Carty M, Bowie AG. SARM: from immune regulator to cell executioner. Biochem Pharmacol. 2019.
Key Points:
a) Central nervous system degeneration, (loss of nerve cells and their processes) plays an important role in progressive forms of MS.
b) An important cause of degeneration is impaired nerve cell energy metabolism due to impaired function of their “energy factories”, called mitochondria.
c) SARM, a protein found on nerve cell processes (axons), is an important regulator of cell death. Activation of SARM results in nerve cell death. One way that SARM kills nerve cells is by impairing mitochondrial function.
d) Reducing SARM activity in experimental animals results in decreased nerve cell death and increased resistance to both chemical and physical injury.
e) The role of SARM in the degenerative phase of MS needs to be studied, as reducing SARM activity may reduce nerve cell death and result in resistance to toxins produced by the immune system.
The immune system plays a critical role in the development of MS. Its roles are multiple, being involved in both tissue destruction and tissue healing. The complexity of the interactions between the immune system and the central nervous system can be overwhelming, but by looking at limited events some clarity is possible. Most importantly is understanding that there are two components of mammalian immune systems, the innate immune system and the adaptive immune system. The innate immune system can be viewed as the “first responder” to any tissue injury or tissue invasion. Cells of the innate immune system are different from cells of the adaptive immune system. They have the capacity to respond immediately to particular bacterial substances, such as complex sugars, and to sites of tissue injury. The receptors present on the surfaces of innate immune cells that allow them to recognize bacterial products are different than receptors on cells of the adaptive immune system. One major family of innate immune system receptors is the “toll-like” receptors or TLR. Triggering many of the TLRs leads to cascades of events that results in activating innate immune cells. This causes them to release substances that can destroy bacteria and viruses.
One of the TLRs is called SARM (sterile alpha and HEAT/Armadillo motif). Most interestingly it is found not only in cells of the innate immune system, but also in nerve cells of the central nervous system, especially neurons. SARM is further concentrated in the projections of neurons, called axons. SARM has multiple effects on the innate immune system as well as on cells of the adaptive immune system. It also has a major effect on nerve cell metabolism, impairing the energy-producing functions of mitochondria present in axons. Multiple studies showed that energy function in the neurons of persons with MS is impaired, probably related to abnormal mitochondrial function. This can result in cell death and SARM has an important role in inducing cell death via a mechanism known as “apoptosis.”
The role of degeneration, as opposed to acute inflammation, is felt to be of particular importance in the progressive forms of MS, such as secondary progressive MS and primary progressive multiple sclerosis. There are mildly effective treatments for progressive MS (e.g. ocrelizumab and siponimod), but much greater efficacy is needed. In multiple experiments in mice, involving traumatic and chemical injury, as well as central nervous system viral infections, inhibition of SARM resulted in greatly reduced loss of neurons, and increased resistance to nerve injury. Evaluation of the potential role of SARM in the degenerative phase of progressive MS could lead to an important new therapeutic approach to this phase of the disease.
Paper Abstract: SARM is the fifth and most conserved member of the Toll/Il-1 Receptor (TIR) adaptor family. However, unlike the other TIR adaptors, MyD88, Mal, TRIF and TRAM, SARM does not participate in transducing signals downstream of TLRs. By contrast SARM inhibits TLR signaling by interacting with the adaptors TRIF and MyD88. In addition, SARM also has positive roles in innate immunity by activating specific transcriptional programs following immune challenge. SARM has a pivotal role in activating different forms of cell death following cellular stress and viral infection. Many of these functions of mammalian SARM are also reflected in SARM orthologues in lower organisms such as C. elegans and Drosophila. SARM expression is particularly enriched in neurons of the CNS and SARM has a critical role in neuronal death and in axon degeneration. Recent fascinating molecular insights have been revealed as to the molecular mechanism of SARM mediated axon degeneration. SARM has been shown to deplete NAD+ by possessing intrinsic NADase activity in the TIR domain of the protein. This activity can be activated experimentally by forced dimerization of the TIR domain. It is thought that this activity of SARM is normally switched off by the axo-protective activities of NMNAT2 which maintain low levels of the NAD+ precursor NMN. Therefore, there is now great excitement in the field of SARM research as targeting this enzymatic activity of SARM may lead to the development of new therapies for neurodegenerative diseases such as multiple sclerosis and motor neuron disease.