Abstract
There are over 50 lysosomal hydrolase deficiencies, many of which cause neurodegeneration, cognitive decline and death. In recent years, a number of broad innovative therapies have been proposed and investigated for lysosomal storage diseases (LSDs), such as enzyme replacement, substrate reduction, pharmacologic chaperones, stem cell transplantation, and various forms of gene therapy. Murine models that accurately reflect the phenotypes observed in human LSDs are critical for the development, assessment and implementation of novel translational therapies. The goal of this review is to summarize the neurodegenerative murine LSD models available that recapitulate human disease, and the pre-clinical studies previously conducted. We also describe some limitations and difficulties in working with mouse models of neurodegenerative LSDs.
Highlights
The lysosome orchestrates a number of cellular homeostatic processes, primarily focused on the catabolism of diverse macromolecules
Lysosomes contain more than 50 unique acid hydrolases, each facilitating the degradation of specific metabolites including glycosides, sulfates, phosphates, various lipids, phospholipids, proteins and nucleic acids
Mouse models have been used for biomedical research since the beginning of the 20th century (Ericsson et al, 2013)
Summary
The lysosome orchestrates a number of cellular homeostatic processes, primarily focused on the catabolism of diverse macromolecules. Due to the heterogeneous accumulation of enzymatic substrates among multiple tissues and organs, the phenotypes among LSDs vary widely and often include visceral, ocular, hematologic, skeletal and neurological manifestations Those related to the involvement of the central nervous system (CNS) may cause progressive neurodegeneration and severe cognitive impairment. It is not surprising that many LSDs have nervous system involvement and that various aging-related neurodegenerative diseases are caused, at least in part, by endolysosomal dysfunction These include Parkinson’s (Anglade et al, 1997), Alzheimer’s (Nixon et al, 2005), Huntington’s diseases (Rudnicki et al, 2008), and amyotrophic lateral sclerosis (Sasaki, 2011) caused by the accumulation of aberrant or misfolded proteins. We review currently available mouse models for neurodegenerative LSDs and discuss how those models have been used for pre-clinical trials and have helped move therapies forward
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