MDA’s latest round of ALS research grants focuses on basic mechanisms in the disease process, with an emphasis on targeting misfolded proteins such as TDP43, FUS and SOD1.
Proteins are cellular workhorses, responsible for virtually every function in the body. A protein is a long chain of amino acids, folded into a precise shape. If a protein misfolds, it cannot function properly and must be broken down by the cell to prevent it from causing problems. Otherwise, misfolded proteins can stick together and form clumps in the cells called aggregates. Misfolded proteins are found in the motor neurons of nearly all people with amyotrophic lateral sclerosis (ALS), and studies suggest that aggregates may play a central role in the disease process.
Two new MDA grants for ALS research, totaling $477,410, address issues of protein misfolding. Three additional MDA grants totaling $900,000 fund the study of motor neuron loss in related diseases, which also could lead to important findings for ALS.
These grants are part of 31 new grants totaling $8.5 million that were approved by MDA’s Board of Directors in July and took effect Aug. 1. All 31 grants can be viewed in the Summer 2013 Grants at a Glance slideshow.
Studying defects in protein recycling
Constanza Cortes, a postdoctoral researcher at the University of California at San Diego, is studying the role of a recycling system called autophagy in ALS and another motor neuron disease, spinal-bulbar muscular atrophy (SBMA or Kennedy disease). While the causes of the two diseases differ, both involve defects in autophagy, the system cells use to break down and recycle large proteins and subcellular structures.
Autophagy (“awe-TOF-uh-gee”) is critical for cell health, but relatively little is known about how the process works in motor neurons. Autophagy should take care of the accumulated proteins in motor neurons before they cause problems, but the process appears to be disrupted in ALS and SBMA.
Cortes' goal is to learn more about what regulates autophagy in motor neurons, and how that regulation goes awry in these two diseases.
(MDA also is funding research into the role of autophagy in type 2B Charcot-Marie-Tooth disease, another neurodegenerative disease under MDA’s umbrella.)
Breaking up protein aggregates
James Shorter, associate professor of biochemistry and biophysics at the University of Pennsylvania in Philadelphia, is exploring whether it is possible to break up aggregated proteins in ALS, and refold them into their proper shape. By doing so, he hopes it may be possible to rescue endangered motor neurons.
Shorter is evaluating the therapeutic potential of proteins called disaggregases, derived from yeast cells. His targets will be the various proteins known to form aggregates in ALS, including TDP43, FUS and SOD1. If the disaggregases can break up the aggregates in animal models, and if that is beneficial, further work may be warranted to develop the strategy as a therapy in humans.
Studying motor neurons in SBMA and SMA
Motor neurons are the muscle-controlling nerve cells that are lost in ALS. Three new MDA grants fund projects that look at motor neurons in SBMA and spinal muscular atrophy (SMA), two other diseases in which motor neurons are lost.
While these diseases have different causes than ALS, it’s likely that a deeper understanding of motor neuron vulnerability and protection in these diseases would have direct benefit in developing treatments in ALS.
Motor neurons and the neuromuscular synapse: A neuromuscular synapse is the connection between the motor neuron and muscle cell, through which the motor neuron transmits signals that controls muscle contraction. One of the first events leading to motor neuron death is the loss of connection between neuron and muscle at the synapse.
Umrao Monani, associate professor at Columbia University Medical Center in New York City, has received MDA funding to study how these synapses develop, and how that process is disrupted in SMA. That may lead to a better understanding of this process in ALS, as well.
Motor neurons and SBMA: Albert La Spada, professor of cellular and molecular medicine, neurosciences and pediatrics at the University of California, San Diego, received a grant to support research in SBMA that focuses on the causes of neurodegeneration (loss of motor neurons) in this disease.
La Spada is investigating how the SBMA-causing mutation in the androgen receptor protein leads to the death of motor neurons, focusing on changes in metabolism and impaired degradation of worn-out or defective proteins.
Antisense oligonucleotides targeted to different genetic mutations are being tested in ALS, and results from La Spada's work in SBMA may help advance this work.
Motor neurons and respiration: Bennett Novitch is studying the development of motor neurons that control respiration, which are affected early in type 1 SMA, which manifests in infancy.
One theory about motor neuron diseases is that the neurons that die earliest are the ones that are most vulnerable, a vulnerability that may arise during development. Novitch, assistant professor of neurobiology at the University of California, Los Angeles, hopes to learn more about normal motor neuron development and gain insight into the processes that may make respiratory motor neurons especially vulnerable.