Niemann-Pick disease type C (NPC) is an inherited lysosomal storage disease 
characterised by accumulation of cholesterol and glycosphingolipids. NPC 
patients suffer a progressive neurodegenerative phenotype presenting with motor 
dysfunction, mental retardation and cognitive decline. To examine the onset and 
progression of neuropathological insults in NPC we have systematically examined 
the CNS of a mouse model of NPC1 (Npc1(-/-) mice) at different stages of the 
disease course. This revealed a specific spatial and temporal pattern of 
neuropathology in Npc1(-/-) mice, highlighting that sensory thalamic pathways 
are particularly vulnerable to loss of NPC1 resulting in neurodegeneration in 
Npc1(-/-) mice. Examination of markers of astrocytosis and microglial activation 
revealed a particularly pronounced reactive gliosis in the thalamus early in the 
disease, which subsequently also occurred in interconnected cortical laminae at 
later ages. Our examination of the precise staging of events demonstrate that 
the relationship between glia and neurons varies between brain regions in 
Npc1(-/-) mice, suggesting that the cues causing glial reactivity may differ 
between brain regions. In addition, aggregations of pre-synaptic markers are 
apparent in white matter tracts and the thalamus and are likely to be formed 
within axonal spheroids. Our data provide a new perspective, revealing a number 
of events that occur prior to and alongside neuron loss and highlighting that 
these occur in a pathway dependent manner.