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Identification of TMEM106B-binding proteins in mouse brain

ABSTRACT: TMEM106B is an endolysosomal transmembrane protein associated with many brain disorders, such as frontotemporal lobar degeneration, Alzheimer’s disease, and hypomyelinating leukodystrophy. In addition, recent cryo-EM studies have identified amyloid fibrils of carboxyl-terminal TMEM106B in the brains of those with neurodegeneration. However, so far little is known about precise functions of TMEM106B in the endolysosome and how the protein is involved in a great variety of human conditions at molecular levels. In this project, we sought to identify interaction partners of TMEM106B in the mouse brain by using immunoprecitation and liquid chromatography tandem mass spectrometry protein identification procedure.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain

SUBMITTER: Hideyuki Takahashi

LAB HEAD: Stephen M. Strittmatter

PROVIDER: PXD043192 | Pride | 2024-08-06

REPOSITORIES: Pride

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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.

			Action	DRS
	F503436.mgf	Mgf
	F503436.xml	Xml
	F503437.mgf	Mgf
	F503437.xml	Xml
	QEp17-2052_Takahashi_TMEM106B_KO.raw	Raw

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Identification of TMEM106B-binding proteins in mouse brain

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