The first lysosomal storage disorder Perlstein Lab is focusing on is Niemann-Pick disease, Type C (NPC). We decided to start with NPC not only because it is one of the most well studied lysosomal storage disorders, but also because the gene that is mutated in this disease is conserved in fish, flies, worms, and yeast. This deep evolutionary conservation allows us to validate our platform across all our model organisms.
NPC affects about 1 in 150,000 people and is primarily characterized by neurological complications that often begin early in childhood, and ultimately cause premature death. Symptoms often include loss of movement coordination, slurred speech, difficulty swallowing, seizures, paralysis, and dementia. Like other lysosomal storage disorders, symptoms worsen over time.
NPC is caused by mutations in the gene NPC1, and to a much lesser extent the related gene NPC2. NPC1 encodes for a transmembrane protein that acts as a gatekeeper for cholesterol, allowing it to exit the lysosome. When NPC1 is mutated, there is a buildup of cholesterol within the lysosome, which interferes with the traffic flow of molecules within the cell. Mutations in NPC1 account for 95% of NPC disease cases, while mutations in NPC2 occur in just 5% of patients. Both types of mutations are autosomal recessive, meaning two carrier parents have a 25% chance of having a child with NPC.
As described in our introductory lysosomal storage disorder blog post, the defect in NPC1 or NPC2 leads to an aberrant accumulation of cholesterol and other lipids inside the lysosome. In the factory analogy, NPC1 protein is better depicted as a broken down transport truck that is unable to traffic cholesterol out of the lysosome.
The trapping of cholesterol inside lysosomes decreases cholesterol availability for the rest of the cell and the body, which impacts the ability to make cell membrane and hormones, including neurosteroids. The accumulation tends to happen in the liver, spleen and brain, and can also cause structural changes to nerve cells. The exact mechanism of how the NPC1 gene mutation leads to cholesterol accumulation is not fully understood.
There is currently no cure for NPC. However, ongoing early-stage clinical trials with hydroxypropyl-beta-cyclodextrin have shown promise in delaying the onset of symptoms. Other experimental treatments are also being investigated.
At Perlstein Lab, we are taking a different approach to discovering new drugs for NPC by modeling known mutations of NPC1 in primordial animal models. As stated above, the NPC1 gene is well conserved among eukaryotes, and other scientists have previously validated models of the disease in yeast, worm, fly, and fish. By using similar organism models, we hope to find compounds that rescue the affects of specific mutations and correct the underlying cellular defects of the disease.