Disturbance of intracellular trafficking plays a major role in several 
neurodegenerative disorders including Alzheimer or Parkinson's disease. The 
Chediak-Higashi syndrome (CHS), a life-threatening autosomal recessive disease 
with frequent mutations in the LYST gene, and its animal model, the beige mouse, 
are both characterized by lysosomal defects with accumulation of giant 
lysosomes. Clinically they manifest as hypopigmentation, abnormal bleeding and 
increased susceptibility to infection with various degrees of involvement of the 
nervous system. In the course of a recessive N-ethyl-N-nitrosurea (ENU) 
mutagenesis screen, we identified the first murine missense mutation in the 
lysosomal trafficking regulator gene (Lyst(Ing3618)) located at a highly 
conserved position in the WD40 protein domain. Nearly all described human Lyst 
alleles lead to protein truncation and fatal childhood CHS. Only four different 
missense mutations have been reported in patients with adolescent or adult forms 
of CHS involving the nervous system. Interestingly, the Lyst(Ing3618) model 
presents with a predominant neurodegenerative phenotype with progressive 
degeneration and loss of Purkinje cells and lacks severe impairment of the 
immune system. Therefore, the Lyst(Ing3618 )allele could represent a new model 
for adult CHS with neurological impairment. It could also provide an important 
tool to elucidate the role of neuronal lysosomal trafficking in the 
pathophysiology of neurodegeneration.