An Inducible Mouse Model of Late Onset Tay–Sachs Disease

Abstract

Mouse models of the GM2 gangliosidoses, Tay–Sachs and Sandhoff disease, are null for the hexosaminidase α and β subunits respectively. The Sandhoff (Hexb−/−) mouse has severe neurological disease and mimics the human infantile onset variant. However, the Tay–Sachs (Hexa−/−) mouse model lacks an overt phenotype as mice can partially bypass the blocked catabolic pathway and escape disease. We have investigated whether a subset of Tay–Sachs mice develop late onset disease. We have found that ∼65% of the mice develop one or more clinical signs of the disease within their natural life span (n = 52, P < 0.0001). However, 100% of female mice with repeat breeding histories developed late onset disease at an earlier age (n = 21, P < 0.0001) and displayed all clinical features. Repeat breeding of a large cohort of female Tay–Sachs mice confirmed that pregnancy induces late onset Tay–Sachs disease. Onset of symptoms correlated with reduced up-regulation of hexosaminidase B, a component of the bypass pathway.

Keywords

• GM2 gangliosidosis
• lysosomal storage disease
• glycosphingolipid
• hexosaminidase
• neurodegeneration