Mutant Astrocytes Play a Role in the Degeneration of Motor Neurons in Amyotrophic Lateral Sclerosis

Serge Przedborski, Ph.D.
Columbia University
R21ES013177

Astrocytes carrying a version of the mutant protein that causes amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, are responsible for the death of motor neurons, reports NIEHS grantee Serge Przedborski in the May 2007 issue of Nature Neuroscience.

Mutations in the gene for superoxide dismutase (SOD1) are known to cause ALS, in which progressive degeneration of motor neurons leads to paralysis and certain death. In the NIEHS funded study and an accompanying study published simultaneously, the authors expressed this mutant protein in a variety of single cell types in culture. Motor neurons degenerated and died when they were co-cultured with astrocytes expressing mutant SOD1, while mutant SOD1 in neurons, fibroblasts or microglia did not cause neuronal death.

Przedborski and colleagues also report that the astrocytes expressing mutant SOD1 killed only spinal motor neurons that degenerate in ALS and not other types of neurons. They show that cell death was due to a soluble toxic factor released by the astrocytes. These findings suggest that stem cell therapy focused on replacing damaged neurons may not be feasible in ALS because mutant astrocytes would most likely kill the replacement neurons. If the toxic factor can be identified in future studies, this finding may offer novel strategies for therapy.

Citation: Nagai M, Re DB, Nagata T, Chalazonitis A, Jessell TM, Wichterle H, Przedborski S. Astrocytes expressing ALS-linked mutated SOD1 release factors selectively toxic to motor neurons. Nat Neurosci. 2007 May;10(5):615-22.