Protective mechanisms by glial cell line-derived neurotrophic factor and cerebral dopamine neurotrophic factor against the α-synuclein accumulation in Parkinson's disease

Biochemical Society Transactions, Journal Year: 2023, Volume and Issue: 51(1), P. 245 - 257

Published: Feb. 16, 2023

Synucleinopathies constitute a disease family named after alpha-synuclein protein, which is significant component of the intracellular inclusions called Lewy bodies. Accompanying progressive neurodegeneration, bodies and neurites are main histopathologies synucleinopathies. The complicated role in pathology makes it an attractive therapeutic target for disease-modifying treatments. GDNF one most potent neurotrophic factors dopamine neurons, whereas CDNF protective neurorestorative with entirely different mechanisms action. Both have been clinical trials common synucleinopathy, Parkinson's disease. With AAV-GDNF ongoing trial being finalized, their effects on abnormal accumulation great interest. Previous animal studies overexpression model shown that was ineffective against accumulation. However, recent study cell culture models fibril inoculation has demonstrated opposite by revealing GDNF/RET signaling cascade required effect aggregation. CDNF, ER resident to bind directly. reduced uptake fibrils neurons alleviated behavioral deficits induced injected into mouse brain. Thus, can modulate symptoms pathologies disease, perhaps, similarly other Their unique preventing alpha-synuclein-related should be studied more carefully develop therapies.

Language: Английский

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Antibodies and α-synuclein: What to target against Parkinson's Disease?

Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics, Journal Year: 2023, Volume and Issue: 1872(2), P. 140943 - 140943

Published: Sept. 30, 2023

Parkinson's Disease (PD) is strongly linked to the aggregation of protein α-synuclein (α-syn), an intrinsically disordered protein. However, strategies combat PD by targeting α-syn are challenged multiple types aggregates formed both in vivo and vitro, potential influence chemical modifications as yet unresolved question which aggregate (oligomeric or fibrillar) most cytotoxic. Here I briefly review social history α-syn, many efforts raise antibodies against disappointing results clinical trials based on such antibodies. Ultimately a thorough understanding molecular mechanistic properties mAbs towards aggregated species essential prerequisite for any trial, but this missing cases. highlight new microfluidic techniques may address need call more concerted effort standardize antibody studies basis allow us link insights efficacy.

Language: Английский

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Analysis of clinical failure of anti-tau and anti-synuclein antibodies in neurodegeneration using a quantitative systems pharmacology model

Scientific Reports, Journal Year: 2023, Volume and Issue: 13(1)

Published: Sept. 1, 2023

Misfolded proteins in Alzheimer's disease and Parkinson's follow a well-defined connectomics-based spatial progression. Several anti-tau anti-alpha synuclein (aSyn) antibodies have failed to provide clinical benefit trials despite substantial target engagement the experimentally accessible cerebrospinal fluid (CSF). The proposed mechanism of action is reducing neuronal uptake oligomeric protein from synaptic cleft. We built quantitative systems pharmacology (QSP) model quantitatively simulate intrasynaptic secretion, diffusion antibody capture cleft, postsynaptic membrane binding internalization monomeric tau aSyn proteins. Integration with physiologically based pharmacokinetic (PBPK) allowed us gosuranemab, tilavonemab, semorinemab, anti-aSyn cinpanemab prasineuzumab. Maximal for was simulated as 45% (semorinemab) 99% (gosuranemab) CSF, 30% ISF but only 1% 3% leading reduction less than tau. Simulations prasineuzumab suggest free 6-8% 4-6% 1-2% while maximal aggregated predicted reach 80% cleft similar effects on uptake. study generates optimal values selectivity, sensitivity PK profiles antibodies. identifies gradient decreasing CSF key driver efficacy, various improvements drug design emphasizes need QSP modelling support development

Language: Английский

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Human serum-derived α-synuclein auto-antibodies mediate NMDA receptor-dependent degeneration of CNS neurons

Journal of Neuroinflammation, Journal Year: 2024, Volume and Issue: 21(1)

Published: Feb. 28, 2024

Abstract Background Presence of autoantibodies against α-synuclein (α-syn AAb) in serum the general population has been widely reported. That such peripheral factors may be involved central nervous system pathophysiology was demonstrated by detection immunoglobulins (IgGs) cerebrospinal fluid and brain Parkinson’s disease (PD) patients. Thus, blood-borne IgGs reach parenchyma through an impaired blood-brain barrier (BBB). Findings The present study aims to evaluate patho-physiological impact α-syn AAbs on primary cells, i.e., spontaneously active neurons astrocytes. Exposure neuron-astrocyte co-cultures human containing mediated a dose-dependent reduction spontaneous neuronal activity, subsequent neurodegeneration. Removal specifically from prevented neurotoxicity, while purified, commercial antibodies mimicked neurodegenerative effect. Mechanistically, we found strong calcium flux into preceding AAbs-induced cell death, NMDA receptors. receptor antagonists neurodegeneration upon treatment with (auto)antibodies. (auto)antibodies did not affect astrocyte survival. However, presence α-syn, astrocytes reacted secretion chemokine RANTES. Conclusion These findings provide novel basis explain how combination BBB impairment infiltration targeting synuclein contribute PD argue for caution immunization therapies PD.

Language: Английский

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Development of a Simplified Smell Test to Identify Patients with Typical Parkinson’s as Informed by Multiple Cohorts, Machine Learning and External Validation

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 9, 2024

ABSTRACT Background Reduced olfaction is a common feature of patients with typical Parkinson disease (PD). We sought to develop and validate simplified smell test as screening tool help identify PD explore its differentiation from other forms parkinsonism. Methods used the Sniffin’ Sticks Identification Test (SST-ID) University Pennsylvania Smell (UPSIT), together data three case-control studies, compare in 301 or dementia Lewy bodies (DLB) 36 subjects multiple system atrophy (MSA), 32 individuals progressive supranuclear palsy (PSP) 281 neurologically healthy controls. Individual SST-ID UPSIT scents were ranked by area under receiver operating characteristic curve (AUC) values for group classification, 10-fold cross-validation. Additional rankings generated leveraging results eight published collectively including 5,853 unique participants. Lead combinations further validated using (semi-)independent datasets. An abbreviated list was based on those shared UPSIT. Findings made following five observations: (i) DLB generally had worse than controls, published, scores MSA PSP ranking intermediate. (ii) showed distinct discriminative performances, top odorants (licorice, banana, clove, rose, mint, pineapple cinnamon) confirmed external evidence. (iii) A subset only seven demonstrated similar performance that complete 16-scent 40-scent kits, both discovery validation steps. Seven distinguished PD/DLB controls an AUC 0.87 (95%CI 0.85-0.9) PSP/MSA 0.73 0.65-0.8) within cohorts (n=650). (iv) Increased age associated decline olfaction. (v) Males scored lower females, although this finding not significant across all cohorts. Interpretation Screening Parkinson’s-associated hyposmia can be carried out scent identification relies few specific odorants. There, discrimination vs. age-matched more accurate patients. Funding This work supported by: Research Consortium; uOttawa Brain & Mind Institute; Aligning Science Across Parkinson’s Collaborative Network. context Evidence before study Chronic (PD) (DLB), which often precedes motor impairment cognitive dysfunction several years; it also frequently α-synuclein aggregate formation bulb. The presence increases individual’s likelihood having -what has recently been proposed as- neuronal synucleinopathy disease, >24-fold. Despite strong association reduced olfaction, little understood about clinically, such whether affected sex age, same difficulty seen conditions present Moreover, due time-consuming nature traditional administration healthcare workers, extensive olfactory testing routinely performed during neurological assessments movement disorder clinics. Added value analyzed kit battery discriminate between PSP. Comparison juxtaposition studies allowed generation markedly unified tests, described. Group classification each distractors machine learning advanced Item Response Theory methods. Relations tested, first time. Our findings suggest concrete steps implemented would allow simplified, routine future. Implications available evidence Olfaction emerged important assessment part when examining at risk it. simple, containing fewer current options could facilitate rapid clinic settings home, without supervision workers. usefulness non-invasive population health efforts enhanced coupled self-administered survey includes questions related factors PD. As such, large-scale community applications practice family doctors’ offices well specialty clinics operationally feasible cost-effective.

Language: Английский

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Drug repurposing screens identify compounds that inhibit α-synuclein oligomers' membrane disruption and block antibody interactions

Chemical Science, Journal Year: 2023, Volume and Issue: 14(11), P. 3030 - 3047

Published: Jan. 1, 2023

Small soluble oligomers of the protein α-synuclein (αSO) have been linked to disruptions in neuronal homeostasis, contributing development Parkinson's Disease (PD). While this makes αSO an obvious drug target, effective therapeutics against is challenged by its low abundance and structural morphological complexity. Here, we employ two different approaches neutralize toxic interactions made αSOs with cellular components. First, use available data identify four proteins as likely candidates for interactions, namely Cfl1, Uchl1, Sirt2 SerRS. However, despite promising results when immobilized, all 4 only bind weakly solution microfluidic assays, making them inappropriate screening. In contrast, formation stable contacts formed between vesicles consisting anionic lipids not mimics a biological role but also provided platform screen small molecule libraries disruptors these contacts. Of 7 best leads obtained way, 2 significantly impaired other sandwich ELISA assay using αSO-binding monoclonal antibodies nanobodies. addition, 5 suppressed amyloid formation. Thus, repurposing screening that directly targets key culprit PD pathogenesis shows therapeutic potential.

Language: Английский

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AAV-mediated expression of a new conformational anti-aggregated α-synuclein antibody prolongs survival in a genetic model of α-synucleinopathies

npj Parkinson s Disease, Journal Year: 2023, Volume and Issue: 9(1)

Published: June 15, 2023

Prion-like transmission of pathology in α-synucleinopathies like Parkinson's disease or multiple system atrophy is increasingly recognized as one potential mechanism to address progression. Active and passive immunotherapies targeting insoluble, aggregated α-synuclein are already being actively explored the clinic with mixed outcomes so far. Here, we report identification 306C7B3, a highly selective, aggregate-specific antibody picomolar affinity devoid binding monomeric, physiologic protein. 306C7B3 Ser129-phosphorylation independent shows high several different polymorphs, increasing likelihood that it can also bind pathological seeds assumed drive progression patients. In support this, selective aggregates postmortem brains MSA patients was demonstrated, no staining samples from other human neurodegenerative diseases. To achieve CNS exposure an adeno-associated virus (AAV) based approach driving expression secreted within brain (Thy-1)-[A30P]-hα-synuclein mice used. Widespread central transduction after intrastriatal inoculation ensured by using AAV2HBKO serotype, spread areas far away site. Treatment at age 12 months demonstrated significantly increased survival, concentration reaching 3.9 nM cerebrospinal fluid. These results suggest AAV-mediated extracellular, presumably disease-propagating α-synuclein, has great disease-modifying therapy for ensures antibody, thereby mitigating permeability blood-brain barrier.

Language: Английский

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Targeting α‐Synuclein: A Further Viewpoint

Movement Disorders, Journal Year: 2023, Volume and Issue: 38(4), P. 715 - 716

Published: April 1, 2023

Language: Английский

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Clinical failure of anti-tau and anti-synuclein antibodies in neurodegeneration: a quantitative systems pharmacology model analysis

Research Square (Research Square), Journal Year: 2023, Volume and Issue: unknown

Published: May 2, 2023

Abstract Misfolded proteins in Alzheimer’s disease (AD) and Parkinson’s (PD) follow a well-defined connectomics-based spatial progression. Several anti-tau anti-alpha synuclein (aSyn) antibodies have failed to provide clinical benefit trials despite substantial target engagement the experimentally accessible cerebrospinal fluid (CSF). The proposed mechanism of action is reducing neuronal uptake seed-competent protein from synaptic cleft. We built quantitative systems pharmacology (QSP) model quantitatively simulate intrasynaptic secretion, diffusion antibody capture cleft, postsynaptic membrane binding internalization monomeric tau aSyn proteins. Integration with physiologically based pharmacokinetic (PBPK) allowed us gosuranemab, tilavonemab, semorinemab, anti-aSyn cinpanemab prasineuzumab. Maximal for was simulated as 45% (semorinemab) 99% (gosuranemab) CSF, 30% ISF but only 1% 3% leading reduction less than tau. Simulations prasineuzumab suggest free 6-8% 4-6% 1-2% while maximal aggregated predicted reach 80% cleft similar effects on uptake. study generates optimal values selectivity, sensitivity PK profiles antibodies. identifies gradient decreasing CSF key driver efficacy, various improvements drug design emphasizes need QSP modelling support development Trial registration : N/A

Language: Английский

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