Identification of distinct pathological signatures induced by patient-derived α-synuclein structures in nonhuman primates

Abstract

Dopaminergic neuronal cell death, associated with intracellular α-synuclein (α-syn)–rich protein aggregates [termed “Lewy bodies” (LBs)], is a well-established characteristic of Parkinson’s disease (PD). Much evidence, accumulated from multiple experimental models, has suggested that α-syn plays a role in PD pathogenesis, not only as a trigger of pathology but also as a mediator of disease progression through pathological spreading. Here, we have used a machine learning–based approach to identify unique signatures of neurodegeneration in monkeys induced by distinct α-syn pathogenic structures derived from patients with PD. Unexpectedly, our results show that, in nonhuman primates, a small amount of singular α-syn aggregates is as toxic as larger amyloid fibrils present in the LBs, thus reinforcing the need for preclinical research in this species. Furthermore, our results provide evidence supporting the true multifactorial nature of PD, as multiple causes can induce a similar outcome regarding dopaminergic neurodegeneration.

Synucleinopathy alters nanoscale organization and diffusion in the brain extracellular space through hyaluronan remodeling

“…1a, b and Supplementary Fig. 1 ), a similar rate to the histopathological features of this model, that have been extensively described elsewhere 20 , 21 .

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“…To investigate the ECS in a context of neurodegeneration, we employed a unique paradigm of α-syn-induced dopaminergic neuronal loss by unilateral inoculation of Lewy body (LB) fractions derived from PD patients into the substantia nigra (SN) of adult mice 20 , 21 . Control animals received fractions containing only soluble α-syn (noLB), while the LB fractions contained α-syn seeds in its aggregated form.…”

“…Here we report on the dynamics and organization of the brain extracellular microenvironment in a PD pathological context, using a combination of state-of-the-art imaging approaches and an established in vivo model of α-synuclein (α-syn)-induced dopaminergic neurodegeneration 20 , 21 , a proxy of synucleinopathy leading to PD. We describe profound alterations in ECS morphological and diffusional parameters in the substantia nigra of parkinsonian mice at nanometer resolution.…”

CLR01 protects dopaminergic neurons in vitro and in mouse models of Parkinson’s disease

“…1B ), which is in agreement with the effects of CLR01 on recombinant α-syn species previously shown by Prabhudesai et al 7 . We then tested whether CLR01 could reduce the presence of aggregates in LB extracts from PD patients, which were produced as previously described 13 , 15 , 16 . LB extracts and their corresponding non-LB (noLB) control extracts were subjected to the α-syn proximity ligation assay (AS-PLA) and EM to evaluate the presence of oligomers 17 , 18 and the morphology of the aggregates (Supplementary Fig.…”

Vagus Nerve and Stomach Synucleinopathy in Parkinson’s Disease, Incidental Lewy Body Disease and Normal Elderly Subjects: Evidence Against the “Body-First” Hypothesis

“…Although we used an immunohistochemical method that has been repeatedly demonstrated to be highly sensitive and specific for both CNS and PNS -synuclein pathology, as found in multi-center blinded studies [69,70,78,88] and biochemical studies [75], it is possible that the initial form of peripheral -synuclein pathology may differ from that commonly seen in the CNS. Alternate forms may include non-phosphorylated -synuclein, truncated -synuclein [89][90][91] and -synuclein aggregates [39,92].…”