Mucolipidosis type IV (MLIV) is a lysosomal storage disease exhibiting progressive
intellectual disability, motor impairment, and premature death. There is currently
no cure or corrective treatment. The disease results from mutations in the gene encoding
mucolipin-1, a transient receptor potential channel believed to play a key role in
lysosomal calcium egress. Loss of mucolipin-1 and subsequent defects lead to a host
of cellular aberrations, including accumulation of glycosphingolipids (GSLs) in neurons
and other cell types, microgliosis and, as reported here, cerebellar Purkinje cell
loss. Several studies have demonstrated that N-butyldeoxynojirimycin (NB-DNJ, also
known as miglustat), an inhibitor of the enzyme glucosylceramide synthase (GCS), successfully
delays the onset of motor deficits, improves longevity, and rescues some of the cerebellar
abnormalities (e.g., Purkinje cell death) seen in another lysosomal disease known
as Niemann-Pick type C (NPC). Given the similarities in pathology between MLIV and
NPC, we examined whether miglustat would be efficacious in ameliorating disease progression
in MLIV. Using a full mucolipin-1 knockout mouse (Mcoln1-/-), we found that early
miglustat treatment delays the onset and progression of motor deficits, delays cerebellar
Purkinje cell loss, and reduces cerebellar microgliosis characteristic of MLIV disease.
Quantitative mass spectrometry analyses provided new data on the GSL profiles of murine
MLIV brain tissue and showed that miglustat partially restored the wild type profile
of white matter enriched lipids. Collectively, our findings indicate that early miglustat
treatment delays the progression of clinically relevant pathology in an MLIV mouse
model, and therefore supports consideration of miglustat as a therapeutic agent for
MLIV disease in humans.