Functional and neuropathological changes induced by injection of distinct alpha-synuclein strains: A pilot study in non-human primates

Audrey, Fayard; Fenyi, Alexis; Lavisse, Sonia; Sandra, Dovero; Bousset, Luc; Bellande, Tracy; Sophie, Lecourtois; Christophe, Jouy; Guillermier, Martine; Caroline, Jan; Gipchtein, Pauline; Dehay, Benjamin; Bézard, Erwan; Melki, Ronald; Hantraye, Philippe; Romina, Aron Badin

doi:10.1016/j.nbd.2023.106086

Cited by 7 publications

(6 citation statements)

References 36 publications

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“…Of particular relevance to the present work is the observation that the same LB preparation and quantity, when injected in the stomach wall, i.e., in close contact with the enteric nervous system (ENS), eventually leads to nigrostriatal degeneration and central nervous system pathology (though not cortical) 23 . However, what differs in the present study from the previous contributions is that the live phase was 12 months as opposed to 24 months of survival 24 , 25 , 28 .…”

Section: Discussionmentioning

confidence: 95%

“…Previous studies have demonstrated that the injection of different polymorphs of misfolded α-syn can induce lesions reminiscent of synucleinopathies, including the appearance of pathological phosphorylated α-syn, dopaminergic neuron loss, neuroinflammation, and other markers 18 . These injection-based models focus on increasing α-syn levels in the brain through various techniques, including viral vector-based injections, injections of either preformed synthetic α-syn fibrils, or patient-derived brain materials [19][20][21][22][23] . Most of these studies have focused on injections of these materials in the nigrostriatal pathway to better mimic the effects of α-syn on this key pathway critically affected in synucleinopathies.…”

Section: Introductionmentioning

confidence: 99%

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Cortical Lewy body injections induce long-distance pathogenic alterations in the non-human primate brain

Teil,

Dovero,

Bourdenx

et al. 2023

npj Parkinsons Dis.

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Aggregation of α-synuclein (α-syn) is the cornerstone of neurodegenerative diseases termed synucleinopathies, which include Parkinson’s Disease (PD), Dementia with Lewy Bodies (DLB), and Multiple System Atrophy (MSA). These synucleinopathies are characterized by the deposit of aggregated α-syn in intracellular inclusions observable in neurons and glial cells. In PD and DLB, these aggregates, predominantly located in neurons, are called Lewy Bodies (LBs). These LBs are one of the pathological hallmarks of PD and DLB, alongside dopaminergic neuron loss in the substantia nigra. Previous studies have demonstrated the ability of PD patient-derived LB fractions to induce nigrostriatal neurodegeneration and α-syn pathology when injected into the striatum or the enteric nervous system of non-human primates. Here, we report the pathological consequences of injecting these LB fractions into the cortex of non-human primates. To this end, we inoculated mesencephalic PD patient-derived LB fractions into the prefrontal cortex of baboon monkeys terminated one year later. Extensive analyses were performed to evaluate pathological markers known to be affected in LB pathologies. We first assessed the hypothesized presence of phosphorylated α-syn at S129 (pSyn) in the prefrontal cortices. Second, we quantified the neuronal, microglial, and astrocytic cell survival in the same cortices. Third, we characterized these cortical LB injections’ putative impact on the integrity of the nigrostriatal system. Overall, we observed pSyn accumulation around the injection site in the dorsal prefrontal cortex, in connected cortical regions, and further towards the striatum, suggesting α-syn pathological propagation. The pathology was also accompanied by neuronal loss in these prefrontal cortical regions and the caudate nucleus, without, however, loss of nigral dopamine neurons. In conclusion, this pilot study provides novel data demonstrating the toxicity of patient-derived extracts, their potential to propagate from the cortex to the striatum in non-human primates, and a possible primate model of DLB.

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Section: Discussionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 99%

Cortical Lewy body injections induce long-distance pathogenic alterations in the non-human primate brain

Teil,

Dovero,

Bourdenx

et al. 2023

npj Parkinsons Dis.

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“…Increased αSyn deposition also correlated with ribbons injection in a mouse MSA model, while fibrils resulted in increased cellular death 27 . Finally, in non-human primates, intra-putaminal injection of ribbons and fibrils induced strain-specific patterns of αSyn aggregation and phosphorylation 28 .…”

Section: Introductionmentioning

confidence: 90%

Single molecule fingerprinting reveals different growth mechanisms in seed amplification assays for different polymorphs of αSynuclein fibrils

Lau,

Tang,

Kenche

et al. 2024

Preprint

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Alpha-synuclein (aSyn) aggregates, detected in the biofluids of patients with Parkinsons disease, have the ability to catalyze their own aggregation, leading to an increase in the number and size of aggregates. This self-templated amplification is used by newly developed assays to diagnose Parkinsons disease and turned the presence of aSyn aggregates into a biomarker of the disease. It has become evident that aSyn can form fibrils with slightly different structures, called strains or polymorphs, but little is known about their differential reactivity in diagnostic assays. Here we compared the properties of two well-described aSyn polymorphs. Using single molecule techniques, we observed that one of the polymorphs had an increased tendency to undergo secondary nucleation and we showed that this could explain the differences of reactivity observed in in vitro seed amplification assay and cellular assays. Simulations and high-resolution microscopy suggest that a 100-fold difference in apparent rate of growth can be generated by a surprisingly low number of secondary nucleation points (1 every 2,000 monomers added by elongation). When both strains are present in the same seeded reaction, secondary nucleation displaces proportions dramatically and causes a single strain to dominate the reaction as the major end-product.

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“…In general, several in vitro and in vivo studies have indicated that α-Syn misfolding, progressive intraneuronal aggregation, neuroinflammation, several gene (SNCA) mutations (A53T, A30P, E46K, H50Q, A53V, A53E, E83Q, and G51D), self-amplification, and gene polymorphisms are significant causal links to the clinical onset and progression of PD [173]. Fayard et al (2023), in a pilot study, demonstrated for the first time in non-human primates that injection of several strains of α-Syn induced specific functional, morphological, and biochemical alterations, including high aggregation levels of α-Syn in all brain regions and a distinct reduction in the number of neurons in all injected non-human primates which are the features of early but progressive neurodegeneration [174]. Similarly, several studies have demonstrated the role of abnormal filamentous aggregates of the toxic α-Syn in the onset and progression of clinical symptoms and degeneration of the affected part of the brain (brain lesions) in PD.…”

Section: Targeted Degradation and Neuronal Clearance Of Aberrant α-Sy...mentioning

confidence: 99%

Nonintuitive Immunogenicity and Plasticity of Alpha-Synuclein Conformers: A Paradigm for Smart Delivery of Neuro-Immunotherapeutics

Abioye,

Akintade,

Mitchell

et al. 2024

Pharmaceutics

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: Despite the extensive research successes and continuous developments in modern medicine in terms of diagnosis, prevention, and treatment, the lack of clinically useful disease-modifying drugs or immunotherapeutic agents that can successfully treat or prevent neurodegenerative diseases is an ongoing challenge. To date, only one of the 244 drugs in clinical trials for the treatment of neurodegenerative diseases has been approved in the past decade, indicating a failure rate of 99.6%. In corollary, the approved monoclonal antibody did not demonstrate significant cognitive benefits. Thus, the prevalence of neurodegenerative diseases is increasing rapidly. Therefore, there is an urgent need for creative approaches to identifying and testing biomarkers for better diagnosis, prevention, and disease-modifying strategies for the treatment of neurodegenerative diseases. Overexpression of the endogenous α-synuclein has been identified as the driving force for the formation of the pathogenic α-synuclein (α-Syn) conformers, resulting in neuroinflammation, hypersensitivity, endogenous homeostatic responses, oxidative dysfunction, and degeneration of dopaminergic neurons in Parkinson’s disease (PD). However, the conformational plasticity of α-Syn proffers that a certain level of α-Syn is essential for the survival of neurons. Thus, it exerts both neuroprotective and neurotoxic (regulatory) functions on neighboring neuronal cells. Furthermore, the aberrant metastable α-Syn conformers may be subtle and difficult to detect but may trigger cellular and molecular events including immune responses. It is well documented in literature that the misfolded α-Syn and its conformers that are released into the extracellular space from damaged or dead neurons trigger the innate and adaptive immune responses in PD. Thus, in this review, we discuss the nonintuitive plasticity and immunogenicity of the α-Syn conformers in the brain immune cells and their physiological and pathological consequences on the neuroimmune responses including neuroinflammation, homeostatic remodeling, and cell-specific interactions that promote neuroprotection in PD. We also critically reviewed the novel strategies for immunotherapeutic delivery interventions in PD pathogenesis including immunotherapeutic targets and potential nanoparticle-based smart drug delivery systems. It is envisioned that a greater understanding of the nonintuitive immunogenicity of aberrant α-Syn conformers in the brain’s microenvironment would provide a platform for identifying valid therapeutic targets and developing smart brain delivery systems for clinically effective disease-modifying immunotherapeutics that can aid in the prevention and treatment of PD in the future.

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Functional and neuropathological changes induced by injection of distinct alpha-synuclein strains: A pilot study in non-human primates

Cited by 7 publications

References 36 publications

Cortical Lewy body injections induce long-distance pathogenic alterations in the non-human primate brain

Cortical Lewy body injections induce long-distance pathogenic alterations in the non-human primate brain

Single molecule fingerprinting reveals different growth mechanisms in seed amplification assays for different polymorphs of αSynuclein fibrils

Nonintuitive Immunogenicity and Plasticity of Alpha-Synuclein Conformers: A Paradigm for Smart Delivery of Neuro-Immunotherapeutics

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