As parents of children who have been diagnosed with Pelizaeus Merzbacher Disease, you know the cause of the disease is due to mutations in a gene called proteolipid protein. This protein is made by a cell type called the oligodendrocyte meaning it has few, small processes that arise from the cell body that makes the myelin sheath. The myelin sheath is essential for the axon, a process from the neuron that conducts electrical impulses down the axon. Destruction of the myelin sheath is considered the “hallmark” of the disease as its loss is devastating to humans. But a lot goes on within the oligodendrocyte and the other cells in the brain before myelin is destroyed.
Fortunately, well maybe unfortunately, rodents have the same mutations as humans, exhibiting similar neurological symptoms so they can be used to study how myelin is destroyed. Even with the mice and rat models, so much is going on within the cells of the nervous system that it is difficult to figure out the sequence of events that lead to the destruction of myelin. But a couple of families with PMD lack the gene and so do some mice. They haven’t been studied as much as children who have duplications of the gene because their symptoms are not as bad. One of the take home messages from these mice is that you gotta have PLP in just the right amounts, or else.
Our lab studies not only mice with duplications of the gene but also mice lacking the gene. They are very expensive to breed and maintain but with financial support from the PMD FNDN we have been able to maintain colonies of these mice. We had shown in previous papers that mice with duplications (an extra copy) of the gene that this protein gets into mitochondria when it gets duplicated (see our papers: Huttemann et al., 2009; Appikatla et al., 2014). Then things get nasty: microglial cells that are the inflammatory cells of the brain become turned on and make bad molecules called cytokines. That’s perhaps not so surprising but what turns out to be unexpected, is that microglia in mice lacking PLP get turned on very early (one month after birth) before there are noticeable defects in myelin (one year). However, they seem to make some good cytokines and shut down the bad ones. There are also metabolic defects in these null mice that pop up before myelin is destroyed. The take home message here is twofold: one, metabolic defects and microglial activity are up-regulated well before myelin is destroyed; two, PLP must be made or else there dire consequences. The implication is that these defects are probably major contributors to myelin destruction. These defects can be corrected with drugs and other therapies so metabolism needs further investigation in PMD.
The effects of PLP on metabolism can be measured in tissue culture and in mice with an instrument called the Seahorse (Somayajulu 2018). We have shown in tissue culture that metabolism in mice with duplications of the PLP gene have significantly lower metabolic parameters compared to normal mice. By using different drugs and compounds, we can return metabolism to more normal levels. We have already tried one compound in tissue culture and it improves their metabolic parameters. This compound can be tested in mice and we will try other drugs/compounds used in humans that raise metabolic levels. The important thing about finding abnormal metabolism in PLP mutations is that is that we can experimentally test FDA approved drugs/compounds in animals and if we find improvements in terms of behavior and lifespan, then they can be used with human patients in a non-invasive manner.