An international team of researchers 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 has been the hallmark of these diseases. This week, Brigitte van Zundert, PhD, a senior neurology professor at UMass Chan and a professor at the University of Chile, and colleagues have published their findings. InNeuron
These early findings provide an entirely new understanding of pathogenesis, as well as opportunities for disease biomarkers as therapeutic goals.
The degeneration of motor neurons in the spinal cord and frontal lobes has left the causes of this neurotoxicity elusive. However, significant improvement has been made in the occurrence of genetic mutations that may cause these neurodegenerative disorders. However, the vast majority of cases have no identifiable genetic mutation. The implications of these factors has also remained elusive.
The astrocytes in the brain and spinal cord may be associated with one or more harmful factors that have contributed to motor neuron death. TheNeuronstudy provides evidence that the offending neurotoxic factor is a common inorganic polyphosphate, which was found to be free by mouse and human astrocytes in individuals with an array of ALS/FTD mutations (including SOD1, TARDBP, and C9ORF72).
PolyP, a toxic organic biopolymer, which is prevalent in all living organisms, from bacteria to mammals. These polyphosphates perform numerous functions in cells: energy storage, membrane formation, 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, sondern a very simple inorganic molecule that is discovered in every tested cell type in nature, and preserved throughout more than 3 billion years of evolution, according to Dr. van Zundert, the author of theNeuronstudy.
An important finding from the study is that human cerebrospinal fluid samples from familial and sporadic ALS samples revealed increased polyP concentrations.
According to van Zundert, exposure of spinal cord neurons to polyP had the harmful effects of ALS astrocyte cultures, causing hyperexcitability, increased Ca2+ flow into neurons, and increased motoneuron death.
Van Zundert, Brown, and colleagues found that motor neurons can be rescued from the astrocyte toxicity by reducing polyP levels.
According to van Zundert, the findings are encouraging that increasing polyP levels extracellularly might be an innovative therapeutic approach for different types of ALS/FTD.
In 2014, van Zundert became aware that increasing electrical excitability of motor neurons is a beneficial part of mouse models of ALS. In addition, he learned that this molecule can be used as a glial transmitter to mediate communication between astrocytes and neurons.
ALS and FTD are devastating, incurable illnesses. ALS is a progressive neurodegenerative disorder that involves the loss of motor neurons that control voluntary muscles. About 10% of ALS is familialinherited from a persons parentsand is caused by a genetic mutation in a patient''s DNA. The remaining 90 percent of cases are 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.
Unlike Picks disease, FTD is one of the most common forms of early-onset dementia, second only to Alzheimers disease. FTD is caused by the loss of neurons in the frontal or temporal lobes.