Lysosomes are enzymes that act as cellular recyclers. Every cell in our body generates waste. Lysosomes break down worn-out components of cells and recycle their parts. Dr. Diwan says there are about 50 different types of lysosomal storage disorders, which arise from either genetic mutations in lysosomal enzymes or a key structure component of the lysosome. Even though individual lysosome storage diseases are rare, taken together, these disorders occur in approximately one out of 7,000 births.
These diseases create life-limiting conditions, common manifestations of which are failure to thrive and frequent hospitalizations. Because they affect the health of the central nervous system, these diseases can cause behavioral and developmental disorders. Dr. Diwan says that 70 percent of them also affect the heart as the disease progresses.
“We know that one of the key roles of lysosomes is to break down fat stored in cells so it can be used to create energy our bodies need to function,” Dr. Diwan says. “A recent exciting body of work suggests that lysosomes also control the nutritional state of the cells.”
So what happens when cells can’t access their stored fat or regulate their nutritional state? Simply stated, it depends on which mutated lysosome enzyme is involved. For example, mucopolysaccharidoses are a group of disorders caused by the absence or malfunctioning of lysosome enzymes needed to break down long chains of carbohydrates that help build bone, cartilage, tendons, corneas, skin and connective tissue. Another is Pompe disease, a neuromuscular disorder that causes progressive muscle weakness. Its origin is a defective gene that results in acid alphaglucosidase, a deficiency of the lysosome enzyme that makes it unable to break down glycogen. The resulting excessive build-up of this sugar gets stashed in a specialized compartment of muscle cells throughout the body, crowding out nutrients.
However, while most lysosome storage diseases may start off as a problem with only one of the enzymes, that problem rapidly affects other lysosomes, creating global dysfunction that includes a reduction in cellular fat stores and other nutrients important for normal cell metabolism.
“Many manifestations of these disorders end up being fairly similar, which is why we think there is a final pathway where the lysosome becomes dysfunctional,” Dr. Diwan says. “If we can better understand the underlying common biology in these disorders, we can look for better ways to stop their progression or even reverse their damage. If we can identify the byproducts of the fats lysosomes are supposed to break down, we can begin creating nutritional supplements that could replace those fats and help prevent disease progression.”
For this research, Dr. Diwan has brought together investigators with diverse backgrounds. Co-investigator Mark Sands, PhD, medicine, will lend his expertise in lysosome storage diseases to the project. Dr. Sands’ laboratory made the observation that many lysosome storage diseases demonstrate reduced fat stores. Stephen Kornfeld, MD, PhD, developmental biology, brings to the project expertise in the animal model they will be using. Together, these researchers developed the hypothesis that this group of diseases shares very similar origins in children.
CDI funding will enable these investigators to build C. elegans models of different types of lysosome storage diseases. C. elegans are worms whose translucence makes them useful in studies that ask biological questions. They also have short lifespans, which cuts the time needed to watch them fully develop from months or years to just days. These organisms were the first whose genome was completely mapped.
“There are 1,000 cells in an adult worm,” Dr. Diwan says. “We know how each of these cells comes into being from the time of fertilization. This allows us to manipulate their genes and observe the effects of that manipulation with mathematical precision.”
In the first phase of their project, funded by the CDI, the researchers will use their worm models to discover which byproducts of lysosome enzyme recycling, or metabolites, are key to survival during starvation. Phase two of the study will be to research the effects these metabolites have in mouse models when paired with certain dietary manipulations. For example, based on findings from the first phase of the study, they may feed the mice a diet rich in simple sugars and polyunsaturated fatty acids to test if that would help rebuild their fat stores.
“Our early worm experiments lead us to believe that supplementing the organism’s diet with simple nutrients, such as glucose and polyunsaturated fats, may actually be a very good way to avoid nutrient deficiencies lysosome storage diseases create,” Dr. Diwan says. “This seems to be because these simple nutrients can bypass the lysosome dysfunction and allow the fat stores to be replenished.”
The researchers’ hope is to leverage their phase-one study results to gain the funding needed to take what they learn to the mouse model. From there, it will be on to public funding sources, such as the National Institutes of Health.
Dr. Diwan says this work could have broad implications into the origins of other diseases. “One might wonder why three adult medicine physicians would be interested in a disease that has its origins in childhood. The answer is clear if you consider that lysosome dysfunction could play a role in common adult disease, such as heart disease and Alzheimer’s. Knowing the developmental biology of lysosomes could one day lead to us being able to alter their dysfunction and reduce the risk of heart failure or delay the progression of Alzheimer’s. Those are big challenges, but the CDI has given us the opportunity to start somewhere.”