NIH Renews Grant for Study of Neurodegenerative Diseases

Crucial Miller School research on the mechanisms of protein folding and stabilization, important factors in understanding the underlying causes of diseases such as cystic fibrosis, amyloidoses and some forms of autism, was given another funding green light by the National Institutes of Health’s National Institute of Neurological Diseases and Stroke.

The grant for the research, which is part of the decades-long scientific undertaking by Richard L. Rotundo, Ph.D., professor of cell biology, physiology and biophysics and neuroscience, was renewed for $2.75 million over five years. The previous award was for $1.29 million over four years.

“We’re excited that the NIH continues to validate the importance of our research,” said Rotundo. “Protein folding disorders are one of the major consequences of mutations because slight changes in the amino acid sequence of a protein can cause it to become unstable and degraded inside the cell. That’s basically the same as not having the protein at all.”

Specifically, the NIH funding is intended to advance the novel study of the enzyme acetylcholinesterase folding and of ways to improve its ability to fold correctly in vivo. Acetylcholinesterase, or AChE, is the enzyme that, through its hydrolytic activity, breaks down the neurotransmitter acetylcholine in the central and peripheral nervous systems including nerve-muscle connections. The enzyme terminates the signal between nerves and muscle that initiates muscle contraction. After the contractions it is necessary for acetylcholine to be broken down so the muscles involved will be able to relax. Otherwise spasms or even paralysis can occur.

Rotundo and his team have been making steady progress in finding ways to overcome the problems that arise when there are deficiencies in neuromuscular acetylcholinesterase.

Agents such as biological toxins, pesticides, and nerve gases that inhibit AChE can quickly induce paralysis. A goal of Rotundo’s laboratory is to identify means to promote cellular production of new AChE molecules in order to overcome the potentially lethal effects of such agents. The team has discovered a means of increasing the enzyme’s production in a mouse model using a peptide that, when injected into the mice, is taken up by the muscle cells. Once inside the cells, the peptide stabilizes newly synthesized acetylcholinesterase molecules and results in an increase of the enzyme at the neuromuscular synapses where the neuron is releasing acetylcholine to stimulate muscular contraction.

So far, tests indicate that this increase in AChE production provides protection against normally lethal doses of nerve agents or pesticides. These studies are the first to show that it is possible to use introduced molecules to promote protein folding and stabilization in vivo.

The success of this strategy, if it can be extended to humans, suggests possibilities for intervention in other human diseases that are known to involve protein misfolding during synthesis. Such possibilities include lysosomal storage diseases, cystic fibrosis, and Alzheimer’s, for which there are as yet no known strategies for intervention in the underlying protein misfolding.

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