Abstract
Mucopolysaccharidosis IIIB (MPS IIIB) is an inherited metabolic disease due to deficiency of α-N-Acetylglucosaminidase (NAGLU) enzyme with subsequent storage of undegraded heparan sulfate (HS). The main clinical manifestations of the disease are profound intellectual disability and neurodegeneration. A label-free quantitative proteomic approach was applied to compare the proteome profile of brains from MPS IIIB and control mice to identify altered neuropathological pathways of MPS IIIB. Proteins were identified through a bottom up analysis and 130 were significantly under-represented and 74 over-represented in MPS IIIB mouse brains compared to wild type (WT). Multiple bioinformatic analyses allowed to identify three major clusters of the differentially abundant proteins: proteins involved in cytoskeletal regulation, synaptic vesicle trafficking, and energy metabolism. The proteome profile of NAGLU−/− mouse brain could pave the way for further studies aimed at identifying novel therapeutic targets for the MPS IIIB. Data are available via ProteomeXchange with the identifier PXD017363.
Highlights
Mucopolysaccharidosis type IIIB (MPS IIIB) is an inherited metabolic disease caused by the deficiency of the enzyme α-N-Acetylglucosaminidase (NAGLU, EC: 3.2.1.50) required for the degradation of the glycosaminoglycan (GAG) heparan sulfate (HS) [1,2]
Microtubule involvement in the MPS neurological component is supported by our results where we found altered expression levels of proteins such as Stathmin (Stmn1) and microtubule-associated protein 6 (Map6) detected in MPS IIIB mouse brain
In this work we analyze for the first time the differences in the proteome profiles between brains from MPS IIIB vs. wild type (WT) mice and we highlight that alterations in metabolic pathways, organelle homeostasis, and cytoskeletal system may play a fundamental role in the neuropathology of MPS IIIB
Summary
Mucopolysaccharidosis type IIIB (MPS IIIB) is an inherited metabolic disease caused by the deficiency of the enzyme α-N-Acetylglucosaminidase (NAGLU, EC: 3.2.1.50) required for the degradation of the glycosaminoglycan (GAG) heparan sulfate (HS) [1,2]. The undigested HS accumulates in different tissues leading to progressive cellular damage and organ dysfunction, with the central nervous system (CNS) being the primary site of the pathology [3,4,5,6,7]. Different pathophysiological mechanisms have been investigated both in the brain of MPS IIIB patients and in animal models of the disease [9], the etiology of the neurological dysfunction in MPS IIIB is still unclear. Accumulation of specific HS glycoforms in neurons and glial cells in the brain of MPS IIIB mouse model has been associated with increased expression of HS biosynthetic enzymes, may contributing to the neuropathology of MPS IIIB by exacerbating the lysosomal HS storage.
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