Caitlin Dingwall
Program: Molecular Genetics and Genomics
Current advisor: Jeffrey Milbrandt, MD, PhD
Undergraduate university: University of Illinois-Urbana/Champaign
Research summary
Axon degeneration (AxD) is an early and often causative event in many neurodegenerative diseases, yet no treatments exist to halt the breakdown of axons. In healthy axons, the axon survival factor NMNAT2 inhibits SARM1, the central executioner of programmed axon degeneration. NMNAT2 is a highly labile protein produced in the soma and trafficked into the axon. Nerve injury blocks axonal transport
and leads to rapid depletion of axonal NMNAT2, causing NMN buildup and NAD+ loss. Recent breakthroughs led to the discovery that SARM1 is activated by an increase in the NMN to NAD+ ratio.
While the SARM1 axon degeneration pathway is classically thought of as a programmed injury response to acutely damaged axons, there is growing evidence that this program is aberrantly activated in progressive neurodegenerative disease. Researchers have developed an abundance of acute injury models involving SARM1 activation; however, a chronic model of subacute SARM1 activation has been unavailable. Such a model is necessary for testing therapeutics in conditions more akin to human progressive neurodegenerative disorders, which my enclosed thesis work now shows to involve previously unappreciated complex biological mechanisms.
In our first study, we identified two rare NMNAT2 loss-of-function variants in two brothers afflicted with a progressive neuropathy syndrome. We generated a mouse model of the human syndrome and found that these Nmnat2 mutant mice survive to adulthood but develop progressive motor dysfunction, peripheral axon loss, and macrophage infiltration. These disease phenotypes are all SARM1-dependent. While all recent mechanistic progress on SARM1 has defined it as the central driver of a cell-autonomous degenerative program via its NAD+ hydrolase activity, we made the remarkable discovery that macrophage depletion therapy blocks and reverses neuropathic phenotypes in the Nmnat2 hypomorph mice, identifying a SARM1- dependent neuroimmune mechanism as a key driver of disease pathogenesis.
Importantly, these findings indicate that macrophages are downstream effectors of SARM1 activation in vivo, placing SARM1 at the nexus between neuroinflammation and neurodegeneration. What mediates the molecular crosstalk between the SARM1 degeneration pathway and the immune system to activate macrophages? In our second study, we find that chronic SARM1 activation triggers axonal blebbing and externalization of phosphatidylserine (PS) – a phagocytic “eat-me” signal – on stressed- but-viable axons. PS exposure (exPS) induces macrophage activation and reducing exPS blocks phagocytic axon loss in vitro and preserves axon function in vivo. We conclude that exPS represents a SARM1-dependent early axonal danger signal, and blockade of phagocytic recognition and engulfment of stressed-but-viable axons may represent an attractive therapeutic target for management of neurological disorders involving SARM1 activation.
Collectively, our studies make provocative discoveries that challenge the prior axon-centric degeneration paradigm. We find that a major pro-degenerative role of SARM1 involves the activation of macrophages via exposure of an early axonal danger signal in parallel with its canonical cell-autonomous destructive functions. These findings lay the groundwork for understanding how SARM1 activation orchestrates an inflammatory response to compromised axons and will serve as a platform for designing precision therapeutics to better treat chronic neurodegenerative diseases.
Graduate publications
Wu T, Zhu J, Strickland A, Ko KW, Sasaki Y, Dingwall CB, Yamada Y, Figley MD, Mao X, Neiner A, Bloom AJ, DiAntonio A, Milbrandt J. 2021 Neurotoxins subvert the allosteric activation mechanism of SARM1 to induce neuronal loss. Cell Rep, 37(3):109872.