From the Bench: The Wainger Lab at Massachusetts General Hospital

At the Sean M. Healey & AMG Center for ALS, compassionate clinical care converges with cutting-edge research every day. The laboratories at the Charlestown Navy Yard are humming with investigators researching the latest breakthroughs in ALS and bringing us closer to a cure.

The Wainger Lab at Massachusetts General Hospital conducts research on how abnormalities of motor and sensory neuron physiology contribute to diseases such as ALS and chronic pain. In this issue we spotlight the labs’ recently published paper that focuses on stimulator of interferon genes (STING) within neurons.

Neuroinflammation – part of the injury response within the central nervous system – has been thought to be driven by immune-like cells within the brain and spinal cord called microglia. In a recent paper led by the Wainger Lab, entitled “Neuronal STING activation in amyotrophic lateral sclerosis and frontotemporal dementia”, Christine Marques and colleagues investigate a well-established and important pathway called STING, or stimulator of interferon genes. The STING pathway has been implicated in neuroinflammation, however, through a process restricted to inflammatory cells like microglia.

 In samples from people with ALS and from s, rodent models of ALS, the team identified that STING signaling is present and functional with central nervous system neurons. Moreover, across the stem cell-derived neurons, mouse models, and human samples, STING activation was pronounced in ALS neurons but almost absent in control neurons. Indeed, blocking STING activation with a pharmacological inhibitor reduced the inflammatory signaling within the neurons, thus validating the importance of STING in neuron-intrinsic neuroinflammation in ALS.

 A critical facet of understanding neurodegenerative diseases is cell-type specificity. For example, why are motor neurons in the spinal cord and brain the primary target of ALS, whereas other neurons, such as in the sensory cortex and cerebellum, are much less affected? One of the most interesting of Marques’ results is that activation of neuronal STING was occurring specifically in the neurons most vulnerable to ALS. Additional work will be necessary to understand how neuronal STING activation integrates with established inflammatory pathways with microglia. However, the fact that neuronal STING is specifically active within the vulnerable neurons suggests that it may contribute either to initiating toxicity or rendering vulnerability to motor neurons in ALS.

 Healey & AMG Center team members included Christine Marques and colleagues within the Wainger lab (Aaron Held, Katherine Dorfman, Joon Sung, Catherine Song, and Sid Kavuturu), members of (Corey Aguilar, Tommaso Russo), and Mark Albers.