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Development of early-stage alpha-synucleinopathy is not governed by myelin status in mice of either sex

ABSTRACT: Lewy body disorders are characterized by alpha-synucleinopathic inclusions that tend to develop in neurons extending long, thin, and unmyelinated fibers. It is unknown if this selective vulnerability reflects poor myelination per se. We have observed that preformed fibrils (PFFs) of alpha-synuclein tend to induce pathology in gray matter, even when infused into regions penetrated by white matter bundles. In addition, we found that levels of insoluble, hyperphosphorylated alpha-synuclein correlate inversely with myelin markers in the postmortem amygdala of men—but not women—with Lewy body disease. Thus, we tested if myelin disruption with pharmacologic or genetic tools exacerbates alpha-synucleinopathic lesions in a model of early-stage, limbic Lewy body disease. In genetically outbred CD-1 mice infused with PFFs in the caudal olfactory bulb, the myelin-disruptor cuprizone caused subtle exacerbation of α-synucleinopathy, but without impacting PFF-induced neuron loss or behavior deficits. Furthermore, in C57BL/6J mice heterozygous for myelin basic protein (Mbp+/shi), PFF-induced increases in the insolubility and hyperphosphorylation of alpha-synuclein were not amplified and histological outcomes were not markedly exacerbated. Given our observations of inverse correlations between α-synucleinopathy and myelin markers in the human male amygdala, Lewy body disease may disrupt myelination, rather than poor myelination status regulating the emergence of limbic α-synucleinopathy. This new perspective is reinforced by suppressed expression of select oligodendrocytic markers in the amygdalae of men with Lewy body disease compared to women. Thus, resilient neurons may defy the initial development of Lewy-related pathologies due to properties unrelated to myelination per se.

ORGANISM(S): Homo sapiens

PROVIDER: GSE297212 | GEO | 2025/05/20

REPOSITORIES: GEO

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Project description:Parkinson’s disease (PD) is a neurodegenerative disease characterized by progressive motor symptoms and alpha-synuclein (αsyn) aggregation in the nervous system. For unclear reasons, PD patients with certain GBA mutations (GBA-PD) have a more aggressive clinical progression. Two testable hypotheses that can potentially account for this phenomenon are that GBA1 mutations promote αsyn spread or drive the generation of highly pathogenic αsyn polymorphs (i.e., strains). We tested these hypotheses by treating homozygous GBA1 D409V knockin (KI) mice with human α-syn-preformed fibrils (PFFs) and treating wild-type mice (WT) with several αsyn-PFF polymorphs amplified from brain autopsy samples collected from patients with idiopathic PD and GBA-PD patients with either homozygous or heterozygous GBA1 mutations. Robust phosphorylated-αsyn (PSER129) positive pathology was observed at the injection site (i.e., the olfactory bulb granular layer) and throughout the brain six months following PFF injection. The PFF seeding efficiency and degree of spread were similar regardless of the mouse genotype or PFF polymorphs. We found that PFFs amplified from the human brain, regardless of patient genotype, were generally more effective seeders than wholly synthetic PFFs (i.e., non-amplified); however, PFF concentration differed between these two studies, and this might also account for the observed differences. To investigate whether the molecular composition of pathology differed between different seeding conditions, we permed Biotinylation by Antibody Recognition on PSER129 (BAR-PSER129). We found that for BAR-PSER129, the endogenous PSER129 pool dominated identified interactions, and thus, very few potential interactions were explicitly identified for seeded pathology. However, we found Dctn2 interaction was shared across all PFF conditions, and Nckap1 and Ap3b2 were unique to PFFs amplified from GBA-PD brains of heterozygous mutation carriers. In conclusion, both the genotype and αsyn strain had little effect on overall seeding efficacy and global PSER129-interactions.

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Development of early-stage alpha-synucleinopathy is not governed by myelin status in mice of either sex

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