A Novel NAD Signaling Mechanism in Axon Degeneration and its Relationship to Innate Immunity

Abstract

Axon degeneration represents a pathological feature of many neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease where axons die before the neuronal soma, and axonopathies, such as Charcot-Marie-Tooth disease and hereditary spastic paraplegia. Over the last two decades, it has slowly emerged that a central signaling pathway forms the basis of this process in many circumstances. This is an axonal NAD-related signaling mechanism mainly regulated by the two key proteins with opposing roles: the NAD-synthesizing enzyme NMNAT2, and SARM1, a protein with NADase and related activities. The crosstalk between the axon survival factor NMNAT2 and pro-degenerative factor SARM1 has been extensively characterized and plays an essential role in maintaining the axon integrity. This pathway can be activated in necroptosis and in genetic, toxic or metabolic disorders, physical injury and neuroinflammation, all leading to axon pathology. SARM1 is also known to be involved in regulating innate immunity, potentially linking axon degeneration to the response to pathogens and intercellular signaling. Understanding this NAD-related signaling mechanism enhances our understanding of the process of axon degeneration and enables a path to the development of drugs for a wide range of neurodegenerative diseases.

NMNAT2 in cortical glutamatergic neurons exerts both cell and non-cell autonomous influences to shape cortical development and to maintain neuronal health

“…Sarm1 (Sterile alpha and TIR motif containing1) is a NAD(P) glycohydrolase and a prominent executor of programmed axon death (Angeletti et al, 2022; Hopkins et al, 2021). Compelling evidence shows that an increase in NMN to NAD+ ratio after NMNAT2 loss activates Sarm1 to trigger axon degeneration (Figley et al, 2021).…”

“…Sarm1 (Sterile alpha and TIR motif containing1) is a NAD(P) glycohydrolase and a prominent executor of programmed axon death (Angeletti et al, 2022;Hopkins et al, 2021).…”

Progressive axonopathy when oligodendrocytes lack the myelin protein CMTM5

“…In the Wld s pathway, a key regulator of axonal degeneration is the enzyme sterile alpha and TIR motif containing protein 1 (SARM1) (Gerdts et al, 2013;Osterloh et al, 2012). Both, the Wld s mutation and deletion of the Sarm1 gene can delay axonal degeneration (Coleman et al, 1998;Hopkins et al, 2021), involving the maintenance of high NAD + levels along the axon (di Stefano et al, 2015;Gilley & Coleman, 2010;Hopkins et al, 2021;Wang et al, 2005).To the best of our knowledge, CMTM5-deficient mice represent the first model in which the axonopathy that emerges upon deletion of a CNS myelin protein is ameliorated by the Wld s mutation. Only the degeneration of axons in the PNS of mice lacking myelin protein zero (MPZ/P0) is robustly delayed by the presence of the Wld s mutation (Samsam et al, 2003).…”

Structural Evolution of TIR-Domain Signalosomes

“…While SARM1 has a number of suggested roles in the regulation of innate immunity, the central function appears to be to serve as the executioner of Wallerian or programmed axon degeneration, a highly conserved pathway of injury-induced axon degeneration (51)(52)(53)(54). SARM1 facilitates rapid depletion of NAD + in response to axon injury, leading to subsequent axon demise (10,11,55).…”