SARM1 (Sterile Alpha and TIR Motif-Containing Protein 1)
Human sterile alpha and TIR motif-containing protein 1 (SARM1) gene was first cloned and described located at chromosome 17q11 by Mink et al. in 2001. It encodes a protein with domains of sterile alpha motif (SAM) and Armadillo motif (ARM) thus naming SARM (Mink et al. 2001). Later, a Toll/interleukin-1 receptor (TIR) domain was annotated in the C-terminal region of SARM; therefore it was renamed as SARM1 (O’Neill et al. 2003; Mink and Csiszar 2005). TIR domain is present in Toll-like receptors (TLRs), cytokine receptors, and cytoplasm adaptors that mediate innate immune responses to against microbiota infection. There are 10 TLRs in human and 13 TLRs in mice. Those TLRs recognize different components of pathogens and trigger signaling through TIR-TIR domain interactions with distinct TLR adaptors (O’Neill and Bowie 2007). Currently, TLR adaptors have five members including myeloid differentiation primary response gene 88 (MYD88), MYD88 adaptor-like (MAL), TIR domain-containing adaptor-inducing interferon (TRIF), TRIF-related adaptor molecule (TRAM), and SARM1. Among them, SARM1 is the most evolutionarily conserved TLR adaptor; its orthologs are present in various species from worms (C. elegans) to human (Mink et al. 2001; Yuan et al. 2010). As the Sarm1 knockout mice and the specific antibody were generated, the properties and biological function of SARM1 have been investigated in the immune and nervous systems.
Properties of SARM1
SARM1 Protein Features
Expression Pattern of Sarm1
The expression pattern of Sarm1 was examined at both mRNA and protein levels (Kim et al. 2007; Chen et al. 2011). These studies revealed that SARM1 is profoundly expressed in mouse brain but not in the immune or other tissues. The SARM1 levels are highest from embryonic day 18 to postnatal day 7 and are reduced by 60% in adult. Furthermore, SARM1 is specifically present in neurons, including both excitatory and inhibitory neurons, but not microglial cells (Chen et al. 2011; Lin et al. 2014b). In neurons, SARM1 proteins are widely distributed in the soma, axon, dendrite, and dendritic spine (Chuang and Bargmann 2005; Kim et al. 2007; Chen et al. 2011). The data of immunostaining using a specific SARM1 antibody and knockin strategy tagging GFP to endogenous SARM1 clearly showed that SARM1 proteins are majorly cytoplasmic with only very small portion associated with the mitochondria (Kim et al. 2007; Chen et al. 2011; Osterloh et al. 2012). However, overexpressed SARM1 proteins predominantly associate with the outer mitochondrial membrane and trigger cell death (Kim et al. 2007; Panneerselvam et al. 2012). The reason of this distinct subcellular localization of endogenous and exogenous Sarm1 is currently unknown. Perhaps an unknown mechanism modulates Sarm1 localization, particularly prevention from mitochondria association, to avoid cell death.
Physiological Roles of SARM1
In the past decade, accumulating studies have shown that SARM1 plays multiple roles in defense of pathogen infection and brain development. It also mediates neuronal degeneration processes, such as Wallerian degeneration and ALS.
Innate Immune Response
Using cultured hippocampal neurons, it has been shown that SARM1 receives signals from synaptic syndecan-2 and acts through the ASK1-MEK4/7-JNK pathway to control neuronal morphogenesis (Fig. 3c) (Chen et al. 2011). Given that SARM1 expression is earlier than syndecan-2, SARM1 likely receives signal(s) from other factor(s) and modulates neuronal development. Echoing the in vitro studies, SARM1 knockdown mice have smaller brain, less complex dendritic arbor, and aberrant spine density that result in impaired synaptic transduction (Chen et al. 2011; Lin et al. 2014a). These brain developmental defects also reflect in abnormal behaviors of the animals. SARM1 knockdown mice show deficits in associative memory, cognitive flexibility, and social interactions (Lin et al. 2014a; Lin and Hsueh 2014). Taken together, SARM1 regulates neural development in many different aspects, which are important for building up a functional brain with proper neuronal connections.
Axonal Degeneration and Cell Death
In addition to neural development, SARM1 also involves in controlling cell death and axonal degeneration. First of all, using SARM1 knockout mice, it has been demonstrated that loss of SARM1 in neurons prevents cell death under oxygen and glucose deprivation stress (Kim et al. 2007). It suggests that a destruction signaling is mediated by SARM1.
Secondarily, SARM1 is critical for Wallerian degeneration, a form of programmed self-destruction process that promotes axon breakdown in neurodegenerative diseases and axonal injury (Coleman and Freeman 2010; Conforti et al. 2014). A large-scale screening of mutant flies resistant to axon degeneration after axotomy identified SARM1 as the key mediator to trigger axon degeneration (Osterloh et al. 2012). In both flies and mice, loss of Sarm1 effectively suppresses Wallerian degeneration for weeks after axotomy, indicating that pro-degenerative signaling controlled by SARM1 is highly conserved in different species (Osterloh et al. 2012).
In addition to Wallerian degeneration, Sarm1 knockout also attenuates axon degeneration after traumatic brain injury (McLaughlin et al. 2016). Moreover, loss of Sarm1 prevents motor neuron degeneration in an amyotrophic lateral sclerosis (ALS) disease model of C. elegans (Veriepe et al. 2015). These very recent studies support a role of SARM1 in neurodegenerative disorders.
Within a couple years, the function of SARM1 is largely explored in fields of innate immunity, neuronal development, and axonal degeneration. As a protein contained three protein-protein interaction domains (ARM, SAM, and TIR), SARM1 is expected to serve as an adaptor and involves in several signaling pathways. Being the identified fifth TLR adaptor, SARM1 acts very differently from the others, either cannot induce cytokine expression or activate TLR signaling. With the predominantly expression in the neuron and brain, the function of SARM1 in neuron has drawn more researchers’ attentions than before. Despite the argument in host defense system, SARM1 is required for neuronal morphogenesis and neuronal fate specification during development. On the other hand, SARM1 activates the death signal in the injured distal axons and leads to axonal destruction. Thus far, it is unclear how SARM1 can carry out these two distinct functions in neurons by using similar MAPK signaling pathway. It has been suggested that the conformational change of SARM1 modulates SARM1 function. Since the N-terminal regulatory domain of SARM1 modulates SARM1 signaling, it would be important to identify the interacting and/or the modification proteins of this region during neuronal development and axon injury.
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