Comparative Hippocampal Proteome and Phosphoproteome in a Niemann–Pick, Type C1 Mouse Model Reveal Insights into Disease Mechanisms

Niemann–Pick
disease, type C (NPC) is a neurodegenerative,
lysosomal storage disorder in individuals carrying two mutated copies
of either the NPC1 or NPC2 gene.
Consequently, impaired cholesterol recycling and an array of downstream
events occur. Interestingly, in NPC, the hippocampus displays lysosomal
lipid storage but does not succumb to progressive neurodegeneration
as significantly as other brain regions. Since defining the neurodegeneration
mechanisms in this disease is still an active area of research, we
use mass spectrometry to analyze the overall proteome and phosphorylation
pattern changes in the hippocampal region of a murine model of NPC.
Using 3 week old mice representing an early disease time point, we
observed changes in the expression of 47 proteins, many of which are
consistent with the previous literature. New to this study, changes
in members of the SNARE complex, including STX7, VTI1B, and VAMP7,
were identified. Furthermore, we identified that phosphorylation of
T286 on CaMKIIα and S1303 on NR2B increased in mutant animals,
even at the late stage of the disease. These phosphosites are crucial
to learning and memory and can trigger neuronal death by altering
protein–protein interactions.