ALS Astrocyte Neurotoxicity a Result of Loss of MHCI in Motor Neurons

New research shines a light on the role of MHCI in astrocyte-induced death of motor neurons in amyotrophic lateral sclerosis and pointing to a potential therapeutic target

Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is a devastating progressive neurodegenerative disease that results in the death of motor neurons, the nerve cells that control muscles. Eventually, individuals with ALS will lose their ability to walk, move, swallow and breathe.

Until recently, the role of astrocytes, glial cells that normally support motor neurons, in motor neuron death has been a mystery, but research from scientists at Nationwide Children’s Hospital sheds new light on molecular mechanisms responsible for motor neuron death in ALS. In a study published in Nature Medicine, Brian Kaspar, PhD, principal investigator in the Center for Gene Therapy in The Research Institute at Nationwide Children’s, and his team demonstrate the explicit loss of major histocompatibility complex I (MHCI) expression in the outer membrane of motor neurons in ALS, leading to motor neuron vulnerability to ALS astrocyte toxicity.

“We wanted to find out what astrocytes were doing — or not doing — to kill motor neurons,” explains Dr. Kaspar. “We found unequivocal evidence of the role of MHCI on the motor neurons in signaling the astrocytes.”

For each subtype of MHCI protein, there is a receptor that binds to it, much like a lock and key. If MCHI proteins are the keys, then killer inhibitory receptors (KIRs) are the locks. In their study, Dr. Kaspar and his team not only provide evidence of the protective effect of MHCI against astrocyte toxicity in ALS but also identify the killer inhibitory receptors (KIRs) associated with the specific subclass of MHCI (HLA-F) involved in human motor neurons.

“We showed, in both animal and human studies, the loss of MHCI is destructive to the motor neurons and increases in MHCI are protective,” says Dr. Kaspar, who is also associate professor in the Department of Pediatrics and Department of Neuroscience at The Ohio State University College of Medicine. “We knew from past research that ALS astrocytes were responsible for killing motor neurons. Now we have another piece to the puzzle.”

According to the study, a dramatic loss of MHCI (HLA-F) from motor neurons is observed in the spinal cords of subjects affected by ALS. This finding is supported by evidence obtained in animal models and in vitro experiments using animal and human cells, which give insight on the protective nature of MHCI (HLA-F). Specifically, MHCI expression in the animal model was modulated using adeno-associated viral vector serotype 9 (AAV9), resulting in increased expression of MHCI and markedly extended survival.

The protective nature of MHCI (HLA-F) points to a potential translational target to delay the progression of ALS, since HLA-F expression may significantly impact disease progression in patients. In the in vitro experiments, human motor neurons expressing higher levels of HLA-F experienced reduced astrocyte toxicity. However, it remains to be seen whether or not this can be translated into a clinical trial and meaningful therapy for patients.

“Taken together, the results provide strong evidence that a single MHCI molecule, HLA-F, can protect motor neurons from both inherited and spontaneous ALS astrocyte-induced toxicity, which is a prerequisite for delaying motor neuron death in these patients,” Dr. Kaspar says.

Image shows an astrocyte.
Until recently, the role of astrocytes, glial cells that normally support motor neurons, in motor neuron death has been a mystery, but research from scientists at Nationwide Children’s Hospital sheds new light on molecular mechanisms responsible for motor neuron death in ALS. Astrocyte image is for illustrative purposes only. Credit: Neurorocker.

Not only is this work opening doors to new possibilities in ALS research and therapeutics, MHCI has also been shown to be instrumental in neural development. According to Dr. Kaspar, studies now indicate that it may be integral in neurodegenerative situations as well.

“While we have gained much information about the role of MHCI and astrocyte toxicity through this research, we are really just scratching at the surface of all we need to understand,” Dr. Kaspar says.

About this ALS research

Source: Gina Bericchia – Nationwide Children’s Hospital
Image Credit: Image is credited to Neurorocker and is licensed CC BY 3.0.
Original Research: Abstract for “Major histocompatibility complex class I molecules protect motor neurons from astrocyte-induced toxicity in amyotrophic lateral sclerosis” by SungWon Song, Carlos J Miranda, Lyndsey Braun, Kathrin Meyer, Ashley E Frakes, Laura Ferraiuolo, Shibi Likhite, Adam K Bevan, Kevin D Foust, Michael J McConnell, Christopher M Walker and Brian K Kaspar in Nature Medicine. Published online February 29 2016 doi:10.1038/nm.4052


Abstract

Major histocompatibility complex class I molecules protect motor neurons from astrocyte-induced toxicity in amyotrophic lateral sclerosis

Astrocytes isolated from individuals with amyotrophic lateral sclerosis (ALS) are toxic to motor neurons (MNs) and play a non–cell autonomous role in disease pathogenesis. The mechanisms underlying the susceptibility of MNs to cell death remain unclear. Here we report that astrocytes derived from either mice bearing mutations in genes associated with ALS or human subjects with ALS reduce the expression of major histocompatibility complex class I (MHCI) molecules on MNs; reduced MHCI expression makes these MNs susceptible to astrocyte-induced cell death. Increasing MHCI expression on MNs increases survival and motor performance in a mouse model of ALS and protects MNs against astrocyte toxicity. Overexpression of a single MHCI molecule, HLA-F, protects human MNs from ALS astrocyte–mediated toxicity, whereas knockdown of its receptor, the killer cell immunoglobulin-like receptor KIR3DL2, on human astrocytes results in enhanced MN death. Thus, our data indicate that, in ALS, loss of MHCI expression on MNs renders them more vulnerable to astrocyte-mediated toxicity.

“Major histocompatibility complex class I molecules protect motor neurons from astrocyte-induced toxicity in amyotrophic lateral sclerosis” by SungWon Song, Carlos J Miranda, Lyndsey Braun, Kathrin Meyer, Ashley E Frakes, Laura Ferraiuolo, Shibi Likhite, Adam K Bevan, Kevin D Foust, Michael J McConnell, Christopher M Walker and Brian K Kaspar in Nature Medicine. Published online February 29 2016 doi:10.1038/nm.4052

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