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Developmental Biology - ALS

A Target For ALS

Harvard University research reveals a potential therapeutic target for ALS...

A new discovery opens doors to improving diagnostics and developing a new therapy for the majority of ALS patients. Research led by stem cell scientists at Harvard University points to a potential new biomarker and drug target for amyotrophic lateral sclerosis (ALS), a neurological disease that is extremely difficult to diagnose and treat.

Published in Nature Neuroscience, the study used stem cell models of human motor neurons to reveal that gene STMN2 is a potential therapeutic target, demonstrating the value of human stem cells in drug discovery.

Diagnosing and Treating ALS

Patients with ALS experience the loss of motor neurons and progressive paralysis. Following a long diagnostic journey, they may survive up to five years. Two ALS drugs have been approved by the U.S. Food and Drug Administration (FDA), but they act only to slow the disease.

In addition to a cure - or even a treatment that is effective for more ALS patients - a robust test for ALS is sorely needed. For that to happen, scientists need to find a reliable biomarker of the disease.

TDP-43: A Hallmark of ALS

About 10 years ago, scientists found aggregates of a protein called TDP-43 in the post-mortem neurons of ALS patients. This protein should have been in the nucleus of those neurons, but instead was found in the cell cytoplasm.

Clearly, some of the genes at work in the neurons' trash-disposal system (the proteasome) were interacting with TDP-43 in a way that led to ALS. But which genes are involved and what are they doing?

The gene that encodes for TDP-43 can be mutated to trigger ALS. Passed on to future generations, they develop either ALS or in some cases, frontotemporal dementia (FTD). Since TDP-43 aggregates were discovered in ALS patients, these aggregates are now a hallmark for the disease.

What Researchers Found

TDP-43 is one of many proteins that binds to RNA, which is responsible for transmitting gene information and translating it into a recipe for proteins. For example, those proteins found in a growing neuron.

For the first time scientists set out to identify all the possible types of RNA regulated by the TDP-43 protein in human neurons. Until now, studies like this were only carried out in mice and cancer cell lines. Now scientists can look at what happens to each gene when TDP-43 is manipulated.

Reduced TDP-43 levels in human stem cell-derived motor neurons was analysed using RNA-sequencing, showing scientists how gene expression changes. Among the thousand or so genes that reflected change, one stood out: Stathmin2 (STMN2) a gene important in neural outgrowth and repair. STMN2 changed consistently in step with TDP-43.
"Once we had a connection between the TDP-43 and the loss of this other critical gene, STMN2, we could see how a motor neuron might begin to fail in ALS.

"With the discovery that our human stem cell model had predicted exactly what was happening in patients, Joe went on to test whether fixing Stathmin2 could rescue motor neuron degeneration caused by disturbance to TDP-43.

"In a beautiful series of experiments that I believe provide great hope for patients, he went on to show this was exactly the case: rescuing expression of Stathmin2 rescued motor neuron growth."

Kevin Eggan PhD, Professor of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Mass., USA.

The Culprit

The researchers observed that without TDP-43, STMN2's perfectly read protein-making instructions turn into nonsense.
"We discovered that when TDP-43 levels are diminished in the nucleus, an exon is spliced into STMN2 messenger RNA. This exon basically deletes its instructions for making functional protein. It becomes impossible for STMN2 to create a vital component to repair or grow motor neuron axons."

Joseph R. Klim PhD, Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA; Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA; Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA

Double and Triple Checking

The next step was to see if their findings reflected the reality of a patient's biology. They obtained data from RNA sequencing studies that used post-mortem samples from ALS patients. Those rare datasets, compared with controls, echoed the team's original findings in human stem cell models. The data from ALS-patient spinal cords mapped to the cryptic exon, but data from the controls did not.

Luis Williams of Q-State Biosciences, whose PhD thesis in HSCRB was the first major step in this study, adds:
"Because we had pluripotent stem cells of human origin, we could make cells in a dish that are relevant to ALS and investigate this very specific problem in the right context: with a human genome and all of the genetic factors that regulate motor neurons."

Why It Matters
"These experiments point towards a clear path for testing whether repairing Stathmin2 in patients can slow or stop their disease. The discovery we have made suggests a clear approach for developing a potential therapy for ALS - one that would intervene in all but a very small number of individuals, regardless of the genetic cause of their disease."

Kevin Eggan PhD, Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA; and, Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA

The findings that amyotrophic lateral sclerosis (ALS) patients almost universally display pathological mislocalization of the RNA-binding protein TDP-43 and that mutations in its gene cause familial ALS have nominated altered RNA metabolism as a disease mechanism. However, the RNAs regulated by TDP-43 in motor neurons and their connection to neuropathy remain to be identified. Here we report transcripts whose abundances in human motor neurons are sensitive to TDP-43 depletion. Notably, expression of STMN2, which encodes a microtubule regulator, declined after TDP-43 knockdown and TDP-43 mislocalization as well as in patient-specific motor neurons and postmortem patient spinal cord. STMN2 loss upon reduced TDP-43 function was due to altered splicing, which is functionally important, as we show STMN2 is necessary for normal axonal outgrowth and regeneration. Notably, post-translational stabilization of STMN2 rescued neurite outgrowth and axon regeneration deficits induced by TDP-43 depletion. We propose that restoring STMN2 expression warrants examination as a therapeutic strategy for ALS.

Joseph R. Klim, Luis A. Williams, Francesco Limone, Irune Guerra San Juan, Brandi N. Davis-Dusenbery, Daniel A. Mordes, Aaron Burberry, Michael J. Steinbaugh, Kanchana K. Gamage, Rory Kirchner, Rob Moccia, Seth H. Cassel, Kuchuan Chen, Brian J. Wainger, Clifford J. Woolf and Kevin Eggan.

This research was supported by HHMI, Project ALS, HSCI, Target ALS and the NINDS grant NIH5R01NS089742 to K.E. J.R.K. is the Project ALS Tom Kirchhoff Family Postdoctoral Fellow. B.N.D.-D. was supported by the Milton Safenowitz postdoctoral fellowship from the ALS Association. A. Burberry was supported by the US National Institutes of Health (1K99AG05780801A1). D.A.M. was funded by the MGH training grant (5T32CA009216) and is grateful for the assistance of the Massachusetts ADRC neuropathology core in preparing tissue samples. B.J.W. is a New York Stem Cell Foundation Robertson Investigator. We thank D. Cleveland for the generous gift of TDP-43 (FL9) antibody.

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Oct 23 2019   Fetal Timeline   Maternal Timeline   News  

Stephen Hawking

Stephen Hawking, Cambridge University physicist (8 January 1942 14 March 2018), speaks during a press conference in London, 2014. His 55 year battle with ALS is thought to be one of the longest. Hawking was cared for by his wives and children throughout his life, and also repeatedly credited the British National Health Service (NHS) for his care, saying: I would not be here without it.
Credit: Independent News.

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