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.
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, explaining how the brain prunes back unused connections
early in life. 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 it’s involvement in eliminating some connections in the brain,
including it’s involvement in neurodegeneration and the role of astrocyte
toxicity, through this research, we are really just scratching at the surface
of all we need to understand,” Dr. Kaspar says.
http://www.nationwidechildrens.org/news-room-articles/loss-of-mhci-in-motor-neurons-leads-to-als-astrocyte-toxicity?contentid=152295
Song SW, Miranda CJ, Braun L, Meyer K, Frakes AE, Ferraiuolo L, Likhite S, Bevan AK, Foust KD, McConnell MJ, Walker CM, Kaspar BK. Major histocompatibility complex class I molecules protect motor neurons from astrocyte-induced toxicity in amyotrophic lateral sclerosis. Nature Medicine. 2016 Feb 29. [Epub ahead of print]
ReplyDeleteAbstract
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.
http://www.nature.com/nm/journal/v22/n4/full/nm.4052.html