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Apr 18

Research Byte: Stimulation of autophagy (“self-eating”) rescues genetic abnormalities in ALS

Packard Center News, Research Bytes
Innovative new research from Packard investigators explores how RNA binding proteins might lead to ALS.

The exact cause of amyotrophic lateral sclerosis (ALS) is unknown, but research has shown that some ALS patients have mutations in their genes that directly contribute to development of the disease. Many of the genes that scientists have identified as instigators of ALS include RNA binding proteins, or RBPs, which are responsible for regulating critical communication processes between your genes and the proteins they create.  A team of researchers directed by Dr. Jared Sterneckert, Group Leader of the Center for Regenerative Therapies at the Technische Universität Dresden and Packard Center-funded investigator, just published innovative new research exploring how RBPs might lead to ALS. In addition to enhancing our understanding of how ALS progresses, their Acta Neuropathologica manuscript also provides compelling proof-of-concept evidence for a promising new treatment strategy for ALS.

RNA is genetic material that can be thought of as the translator between your genes and the functioning proteins they eventually become. Without RNA, your genes are speaking German and your proteins are speaking Chinese… nothing can get done because genes and proteins can’t communicate!  The function of RNA is in turn regulated through RBPs. There are hundreds of RBPs in your cells, but when a handful of these critical messengers mutate they go to the wrong location within the cell and contribute to the development of ALS.  One such RBP that Dr. Sterneckert and colleagues investigated is called FUS.  FUS is normally located in the nucleus, or the control center of the cell, but in ALS, FUS can aggregate outside of the nucleus in the cytoplasm of cells. The importance of FUS to the health of your neurons is evident upon learning that the average age of ALS diagnosis is 55, but over half of all patients with mutations in FUS experience ALS-related pathology before 40 years of age.  Dr. Sterneckert’s team was interested to learn more about how FUS actually causes problems in motor neurons and determine if there is a way to restore normal FUS function, thereby preventing the development of ALS.

The researchers first obtained spinal cord tissue from ALS patients and confirmed that mutations in FUS cause build-up of the protein in the cytoplasm of motor neurons in humans. The researchers then genetically manipulated neurons to have mutations in FUS that caused similar cytoplasmic build-up of FUS that was observed in human tissue. Not only did the FUS accumulation directly cause problems with protein metabolism in the neurons, but it also led to reductions in the levels of other RBPs that contribute to ALS, and in turn, decreased neuronal survival.  Taken together, these findings show that FUS sets off a chain reaction of harmful events to the neuron that involves recruitment of other ALS-related RBPs and causes cell death.

Similar to how humans consume food for energy and produce waste with the digested leftovers, the individual cells in our body also require energy to function and produce waste byproducts.  But cells don’t have kidneys or a gastrointestinal system like humans do, so how do they get rid of their waste?  The answer is through a process called autophagy.  Derived from Greek words meaning “self” (auto) and “eating” (phagein), autophagy involves delivery of cellular waste products to a special compartment in the cell that breaks them down using enzymes.  Dr. Sterneckert’s team found that the neurons with high levels of FUS built up in the cytoplasm also exhibited signs of impaired autophagy. Similarly, when they inhibited autophagy in motor neurons, the researchers found accumulation of pathological cytoplasmic FUS. These findings led the investigators to hypothesize that stimulating autophagy could have an opposite and beneficial effect in ALS.  Using cell culture systems, the researchers found that induction of autophagy with a drug called torkinib led to decreased FUS accumulation, increased levels of beneficial ALS-related RBPs, and improved survival of neurons.  Collaborator and co-author Dr. Udai Bahn Pandey, a Packard Center-funded investigator at the University of Pittsburgh, tested their idea to a fruit fly model of ALS and found that stimulation of autophagy improved motor function in the insects.  

The results from the present study have exciting implications for ALS research. “Our results place impaired protein dynamics at the core of ALS pathogenesis,” write the authors.  Torkinib unfortunately can’t penetrate into the brain in the human body, but similar compounds with enhanced brain permeability are currently in clinical trials for other disease indications.  Further research must be conducted with factors like genetics and stage of disease in mind before clinical translation to ALS is appropriate, but Dr. Sterneckert’s work lays the necessary groundwork for these future studies. Although the focus of this paper was the RBP FUS, they conclude that, “defects in autophagy have been associated with both familial and sporadic ALS cases… we propose that modulating autophagy could be an effective therapeutic for many ALS patients.” 

~Kristen Hollinger 


Photo credit: Technische Universität Dresden

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