Toxic Inorganic polyphosphate from ALS/FTD astrocytes kill motor neurons

An international team of investigators has discovered that an inorganic polyphosphate released by nerve cells known as 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 was published in the journal Neuron.

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 progress has been made in identifying 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, has also remained elusive.

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

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

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

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

“The study shows that exposure of spinal cord neurons to polyP reproduced the toxic effects of media from ALS astrocyte cultures, causing hyperexcitability, increased Ca2+ flow into neurons and enhanced motoneuron death,” said the author.

Additionally, the authors found that motor neurons can be rescued from the astrocyte toxicity by reducing levels of polyP.