Abstract
Sanfilippo syndrome or mucopolysaccharidosis III is a lysosomal storage disorder caused by mutations in genes responsible for the degradation of heparan sulfate, a glycosaminoglycan located in the extracellular membrane. Undegraded heparan sulfate molecules accumulate within lysosomes leading to cellular dysfunction and pathology in several organs, with severe central nervous system degeneration as the main phenotypical feature. The exact molecular and cellular mechanisms by which impaired degradation and storage lead to cellular dysfunction and neuronal degeneration are still not fully understood. Here, we compile the knowledge on this issue and review all available animal and cellular models that can be used to contribute to increase our understanding of Sanfilippo syndrome disease mechanisms. Moreover, we provide an update in advances regarding the different and most successful therapeutic approaches that are currently under study to treat Sanfilippo syndrome patients and discuss the potential of new tools such as induced pluripotent stem cells to be used for disease modeling and therapy development.
Highlights
Lysosomal storage disorders (LSDs) comprise a heterogeneous group of rare inherited metabolic diseases that are characterized by the accumulation of macromolecules inside lysosomes
Mucopolysaccharidoses (MPS) are a group of LSDs accounting for approximately 30% of all LSD cases and arise from mutations in genes involved in glycosaminoglycans (GAGs) degradation, which accumulate inside the lysosomes [1]
We revise the molecular basis of Sanfilippo syndrome from causative mutations to heparan sulfate (HS) accumulation, and we summarize the latest advancements in therapeutic approaches as well as available animal and cellular disease models that can be used for investigating underlying mechanisms and assay potential therapies
Summary
Lysosomal storage disorders (LSDs) comprise a heterogeneous group of rare inherited metabolic diseases that are characterized by the accumulation of macromolecules inside lysosomes. Sanfilippo syndrome is caused by mutations in the enzymes responsible for the degradation of heparan sulfate (HS), a specific GAG, and patients are characterized by severe neurological pathology leading to childhood dementia [3]. A link between Sanfilippo syndrome and Parkinson’s disease was suggested when mutations causing Sanfilippo syndrome were linked to a higher risk of developing Parkinson’s disease and aggregates of alfa-synuclein were found in patient brains [6]. For this reason, a better understanding of Sanfilippo syndrome’s underlying mechanisms can contribute to improve our knowledge on the role of impaired lysosomal function in age-related neurodegenerative disorders. We revise the molecular basis of Sanfilippo syndrome from causative mutations to HS accumulation, and we summarize the latest advancements in therapeutic approaches as well as available animal and cellular disease models that can be used for investigating underlying mechanisms and assay potential therapies
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