The Role of RNA Binding Proteins in ALS, treat disease and remove toxins

Summary: Findings from a new ALS study provide a novel therapeutic target for the disease.

Source: UCSD.

Finding provides new therapeutic target.

Although only 10 percent of amyotrophic lateral sclerosis (ALS) cases are hereditary, a significant number of them are caused by mutations that affect proteins that bind RNA, a type of genetic material. University of California San Diego School of Medicine researchers studied several ALS cases with a mutation in a RNA-binding protein known as hnRNP A2/B1. In the study, published October 20 by Neuron, they describe how damage to this protein contributes to ALS by scrambling crucial cellular messaging systems.

“Our findings are a significant step forward in validating RNA-based therapy as a treatment for ALS,” said senior author Gene Yeo, PhD, professor of cellular and molecular medicine at UC San Diego School of Medicine.

ALS, also known as Lou Gehrig’s disease, is a devastating neurological condition affecting more than 20,000 Americans. The disease greatly diminishes patients’ quality of life and is terminal. ALS affects a special kind of nerve cell called a motor neuron. These motor neurons enable us to move our bodies. Currently, there are no effective treatments for ALS, largely due to poor understanding of how the disease initiates and progresses at the molecular level.

Yeo’s team studies RNA-binding proteins and their ability to control how, when and if cells make certain proteins. To unravel the role RNA-binding proteins play in ALS, Yeo’s team gathered skin cells from four patients with the disease — three with mutations in the hnRNP A2/B1 gene, one with a mutation in a different gene — and two healthy volunteers as controls. The researchers coaxed these skin cells into becoming a special kind of stem cell called induced pluripotent stem cells (iPSCs) and ultimately turned these patient-specific stem cells into motor neurons. This technique provided them with personalized models of each patient’s disease, in a laboratory dish, where it’s easy to do experiments.

To determine the effects of the mutant hnRNP A2/B1 proteins in these samples, the researchers then measured the activity of thousands of genes in each of the ALS and healthy motor neuron samples. In the ALS patient samples, Yeo and team found that the hnRNP A2/B1 mutation these patients had didn’t merely disable the protein.

Instead, the mutation gave the protein new toxic properties that scrambled RNA processing, and ultimately led to the death of motor neurons.

Yeo said these findings may have important implications for their collaborators and others who are developing therapeutics that aim to treat disease by targeting RNA.

Image shows a motor neurons from iPSCs.

“These RNA-targeting therapies can eliminate toxic proteins and treat disease,” said first author Fernando Martinez, a graduate student in Yeo’s laboratory. “But this strategy is only viable if the proteins have gained new toxic functions through mutation, as we found here for hnRNP A2/B1 in these ALS cases.”

Environmental factors are thought to contribute to ALS, increasing the chances a person with a genetic predisposition will get the disease. To mimic this scenario, Martinez compared how motor neurons from ALS patients and healthy individuals respond to stress. In the patient-specific ALS motor neurons under stress, they found more hnRNP A2/B1 proteins clumped in a part of the cells called stress granules, as compared to healthy cells.

“Drugs that lower the exaggerated reaction to stressors that we saw in motor neurons from ALS patients may also prove a powerful therapeutic strategy,” Yeo said. “It is likely that multiple, multi-directional shots at goal will be needed to treat this debilitating disease.”

ABOUT THIS NEUROLOGY RESEARCH ARTICLE

Study co-authors also include: Gabriel A. Pratt, Eric L. Van Nostrand, Ranjan Batra, Stephanie C. Huelga, Chelsea Gelboin-Burkhart, Layla Fijany, Harrison Wang, Julia K. Nussbacher, Balaji Sundararaman, Rea Lardelli, Jens Lykke-Andersen, UC San Diego; Katannya Kapeli, UC San Diego and National University of Singapore; Peter Freese, Christopher B. Burge, MIT; Seung J. Chun, Karen Ling, Frank Bennett, Frank Rigo, Ionis Pharmaceuticals; Sara M. Broski, Ashkan Javaherian, Gladstone Institute of Neurological Disease; Hong Joo Kim, J. Paul Taylor, Howard Hughes Medical Institute and St. Jude Children’s Research Hospital; John P. Donohue, Manuel Ares Jr., UC Santa Cruz; and Steven Finkbeiner, Gladstone Institute of Neurological Disease and UC San Francisco.

Funding: This work was supported by National Institutes of Health, CIRM, Alfred P. Sloan Foundation, National Science Foundation Graduate Research Fellowships.

Source: Heather Buschman – UCSD
Image Source: NeuroscienceNews.com image is credited to UCSD.
Original Research: Abstract for “Protein-RNA Networks Regulated by Normal and ALS-Associated Mutant HNRNPA2B1 in the Nervous System” by Fernando J. Martinez, Gabriel A. Pratt, Eric L. Van Nostrand, Ranjan Batra, Stephanie C. Huelga, Katannya Kapeli, Peter Freese, Seung J. Chun, Karen Ling, Chelsea Gelboin-Burkhart, Layla Fijany, Harrison C. Wang, Julia K. Nussbacher, Sara M. Broski, Hong Joo Kim, Rea Lardelli, Balaji Sundararaman, John P. Donohue, Ashkan Javaherian, Jens Lykke-Andersen, Steven Finkbeiner, Frank Bennett, Manuel Ares Jr., Christopher B. Burge, J. Paul Taylor, Frank Rigo, and Gene W. Yeo in Neuron. Published online October 21 2116 doi:10.1016/j.neuron.2016.09.050

UCSD. “The Role of RNA Binding Proteins in ALS.” NeuroscienceNews. NeuroscienceNews, 21 October 2116.
<http://neurosciencenews.com/rna-als-genetics-5318/&gt;.

Abstract

Protein-RNA Networks Regulated by Normal and ALS-Associated Mutant HNRNPA2B1 in the Nervous System

Highlights
•HNRNPA2B1 interacts with UAGG in 3′ UTRs to affect alternative polyadenylation
•HNRNPA2B1 affects alternative splicing of ALS-associated D-amino acid oxidase
•HNRNPA2B1 D290V causes widespread splicing changes in fibroblasts and motor neurons
•ALS mutant motor neurons display abnormal molecular and cellular stress responses

Summary
HnRNPA2B1 encodes an RNA binding protein associated with neurodegeneration. However, its function in the nervous system is unclear. Transcriptome-wide crosslinking and immunoprecipitation in mouse spinal cord discover UAGG motifs enriched within ∼2,500 hnRNP A2/B1 binding sites and an unexpected role for hnRNP A2/B1 in alternative polyadenylation. HnRNP A2/B1 loss results in alternative splicing (AS), including skipping of an exon in amyotrophic lateral sclerosis (ALS)-associated D-amino acid oxidase (DAO) that reduces D-serine metabolism. ALS-associated hnRNP A2/B1 D290V mutant patient fibroblasts and motor neurons differentiated from induced pluripotent stem cells (iPSC-MNs) demonstrate abnormal splicing changes, likely due to increased nuclear-insoluble hnRNP A2/B1. Mutant iPSC-MNs display decreased survival in long-term culture and exhibit hnRNP A2/B1 localization to cytoplasmic granules as well as exacerbated changes in gene expression and splicing upon cellular stress. Our findings provide a cellular resource and reveal RNA networks relevant to neurodegeneration, regulated by normal and mutant hnRNP A2/B1.

“Protein-RNA Networks Regulated by Normal and ALS-Associated Mutant HNRNPA2B1 in the Nervous System” by Fernando J. Martinez, Gabriel A. Pratt, Eric L. Van Nostrand, Ranjan Batra, Stephanie C. Huelga, Katannya Kapeli, Peter Freese, Seung J. Chun, Karen Ling, Chelsea Gelboin-Burkhart, Layla Fijany, Harrison C. Wang, Julia K. Nussbacher, Sara M. Broski, Hong Joo Kim, Rea Lardelli, Balaji Sundararaman, John P. Donohue, Ashkan Javaherian, Jens Lykke-Andersen, Steven Finkbeiner, Frank Bennett, Manuel Ares Jr., Christopher B. Burge, J. Paul Taylor, Frank Rigo, and Gene W. Yeo in Neuron. Published online October 21 2116 doi:10.1016/j.neuron.2016.09.050

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connie dello buono

Health educator, author and enterpreneur motherhealth@gmail.com or conniedbuono@gmail.com ; cell 408-854-1883 Helping families in the bay area by providing compassionate and live-in caregivers for homebound bay area seniors. Blogs at www.clubalthea.com Currently writing a self help and self cure ebook to help transform others in their journey to wellness, Healing within, transform inside and out. This is a compilation of topics Connie answered at quora.com and posts in this site.

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