Motor neuron toxin associated with ALS identified by UMass Chan investigators

Robert H. Brown Jr., DPhil, MD

An international team of researchers has discovered that an inorganic polyphosphate released by nerve cells called astrocytes in people with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) contributes to the motor neuron death that is the signature of these diseases . The research, by Brigitte van Zundert, PhD, assistant professor of neurology at UMass Chan and professor at Universidad Andres Bello in Chile; Robert H. Brown Jr., DPhil, MD, professor of neurology, and colleagues appear this week in neuron.

“We are encouraged by these initial results,” said Dr. Brown, the Leo P. and Theresa M. LaChance Chair in Medical Research. “These findings offer an entirely new perspective on the pathogenesis of ALS, raising exciting hypotheses and possibilities for both disease biomarkers and therapeutic targets.”

ALS and FTD are characterized by the degeneration of motor neurons in the spinal cord and frontal lobes, but the causes of this neurotoxicity have remained elusive. And while great strides have been made in identifying the genetic mutations that cause these neurodegenerative disorders, the vast majority of cases have no identifiable genetic mutation. How genetic changes affect neurons and the possible impact of toxic factors have also remained elusive.

Brigitte van Zundert, PhD

Previous research has shown that astrocytes – the glial cells of the brain and spinal cord – can release one or more toxic factors that contribute to motor neuron death. the neuron The study provides evidence that the offending neurotoxic factor is a common inorganic polyphosphate, which has been shown to be released by mouse and human astrocytes in cells with an array of ALS/FTD-related mutations (including SOD1, LATEBP and C9ORF72).

The toxic factor, called polyP, is a ubiquitous negatively charged inorganic biopolymer found in the cells of all living organisms, from bacteria to mammals. These polyphosphates perform many functions in cells: energy storage, formation of membrane channels, control of gene activity, regulation of enzymes and response to stress.

“The biggest surprise of our study is that the toxic factor is not a new or rare protein or peptide, but rather a very simple inorganic molecule that is found in every cell type tested in nature and conserved over more than 3 billion years of evolution,” said Dr van Zundert, corresponding author on the neuron study.

An important research finding is that samples of human cerebrospinal fluid from familial and sporadic cases of ALS revealed increased levels of polyP.

“Study shows that exposure of spinal cord neurons to polyP mimics the toxic effects of ALS astrocyte culture media, causing hyperexcitability, increased Ca2+ flux into neurons, and increased motor neuron death” , van Zundert said.

Additionally, van Zundert, Brown and colleagues found that motor neurons can be rescued from astrocyte toxicity by reducing polyP levels.

“Our results strongly support the idea that reducing polyP levels extracellularly may be an innovative therapeutic strategy for various types of ALS/FTD,” van Zundert said.

As a postdoctoral fellow in Brown’s lab in 2008, van Zundert discovered that increased motor neuron electrical excitability is an early and critical feature of mouse models of ALS. van Zundert began considering polyPs as a potential cause of hyperexcitability in 2014, when it was reported that this molecule could act as a glial transmitter that mediates communication between astrocytes and neurons.

ALS and FTD are devastating and incurable diseases. ALS is a progressive neurodegenerative disease that involves the loss of motor neurons that control voluntary muscles. About 10% of ALS cases are familial – inherited from a person’s parents – and are caused by a genetic mutation in a patient’s DNA. The remaining 90% of cases are classified as sporadic and occur in cases with no family history of disease. An estimated 6,000 people in the United States are diagnosed with ALS each year.

Similarly, FTD, originally called Pick’s disease, is one of the most common forms of dementia praecox, second only to Alzheimer’s disease. FTD is caused by the loss of neurons in the frontal or temporal lobes.

This study was supported by several funding agencies, including the ALS Association, Angel Fund for ALS Research, ALS Therapy Alliance, ALS Finding a Cure, ALS ONE, Max Rosenfeld ALS Research Fund, and FightMND and with additional support from the National Institutes of Health and several Chilean government agencies.

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