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Feb 2

New study links stress granules and autophagy with ALS

ALS Headlines, Packard Center News
Packard scientists have created a novel tool that has identified new links between ALS and a motor neuron’s ability to handle aggregation-prone proteins in response to stress.

Packard scientists Jared L. Sterneckert of the Technische Universität Dresden and Udai Pandey of the University of Pittsburgh have created a novel tool that has identified new links between ALS and a motor neuron’s ability to handle aggregation-prone proteins in response to stress. The study, published in Stem Cell Reports, paves the way for the screening of existing FDA-approved drugs that may alleviate the dysfunctional stress response seen in ALS motor neurons.

“The collaboration between our two labs started at a Packard symposium two years ago. Since then, we have developed a better tool for studying ALS and made it available to the whole community,” Pandey says.

Although ALS has a variety of environmental and genetic causes, nearly all ALS patients contain large clumps in the cytoplasm of motor neurons called stress granules. Consisting of dense clumps of RNA and proteins, stress granules are a normal part of the cell’s stress response system. After the environmental stressor has passed, the cell breaks them down, and cellular functions are restored. Not so in ALS. Instead, the stress granules persist and generate detrimental insoluble aggregates. It is believed that aberrant stress granules may lead to the formation of protein aggregates.

In ALS, stress granules recruit a protein called FUS. Researchers have linked mutations in FUS to ALS, and these mutations can cause mislocalization of FUS from its normal home in the nucleus to the cytoplasm, where it is incorporated into stress granules. The appearance of FUS in stress granules also occurs in individuals with frontotemporal dementia (FTD) who lack FUS mutations. Other ALS-associated proteins, including TDP43 and Ataxin2, have also been linked to stress granule formation, making this a major potential target for drug development. Harnessing this connection means understanding the relationship between autophagy, stress granules, and ALS.

Lara Marrone from the Sterneckert lab used CRISPR/Cas9-mediated gene editing to generate neurons from induced pluripotent stem cells (iPSCs) carrying a copy of mutant FUS in cooperation with Andreas Hermann, Simon Alberti and Anthony Hyman. FUS mutant cells showed increased recruitment of FUS protein into stress granules. Inhibiting the mTOR pathway using the drugs rapamycin or torkinib induced autophagy and reduced the amount of FUS in the stress granules. Using fruit flies carrying copies of mutant FUS, the Pandey team, led by Ian Casci, showed that the genetic induction of autophagy increased survival.

The teams screened a library of FDA-approved drugs and identified several anti-depressant and anti-psychotic medications that could both increase autophagy and reduce FUS recruitment into stress granules, indicating their potential to be investigated as prospective ALS treatments and be used to develop new medications.

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