ABSTRACT
Niemann Pick disease is a group of metabolic diseases caused by
specific genetic mutations. There are three types of this disease: type A,
type B and type C.
Types A and B (due to mutations on 11p15.1-p15.4) are caused by the
deficiency of the enzyme acid sphingomyelinase (ASM), required to
metabolize the lipid sphingomyelin.
The Niemann-Pick type C is caused by altered intracellular lipid traffic;
this pathology is characterized by the accumulation of lipids, such as
cholesterol and glycosphingolipids, within the cells. NPDC also causes a
reduction of ASM activity, for this reason all three types have been
considered as forms of the same disease.
NPC patients are not able to metabolize correctly lipids, consequently
cholesterol accumulates in the lysosomal/late endosomal compartments
especially in liver and spleen. In the nervous system not only cholesterol
but also all the other lipid classes are deregulated.
The NPDC is always fatal, in particular, the patients affected by the
juvenile form, due to the I1061T mutation (on 18q11q12), die before
twenty years of age.
A late symptom appearance can prolong the life extension, but it is
With this work a detailed analysis of the cellular mechanisms that cause
neuronal damage has been made. We have used as a cellular model of
the pathology the hippocampal neuroblast line HN9.10e, transfected with
the fusion proteins NPC1 wt-GFP and I1061T-GFP. Living cell imaging
has been used to evaluate the possible dysfunction of subcellular
compartments such as mitochondria and endoplasmic reticulum.
Our experiments indicate that the NPC1 I1061T expression causes
intracellular accumulation of cholesterol. The protein I1061T is less
efficient than the wt protein in the lipid trafficking, undergoes a faster
degradation and also shows an altered intracellular localization.
The protein I1061T expression causes a cell growth slowing down and a
dose-dependent increase in apoptotic death. Moreover, the mutant
protein transfection produces fragmentation of mitochondrial network,
reduction of trans-membrane potential, and activation of the
