Abstract
Niemann–Pick type C (NPC) disease is an autosomal recessive storage disorder, characterized by abnormal sequestration of unesterified cholesterol in the late endo-lysosomal system of cells. Progressive neurological deterioration and the onset of symptoms, such as ataxia, seizures, cognitive decline, and severe dementia, are pathognomonic features of the disease. In addition, different pathological similarities, including degeneration of hippocampal and cortical neurons, hyperphosphorylated tau, and neurofibrillary tangle formation, have been identified between NPC disease and other neurodegenerative pathologies. However, the underlying pathophysiological mechanisms are not yet well understood, and even a real cure to counteract neurodegeneration has not been identified. Therefore, the combination of current pharmacological therapies, represented by miglustat and cyclodextrin, and non-pharmacological approaches, such as physical exercise and appropriate diet, could represent a strategy to improve the quality of life of NPC patients. Based on this evidence, in our review we focused on the neurodegenerative aspects of NPC disease, summarizing the current knowledge on the molecular and biochemical mechanisms responsible for cognitive impairment, and suggesting physical exercise and nutritional treatments as additional non-pharmacologic approaches to reduce the progression and neurodegenerative course of NPC disease.
Highlights
It was observed that Npc1−/− mice showed a significant increase in mRNA levels for both apolipoprotein E and apolipoprotein D, which is known to occur in the presence of nerve damage in the central or peripheral nervous system [58,63,64]
Liu and colleagues demonstrated that a single dose of cyclodextrin administered at 7 days of age in Npc1−/− mice was able to reverse the lysosomal transport defect observed in Niemann–Pick type C (NPC) disease, reducing macrophage activation and influx into the liver and brain, significantly improving liver function and Purkinje cell survival, as well as reducing neurodegeneration and increasing lifespan [104]
Our results showed that the uniform continuous (UC) protocol did not improve synaptic plasticity in Npc1+/− mice compared with the sedentary control group, but on the contrary, a deterioration in the long-term potentiation (LTP) induction phase was evident
Summary
Brown and Goldstein suggested that the NPC1 and NPC2 proteins perform a combined activity during this process, as NPC2 binds unesterified cholesterol and transfers it to the N-terminal domain of membrane-associated NPC1, thereby allowing its transport out of the late endosome/lysosome compartment [10,11]. Exogenous administration of sphingosine induced its rapid accumulation in lysosomes, confirming the role of sphingosines in rapidly translocating across membranes and its subsequent entrapment due to protonation [23,25] These results suggest that the reduction in lysosomal calcium content and subsequent reduced calcium release from lysosomes is directly responsible for the endocytosis defects widely observed in NPC1 cells [24]. The aim of our review was to (i) summarize the current knowledge about the molecular and biochemical mechanisms responsible for cognitive impairment, and (ii) suggest how physical activity and appropriate diet may represent additional strategies to existing pharmacological approaches to reduce the progression and neurodegenerative course of NPC disease
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