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Subtyping Lewy body disorders using proteomics

ABSTRACT: Lewy body disorders (LBD), characterized by the deposition of misfolded α-synuclein (α-Syn), are clinically heterogeneous. We hypothesized that this heterogeneity might reflect α-Syn molecular diversity, between both patients and different brain regions. Using an ultra-sensitive assay, we evaluated α-Syn seeding from 30 LBD patients with different clinical phenotypes and disease durations. Interestingly, α-Syn from patients with rapid disease progression (<3 years) had a higher nigral seeding capacity than the rest of the patients included. We performed a proteomic-wide profiling of the substantia nigra from 5 high and 5 low seeder patients. The proteomic data suggests a significant disruption in mitochondrial function and lipid metabolism in high seeder cases compared to the low seeders.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Brain

DISEASE(S): Parkinson's Disease

SUBMITTER: Ivan Martinez-Valbuena

LAB HEAD: Ivan Martinez

PROVIDER: PXD034441 | Pride | 2022-07-20

REPOSITORIES: Pride

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			Action	DRS
	Experiment_MSB-9935_Toronto_Martinez_010322_56230_from_MSB56230A.mzid.gz	Mzid
	Experiment_MSB-9935_Toronto_Martinez_010322_56230_from_MSB56230A.mzid_Experiment_MSB-9935_Toronto_Martinez_010322_56230_from_MSB56230A.MGF	Mzid
	Experiment_MSB-9935_Toronto_Martinez_010322_56231_from_MSB56231A.mzid.gz	Mzid
	Experiment_MSB-9935_Toronto_Martinez_010322_56231_from_MSB56231A.mzid_Experiment_MSB-9935_Toronto_Martinez_010322_56231_from_MSB56231A.MGF	Mzid
	Experiment_MSB-9935_Toronto_Martinez_010322_56232_from_MSB56232A.mzid.gz	Mzid

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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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Subtyping Lewy body disorders using proteomics

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