Astrocytes carrying common ALS mutation cause motor neuron degeneration

Researchers confirm a new source of motor neuron degeneration in ALS

In a paper published online in PNAS, Packard/P2ALS-funded neuroscientist Nicholas Maragakis and colleagues at Johns Hopkins University implicate astrocytes in motor neuron deterioration in rats. Previous work had shown that astrocytes carrying a mutation in SOD1, one of the most common genetic mutations seen in inherited forms of ALS, could harm otherwise healthy motor neurons in vitro. Today's study confirms these results in an in vivo rat model.

"This work demonstrates for the first time that the SOD1 mutation just in astrocytes can cause motor neuron death in vivo," Maragakis said.  "This is the first time that we've been able to demonstrate that astrocytes are instigators of disease."

Historically, researchers had focused on the pathophysiology of motor neurons in ALS, seeing as they were the cells most damaged by the disease. But over the past eight or nine years, scientists have begun to understand how the cells supporting motor neurons -- astrocytes and microglia -- play a key role in the development of ALS. Two previous studies led by P2ALS investigators, one led by Tom Maniatis (Columbia University) and Kevin Eggan (Harvard University), the other by Serge Przedborski (Columbia)  in collaboration with Tom Jessell and Hynek Wichterle (also from Columbia University), introduced this idea using stem cell-derived in vitro models. More recently, a paper published in July by Brian Kaspar, another P2ALS scientist, showed that astrocytes from ALS patients with familial and sporadic forms of disease were toxic to healthy motor neurons in vitro. The study by Maragakis and colleagues builds upon these previous findings by asking whether astrocytes with the mutated SOD1 gene seen in familial ALS patients harms motor neurons in normal rats.

Maragakis and colleagues transplanted a type of stem cell known as a glial restricted precursor (GRP) that contained the familial ALS version of SOD1 into the spinal cords of healthy rats. The GRP cells can only differentiate efficiently into astrocytes, not motor neurons or microglia, so the researchers knew that any damage to the normal rat's motor neurons would be from the mutated astrocytes.

The rats that received the GRP cells with the SOD1 mutation showed motor neuron damage three months after transplantation. The motor neurons near the transplant site had aggregates of small molecules that were a cellular response to a toxic threat. As well, the rats with the mutated SOD1 astrocytes lost forelimb strength and respiratory function more than control rats. 

These signs mimic many of the features of disease progression of ALS in humans, which provides strong evidence that the mutated form of SOD1 may cause at least some motor neuron degeneration via astrocytes. The researchers believe that astrocytes might cause motor neuron damage by activating the normal transplanted rat’s microglia, cells that closely interact with astrocytes and serve as one of the main immune cells in the central nervous system.

"SOD1 mutations in astrocytes may make motor neurons more vulnerable to either pathological changes or cell death over time," Maragakis said. "The astrocytes with the SOD1 mutation could serve as kindling that leads to the fire of microglial activation and the propagation of disease even in wild-type cells.