Cystic Fibrosis and Niemann Pick Type C Linked Through Cholesterol Abnormalities and cAMP Cell Signaling Pathway

A few months ago, I wrote a blog about the connection points between Duchenne Muscular Dystrophy (DMD) and Niemann Pick Type C (NPC) and how more research dollars are needed for collaborative research projects between the two deadly diseases. Today, I am writing about the connections between Cystic Fibrosis (CF) and Niemann Pick Type C. Cystic Fibrosis (CF) is the most common, fatal hereditary disease in the U.S.  CF is a disorder of the cells that line the lungs, small intestines, sweat glands and pancreas. Sticky, thick mucus contributes to the destruction of lung tissue and impedes gas exchange in the lungs. It also prevents nutrient absorption in the small intestine, and blocks pancreatic ducts from releasing digestive enzymes.  I am not going to get into all of the horrible symptoms of Niemann Pick Type C  — simply imagine a bedridden child with complete paralysis of the eyes and severe dementia and you’ll get the picture. Not exactly the life I dreamed of for my beautiful twins, Addi and Cassi. The CFTR gene is located on chromosome 7, while the Niemann Pick Type C gene is located on Chromosome 18. What do these diseases have in common if the disease causing gene mutations are on different chromosomes? Pathways! Both the CFTR gene and NPC1 gene are regulated by the cAMP pathway and researchers at Case Western Reserve University are proposing that Cystic Fibrosis and Niemann Pick Type C cells chronically activate portions of the cAMP pathway to try and restore either CFTR or NPC1.   The chronic activation of the cAMP pathway could lead to cholesterol accumulation, inflammation and oxidative stress. Interestingly, regulation problems in the cAMP pathway could also be involved in other diseases such as Parkinson’s.

 

I am sure there are many parents in the Cystic Fibrosis community (and possibly many researchers and doctors!) who have no idea that cholesterol processing abnormalities are involved in Cystic Fibrosis or that CF and NPC share similarities. Interestingly, an experimental medication that Addi and Cassi are taking called Zavesca (Miglustat) which is made by Actelion may provide a therapeutic benefit for Cystic Fibrosis patients.  Zavesca is a substrate reduction therapy and Actelion is currently running a small pilot trial for CF patients. Niemann Pick Type C seems to combine the worst of all these larger diseases – from progressive dementia to ataxia and muscular problems to pulmonary issues. Soon to be published works shows that the HIV/AIDS virus requires the Niemann Pick Type C gene to assemble in the body.   What is the common theme here — cholesterol! I hope that Alzheimer’s and Parkinson’s researchers studying the cAMP pathway will start to look at how rare childhood diseases like CF and particularly Niemann Pick Type C can shed light into these more common diseases that affect millions. Maybe the NIH will sponsor a cAMP pathway workshop to bring together researchers from different disease states to collaborate on this critical cell signaling pathway since it is involved in so many illnesses. We need collaboration across different diseases that are interrelated find cures for people!

Calling Jerry Lewis – Scientists Report Understanding Niemann Pick Type C Could Lead To Treatments For Duchenne Muscular Dystrophy

There are new reasons for hope not only for families of Niemann Pick Type C kids but for families with children suffering from Duchenne muscular dystrophy, a fatal recessive X-linked form of muscular dystrophy that strikes 1 in 3500 boys and leads to paralysis and ultimately death.

According to a research paper released from the University of Washington, understanding the mechanism of Niemann Pick Type C (NPC), a fatal progressive neurodegenerative disease that is trying to take the lives of Addi & Cassi could help researchers find new treatments for Duchenne Muscular Dystrophy (DMD) and possibly muscular dystrophy in general.

In the studies conducted by the University of Washington, “transgenic expression of Neimann Pick Type C 1 (NPC1) in skeletal muscle ameliorates muscular dystrophy in the Dtna-/- mouse (which has a relatively mild dystrophic phenotype) and in the mdx mouse, a model for DMD. These results identify a new compensatory gene for muscular dystrophy and reveal a potential new therapeutic target for DMD.”

In addition, the researchers report that “molecular abnormalities in NPC1-null cells suggest possible links to known causes of muscle degeneration. One particularly intriguing connection involves the caveolins. Caveolin-3, the muscle-specific form, binds directly to the dystrophin complex members, β-dystroglycan at the sarcolemma and is required for the correct targeting of the dystrophin complex to cholesterol-sphingolipid rafts/caveolae. A link between caveolin-3 regulation and the muscular dystrophies is well established. Muscles from Duchenne muscular dystrophy patients and mdx mouse muscles have elevated caveolin-3 levels.”

The Muscular Dystrophy Association (MDA) through the help of Jerry Lewis has raise approximately $2 billion for neuromuscular patient care and research since its inception yet a cure has not been found to date.  This paper suggests that new therapies could be found for muscular dystrophy by looking at the NPC1 gene, a gene that causes a rare and fatal childhood disease that strikes only 500 children worldwide.   Does anyone have Jerry Lewis’ number?

Posted by Chris (MOM – Mom On a Mission)