications for drug development.
Topics: Humans; alpha-Synuclein; Phosphorylation; Parkinson Disease; Synucleinopathies; Serine
PubMed: 38128479
DOI: 10.1016/j.neuron.2023.11.020 -
Neuron Nov 2023Enteric symptoms are hallmarks of prodromal Parkinson's disease (PD) that appear decades before the onset of motor symptoms and diagnosis. PD patients possess...
Enteric symptoms are hallmarks of prodromal Parkinson's disease (PD) that appear decades before the onset of motor symptoms and diagnosis. PD patients possess circulating T cells that recognize specific α-synuclein (α-syn)-derived epitopes. One epitope, α-syn, binds with strong affinity to the HLA-DRB115:01 allele implicated in autoimmune diseases. We report that α-syn immunization in a mouse expressing human HLA-DRB115:01 triggers intestinal inflammation, leading to loss of enteric neurons, damaged enteric dopaminergic neurons, constipation, and weight loss. α-Syn immunization activates innate and adaptive immune gene signatures in the gut and induces changes in the CD4 T1/T17 transcriptome that resemble tissue-resident memory (T) cells found in mucosal barriers during inflammation. Depletion of CD4, but not CD8, T cells partially rescues enteric neurodegeneration. Therefore, interaction of α-syn and HLA-DRB115:0 is critical for gut inflammation and CD4 T cell-mediated loss of enteric neurons in humanized mice, suggesting mechanisms that may underlie prodromal enteric PD.
Topics: Mice; Humans; Animals; Parkinson Disease; alpha-Synuclein; HLA-DRB1 Chains; Epitopes; Dopaminergic Neurons; Inflammation
PubMed: 37597517
DOI: 10.1016/j.neuron.2023.07.015