Microglia May Promote Recovery of Motor Neurons in Amyotrophic Lateral Sclerosis

 

In findings published this week in Nature Neuroscience, researchers Krista J. Spiller, Clark R. Restrepo, Tahiyana Khan, and others described creation of a mouse model of amyotrophic lateral sclerosis (ALS) in which a human protein TDP-43 is expressed.(Nature Neuroscience. 2018;21:published online Feb. 20) Patients with ALS have been shown to have TDP-43 accumulations in motor areas of the brain upon autopsy.

Mice expressing TDP-43 had selective degeneration of motor neurons, a hallmark of ALS, and ALS-like symptoms, but no increase in microglia, although a microglial immune response has been suggested as part of the pathophysiology for ALS. When TDP-43 production was suppressed in these mice, however, microglia rapidly proliferated, changing shape and gene expression and clearing TDP-43 from the motor neurons through phagocytosis. Suppression of TDP-43 also cleared ALS-like motor dysfunction unless microglial proliferation was blocked.

These results suggest that the microglial proliferation in ALS may be the body’s attempt to repair the damaged motor neurons rather than the cause of motor-neuron damage.

Senior author Virginia M-Y. Lee, PhD, Director of the Center for Neurodegenerative Disease Research and a professor of Pathology and Laboratory Medicine said, “The prevailing view in the field has been that immune system inflammation contributes to the death of neurons in ALS, but this study shows the opposite - that microglia are actually critical for neuronal survival.”

First author Krista Spiller stated, “The way reactive microglia protect neurons points us towards new ideas for ALS therapies. For example, we want to know if we can encourage the expansion of microglia in early-stage ALS patients to save their motor neurons.”

 

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