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Rabies and other lyssaviruses
Published in Avindra Nath, Joseph R. Berger, Clinical Neurovirology, 2020
Thiravat Hemachudha, Jiraporn Laothamatas, Henry Wilde
Proteomic profiling studies of brains at late stage of rabies-infected dogs showed up-regulation of immunoglobulin heavy chain in the brain stem of paralytic dogs and IFN-α 4 and SARM1 protein in the hippocampus of furious dogs [116]. CRMP-2, representing activated infiltrating T cells, was down-regulated in the spinal cord of both rabies forms but was upregulated in the brain stem of paralytic dogs.
Retinal Ganglion Cell Death in Glaucoma: Advances and Caveats
Published in Current Eye Research, 2023
As mentioned previously, acute intraocular pressure (IOP) triggers apoptosis in RGCs. However, researchers have also discovered that inhibiting necroptosis with necrostatin 1(Nec1) can rescue RGCs and inhibit subsequent retinal inflammatory responses in ischemia-reperfusion models in vivo,41,42 as well as in the oxygen and glucose deprivation model in vitro.41 MLKL not only serves as the final player in canonical necroptosis but also triggers degeneration indirectly. SARM1 is an inducible NAD+ cleavage enzyme that serves as a modulator of axon degeneration. The vitreous injection of TNF-α activates MLKL, which then activates SARM1 NADase activity, leading to calcium influx, axon degeneration, oligodendrocyte loss, and subsequent retinal ganglion cell death.43
Emerging pharmacological strategies for the management of chemotherapy-induced peripheral neurotoxicity (CIPN), based on novel CIPN mechanisms
Published in Expert Review of Neurotherapeutics, 2020
Andreas A. Argyriou, Jordi Bruna, Susanna B. Park, Guido Cavaletti
Axonal degeneration is the most significant final result of any prolonged neurotoxic insult from chemotherapy. Recent evidence has emerged about new contributors involved in axonal degeneration pathways. Axonal degeneration is an active genetically encoded self-destruction program that leads to axonal fragmentation, triggered by Sterile Alpha and TIR Motif Containing 1 (SARM1) after a physical or chemical noxious stimulus. SARM1 pathway is activated by the loss of the axonal survival factor NMNAT2. This protein must constantly be delivered to the axon via anterograde transport from the cell body to maintain SARM1 in an inactivated state. Activated SARM1 induces the rapid destruction of the essential metabolic co-factor nicotinamide adenine dinucleotide (NAD+) and subsequently facilitates calpain activation and axon loss [23]. Accordingly, treatment strategies targeting this pathway are of high interest, especially because impairment of microtubule dynamics is a key feature following exposure to taxanes, bortezomib, and vinca alkaloid compounds.
Implications of NAD metabolism in pathophysiology and therapeutics for neurodegenerative diseases
Published in Nutritional Neuroscience, 2021
Keisuke Hikosaka, Keisuke Yaku, Keisuke Okabe, Takashi Nakagawa
Several studies have revealed the molecular mechanism of SARM1-mediated axonal degeneration. SARM1 is a multi-domain protein possessing sterile alpha motif (SAM) and TIR domains [37,40]. Reportedly, SAM domain mediates multimerization of SARM1, and TIR domain is necessary for execution of axonal degeneration [40]. Importantly, SARM1 initiates axon degeneration by depleting axonal NAD levels [41,42]. Biochemical analyses have revealed that TIR domain itself has an intrinsic NAD glycohydrolase activity, which leads to cleaving NAD into ADP-ribose (ADPR) and NAM [43]. In addition, it has an NAD cyclase activity generating cyclic-ADPR from NAD [43]. TIR domain proteins are evolutionally conserved from bacteria to humans, and both bacteria and archaea TIR domain proteins have enzymatic activity to cleave NAD [44]. Therefore, TIR domain protein is considered a new class of NAD glycohydrolase. SARM1 is localized in mitochondria, and loss of mitochondrial membrane potential triggers axon degeneration by activating SARM1 [45]. Another study has shown that SARM1 activates the mitogen-activated protein kinase (MAPK) signaling pathway and regulates energy homeostasis in axons [46]. Particularly, SARM1 activates c-Jun N-terminal kinase 1 (JNK1) and JNK3 followed by ATP depletion for the execution of axon degeneration. JNK also phosphorylates SARM1 and regulates its NAD cleavage activity [47]. Oxidative stress triggers SARM1 phosphorylation by JNK and inhibits mitochondrial respiration. Increased phosphorylation in SARM1 is also observed in neuronal cells derived from a patient with familial PD [47]. Considering these results, SARM1 may negatively regulate axonal energy metabolism through mitochondria upon various stresses, and the activation of SARM1 results in the depletion of NAD and ATP, followed by axon degeneration. However, TIR domain was originally discovered as an adaptor protein for Toll-like receptors and transduced various innate immune signaling. A recent study has demonstrated that SARM1 regulates the recruitment of immune cells during traumatic axonal injury independent of axon degeneration machinery [48]. Thus, SARM1 may have more diverse roles beyond metabolic control.