Dataset Information

Distribution of phosphorylated alpha-synuclein in non-diseased brain implicates olfactory bulb mitral cells in synucleinopathy pathogenesis.

ABSTRACT: Project aim was to identify protein-protein interactions of the post-translationally modified form of alpha-synuclein. In situ proximity labeling (BAR) was used to enrich for protein-protein interactions. We performed BAR on wild-type and alpha-synuclein knockout olfactory bulb tissues. We include negative capture conditions, where the primary antibody was omitted.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain

DISEASE(S): Disease Free

SUBMITTER: Bryan Killinger

LAB HEAD: Bryan Andrew Killinger

PROVIDER: PXD040392 | Pride | 2023-03-27

REPOSITORIES: Pride

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Dataset's files

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			Action	DRS
	20220411_bbm1840_22-2895_Killinger_12.raw	Raw
	20220411_bbm1840_22-2895_Killinger_15.raw	Raw
	20220411_bbm1840_22-2895_Killinger_18.raw	Raw
	20220411_bbm1840_22-2895_Killinger_19.raw	Raw
	22-2895.sf3	Other

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Publications

Distribution of phosphorylated alpha-synuclein in non-diseased brain implicates olfactory bulb mitral cells in synucleinopathy pathogenesis.

Killinger Bryan A BA Mercado Gabriela G Choi Solji S Tittle Tyler T Chu Yaping Y Brundin Patrik P Kordower Jeffrey H JH

NPJ Parkinson's disease 20230325 1

Synucleinopathies are neurodegenerative diseases characterized by pathological inclusions called "Lewy pathology" (LP) that consist of aggregated alpha-synuclein predominantly phosphorylated at serine 129 (PSER129). Despite the importance for understanding disease, little is known about the endogenous function of PSER129 or why it accumulates in the diseased brain. Here we conducted several observational studies using a sensitive tyramide signal amplification (TSA) technique to determine PSER129 ...[more]

PMID: 36966145

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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.

Dataset Information

Distribution of phosphorylated alpha-synuclein in non-diseased brain implicates olfactory bulb mitral cells in synucleinopathy pathogenesis.

Dataset's files

Publications

Distribution of phosphorylated alpha-synuclein in non-diseased brain implicates olfactory bulb mitral cells in synucleinopathy pathogenesis.

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