Glycosaminoglycans as triggers of neurodegeneration in MPS IIIC and Alzheimer's Disease

• Grant number: 18/17003-6
• Support type: Scholarships abroad - Research Internship - Post-doctor
• Effective date (Start): December 01, 2018
• Effective date (End): November 30, 2019
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: Helena Bonciani Nader
• Grantee: Gustavo Monteiro Viana
• Supervisor abroad: Alexey V Pshezhetsky
• Home Institution: Instituto Nacional de Farmacologia (INFAR). Universidade Federal de São Paulo (UNIFESP). São Paulo , SP, Brazil
• Local de pesquisa : Université de Montréal, Canada
• Associated to the scholarship: 16/25486-1 - Glycosaminoglycans and activation of amyloidogenic pathway in mucopolysaccharidosis type I, BP.PD

Abstract

Mucopolysaccharidosis IIIC (MPS IIIC) is a rare lysosomal disease caused by deficiency of lysosomal enzyme acetyl-CoA:±-glucosaminide N-acetyltransferase (HGSNAT) involved in catabolism of the glycosaminoglycan (GAG) heparan sulfate (HS). Non-degraded HS accumulate in lysosomes in the cells of multiple organs and tissues, causing a progressive and multisystemic pathology. Neurodegeneration is the most prominent feature leading to dementia and death before adulthood. Accumulated GAGs can cause secondary changes in the activity of several lysosomal proteases including cathepsin B (CATB) and affect many cellular functions such as autophagy and viability. However, the potential role of accumulated GAGs in neuronal homeostasis and subsequently in synaptogenesis remains unknown. Our preliminary data demonstrated that alterations in CATB activity also trigger accelerated amyloidogenic processing of the amyloid precursor protein (APP), leading to increased production of ²-amyloid peptides and, consequently, deposition of amyloid senile plaques, a hallmark of Alzheimer's Disease. The current project aims to characterize the mechanism underlying the effect of accumulated intra and extracellular GAGs on amyloidogenic APP processing in cultured primary cortical and hippocampal neurons from wild-type C57BL/6J and MPS IIIC mice.

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

VIANA, GUSTAVO M.; PRIESTMAN, DAVID A.; PLATT, FRANCES M.; KHAN, SHAUKAT; TOMATSU, SHUNJI; PSHEZHETSKY, ALEXEY V. Brain Pathology in Mucopolysaccharidoses (MPS) Patients with Neurological Forms. JOURNAL OF CLINICAL MEDICINE, v. 9, n. 2 FEB 2020. Web of Science Citations: 0.

VIANA, GUSTAVO MONTEIRO; GONZALEZ, ESTEBAN ALBERTO; PALACIO ALVAREZ, MARCELA MACIEL; CAVALHEIRO, RENAN PELLUZZI; DO NASCIMENTO, CINTHIA CASTRO; BALDO, GUILHERME; D'ALMEIDA, VANIA; DE LIMA, MARCELO ANDRADE; PSHEZHETSKY, V, ALEXEY; NADER, HELENA BONCIANI. Cathepsin B-associated Activation of Amyloidogenic Pathway in Murine Mucopolysaccharidosis Type I Brain Cortex. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 21, n. 4 FEB 2020. Web of Science Citations: 0.