Browsing by Author "Walker, Chandler"

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    Circadian Clock, Glucocorticoids and NF-κB Signaling in Neuroinflammation- Implicating Glucocorticoid Induced Leucine Zipper as a Molecular Link
    (Sage, 2022) Srinivasan, Mythily; Walker, Chandler; Biomedical Sciences and Comprehensive Care, School of Dentistry
    Inflammation including neuroinflammation is considered a protective response and is directed to repair, regenerate, and restore damaged tissues in the central nervous system. Persistent inflammation due to chronic stress, age related accrual of free radicals, subclinical infections or other factors lead to reduced survival and increased neuronal death. Circadian abnormalities secondary to altered sleep/wake cycles is one of the earliest signs of neurodegenerative diseases. Brain specific or global deficiency of core circadian trans-activator brain and muscle ARNT (Arylhydrocarbon Receptor Nuclear Translocator)-like protein 1 (BMAL1) or that of the transrepressor REV-ERBα, impaired neural function and cognitive performance in rodents. Consistently, transcripts of inflammatory cytokines and host immune responses have been shown to exhibit diurnal variation, in parallel with the disruption of the circadian rhythm. Glucocorticoids that exhibit both a circadian rhythm similar to that of the core clock transactivator BMAL1 and tissue specific ultradian rhythm are critical in the control of neuroinflammation and re-establishment of homeostasis. It is widely accepted that the glucocorticoids suppress nuclear factor-kappa B (NF-κB) mediated transactivation and suppress inflammation. Recent mechanistic elucidations suggest that the core clock components also modulate NF-κB mediated transactivation in the brain and peripheral tissues. In this review we discuss evidence for interactions between the circadian clock components, glucocorticoids and NF-κB signaling responses in the brain and propose glucocorticoid induced leucine zipper (GILZ) encoded by Tsc22d3, as a molecular link that connect all three pathways in the maintenance of CNS homeostasis as well as in the pathogenesis of neuroinflammation-neurodegeneration.
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    Schwann cell transplantation and descending propriospinal regeneration after spinal cord injury
    (Elsevier, 2015-09-04) Deng, Ling-Xiao; Walker, Chandler; Xu, Xiao-Ming; Department of Anatomy & Cell Biology, IU School of Medicine
    After spinal cord injury (SCI), poor ability of damaged axons of the central nervous system (CNS) to regenerate causes very limited functional recovery. Schwann cells (SCs) have been widely explored as promising donors for transplantation to promote axonal regeneration in the CNS including the spinal cord. Compared with other CNS axonal pathways, injured propriospinal tracts display the strongest regenerative response to SC transplantation. Even without providing additional neurotrophic factors, propriospinal axons can grow into the SC environment which is rarely seen in supraspinal tracts. Propriospinal tract has been found to respond to several important neurotrophic factors secreted by SCs. Therefore, the SC is considered to be one of the most promising candidates for cell-based therapies for SCI. Since many reviews have already appeared on topics of SC transplantation in SCI repair, this review will focus particularly on the rationale of SC transplantation in mediating descending propriospinal axonal regeneration as well as optimizing such regeneration by using different combinatorial strategies. This article is part of a Special Issue entitled SI: Spinal cord injury.
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    Translational Responses of Motor Neurons to Neurodegeneration in ALS Identifies FGF21 as a Critical Myogenic Regulatory Factor That Slows Disease Progression
    (2021-12) Stansberry, Wesley Michael; Oblak, Adrian; Landreth, Gary; Lasagna-Reeves, Cristian; Pierchala, Brian; Walker, Chandler
    The neuromuscular junction (NMJ) is a chemical synapse that is the site of skeletal muscle innervation by spinal motor neurons and the maintenance of the NMJ is critical for preserving musculoskeletal homeostasis. Under normal physiological conditions, spinal motor neurons have significant regenerative potential and can regrow axons in response to peripheral nerve injury. In diseases such as amyotrophic lateral sclerosis (ALS), the NMJ is dismantled and motor neurons selectively degenerate resulting in progressive muscle wasting and eventual fatal paralysis. Interestingly, some motor neurons are more resistant to degeneration, with slow motor neurons persisting for longer and, in some cases, reinnervating fast, vacant NMJ endplates, underscoring the vital role of motor neurons in supporting skeletal muscle in disease states. In this dissertation we explore the role of motor neurons in skeletal muscle maintenance in ALS. We adapted the RiboTag methodology developed by Sanz et al. to perform ribosomal profiling of motor neurons in two mouse models of ALS. In chapter two we evaluated the translatome of spinal motor neurons in the Ubqln2P497S proteostasis model. The most significant finding from this study was the dramatic downregulation of muscle-related transcripts in motor neuron cell bodies in ALS, raising the possibility of motor neurons translating mRNAs previously thought to be muscle cell-type specific in direct support of the skeletal muscles they innervate. In chapter three, another RiboTag screen comparing a sciatic nerve crush model of acute injury and the Sod1G93A ALS model identified Fgf21, a metabolic and stress-inducible hormone, as one of the most upregulated ALS-specific transcripts. Transgenic mouse models where Fgf21 is conditionally knocked out in Sod1G93A motor neurons showed reduced motor neuron survival and NMJ innervation. Behavioral and survival trials with Sod1G93A mice showed a dramatic reduction in locomotion and lifespan when Fgf21 was conditionally knocked out of motor neurons. Taken together, these data suggest Fgf21 functions in a neuroprotective capacity in ALS pathology. Here we evaluate the functions of Fgf21 and the mechanisms by which it promotes motor neuron survival and skeletal muscle innervation and metabolism.