Neuroscience letters
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Amyotrophic lateral sclerosis (ALS) is an adult-onset, lethal, paralytic disorder caused by the degeneration of motor neurons. Our understanding of this disease has been greatly facilitated by studies of familial ALS caused by mutations in the gene encoding superoxide dismutase 1 (SOD1). Evidence indicates that misfolded wild-type SOD1 may also be pathogenic in sporadic ALS. ⋯ The most clinically promising are predicated on approaches that enhance degradation of RNA, such as anti-sense oligonucleotides (ASO) and RNA interference (RNAi); the latter include small inhibitory RNA (siRNA), short hairpin RNA (shRNA) and microRNA (miR). Agents such as shRNA and either native or synthetic miR are capable of permeating the central nervous system (CNS) and efficiently silencing genes in the brain and spinal cord. Here we review recent progress in silencing SOD1, focusing on studies using artificial shRNA or miRNA in combination with potent viral vector delivery systems to mediate SOD1 silencing within the CNS in transgenic SOD1G93A mice and non-human primates.
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Neuroscience letters · Jun 2016
ReviewEpigenetic changes following traumatic brain injury and their implications for outcome, recovery and therapy.
Traumatic brain injury (TBI) contributes to nearly a third of all injury-related deaths in the United States. For survivors of TBI, depending on severity, patients can be left with devastating neurological disabilities that include impaired cognition or memory, movement, sensation, or emotional function. ⋯ Evidence from recent studies support the involvement of epigenetic mechanisms such as DNA methylation, chromatin post-translational modification, and miRNA regulation of gene expression in the post-injured brain. In this review, we discuss studies that have assessed epigenetic changes and mechanisms following TBI, how epigenetic changes might not only be limited to the nucleus but also impact the mitochondria, and the implications of these changes with regard to TBI recovery.
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Neuropathic pain is a significant unmet medical need in patients with variety of injury or disease insults to the nervous system. Neuropathic pain often presents as a painful sensation described as electrical, burning, or tingling. Currently available treatments have limited effectiveness and narrow therapeutic windows for safety. ⋯ Several studies in animal models of neuropathic pain have begun to reveal the functional contribution of dendritic spine dysgenesis in neuropathic pain. Previous reports have demonstrated three primary changes in dendritic spine structure on nociceptive dorsal horn neurons following injury or disease, which accompany chronic intractable pain: (I) increased density of dendritic spines, particularly mature mushroom-spine spines, (II) redistribution of spines toward dendritic branch locations close to the cell body, and (III) enlargement of the spine head diameter, which generally presents as a mushroom-shaped spine. Given the important functional implications of spine distribution, density, and shape for synaptic and neuronal function, the study of dendritic spine abnormality may provide a new perspective for investigating pain, and the identification of specific molecular players that regulate spine morphology may guide the development of more effective and long-lasting therapies.
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Neuroscience letters · Jun 2015
ReviewDemyelinating CMT--what's known, what's new and what's in store?
Inherited neuropathies known collectively as Charcot-Marie-Tooth disease are one of the most common inherited neurological conditions affecting ∼1 in 2500 people. A heterogenous disorder, CMT is divided into subtypes based on the pattern of inheritance and also by neurophysiological studies. ⋯ Understanding the pathogenesis of these disorders requires an intimate knowledge of normal myelin development and homeostasis. Improvements in genetic testing techniques over the last 20 years have contributed majorly to the identification of specific genes, proteins, and molecular pathways that are providing the basis for understanding the disease processes and developing rational approaches to therapy.
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Peripheral neuropathy can lead to neuropathic pain in a subset of patients. Painful peripheral neuropathy is a debilitating disorder, reflected by a reduced quality of life. Therapeutic strategies are limited and often disappointing, as in most cases targeted treatment is not available. ⋯ Functional analyses have shown that these mutations produce a spectrum of pro-excitatory changes in channel biophysics, with the shared outcome at the cellular level of dorsal root ganglion hyperexcitability. Reduced neurite outgrowth may be another consequence of sodium channel mutations, and possible therapeutic strategies include blockade of sodium channels or block of reverse operation of the sodium-calcium exchanger. Increased understanding of the pathophysiology of painful peripheral neuropathy offers new targets that may provide a basis for more effective treatment.