Nervous system disorders are prevalent health issues that will only continue to increase in frequency as the population ages.Dying-back axonopathy is a hallmark of many neurologic diseases and leads to axonal disconne...Nervous system disorders are prevalent health issues that will only continue to increase in frequency as the population ages.Dying-back axonopathy is a hallmark of many neurologic diseases and leads to axonal disconnection from their targets,which in turn leads to functional impairment.During the course of many of neurologic diseases,axons can regenerate or sprout in an attempt to reconnect with the target and restore synapse function.In amyotrophic lateral sclerosis(ALS),distal motor axons retract from neuromuscular junctions early in the disease-course before significant motor neuron death.There is evidence of compensatory motor axon sprouting and reinnervation of neuromuscular junctions in ALS that is usually quickly overtaken by the disease course.Potential drugs that enhance compensatory sprouting and encourage reinnervation may slow symptom progression and retain muscle function for a longer period of time in ALS and in other diseases that exhibit dying-back axonopathy.There remain many outstanding questions as to the impact of distinct disease-causing mutations on axonal outgrowth and regeneration,especially in regards to motor neurons derived from patient induced pluripotent stem cells.Compartmentalized microfluidic chambers are powerful tools for studying the distal axons of human induced pluripotent stem cells-derived motor neurons,and have recently been used to demonstrate striking regeneration defects in human motor neurons harboring ALS disease-causing mutations.Modeling the human neuromuscular circuit with human induced pluripotent stem cells-derived motor neurons will be critical for developing drugs that enhance axonal regeneration,sprouting,and reinnervation of neuromuscular junctions.In this review we will discuss compensatory axonal sprouting as a potential therapeutic target for ALS,and the use of compartmentalized microfluidic devices to find drugs that enhance regeneration and axonal sprouting of motor axons.展开更多
While the peripheral nervous system has the capacity to regenerate following a nerve injury,it is often at a slow rate and results in unsatisfactory recovery,leaving patients with reduced function.Many regeneration as...While the peripheral nervous system has the capacity to regenerate following a nerve injury,it is often at a slow rate and results in unsatisfactory recovery,leaving patients with reduced function.Many regeneration associated genes have been identified over the years,which may shed some insight into how we can manipulate this intrinsic regenerative ability to enhance repair following peripheral nerve injuries.Our lab has identified the membrane bound protease beta-site amyloid precursor protein-cleaving enzyme 1（BACE1）,or beta secretase,as a potential negative regulator of peripheral nerve regeneration.When beta secretase activity levels are abolished via a null mutation in mice,peripheral regeneration is enhanced following a sciatic nerve crush injury.Conversely,when activity levels are greatly increased by overexpressing beta secretase in mice,nerve regeneration and functional recovery are impaired after a sciatic nerve crush injury.In addition to our work,many substrates of beta secretase have been found to be involved in regulating neurite outgrowth and some have even been identified as regeneration associated genes.In this review,we set out to discuss BACE1 and its substrates with respect to axonal regeneration and speculate on the possibility of utilizing BACE1 inhibitors to enhance regeneration following acute nerve injury and potential uses in peripheral neuropathies.展开更多
基金This work was supported by the Muscular Dystrophy Association,No.W81XWH1910229(to MHF)from Department of Defense’s Congressionally Directed Medical Research Program,and Maryland Stem Cell Research Fund,No.2019-MSCRFD-5093(to MHF).
文摘Nervous system disorders are prevalent health issues that will only continue to increase in frequency as the population ages.Dying-back axonopathy is a hallmark of many neurologic diseases and leads to axonal disconnection from their targets,which in turn leads to functional impairment.During the course of many of neurologic diseases,axons can regenerate or sprout in an attempt to reconnect with the target and restore synapse function.In amyotrophic lateral sclerosis(ALS),distal motor axons retract from neuromuscular junctions early in the disease-course before significant motor neuron death.There is evidence of compensatory motor axon sprouting and reinnervation of neuromuscular junctions in ALS that is usually quickly overtaken by the disease course.Potential drugs that enhance compensatory sprouting and encourage reinnervation may slow symptom progression and retain muscle function for a longer period of time in ALS and in other diseases that exhibit dying-back axonopathy.There remain many outstanding questions as to the impact of distinct disease-causing mutations on axonal outgrowth and regeneration,especially in regards to motor neurons derived from patient induced pluripotent stem cells.Compartmentalized microfluidic chambers are powerful tools for studying the distal axons of human induced pluripotent stem cells-derived motor neurons,and have recently been used to demonstrate striking regeneration defects in human motor neurons harboring ALS disease-causing mutations.Modeling the human neuromuscular circuit with human induced pluripotent stem cells-derived motor neurons will be critical for developing drugs that enhance axonal regeneration,sprouting,and reinnervation of neuromuscular junctions.In this review we will discuss compensatory axonal sprouting as a potential therapeutic target for ALS,and the use of compartmentalized microfluidic devices to find drugs that enhance regeneration and axonal sprouting of motor axons.
基金supported by the Muscular Dystrophy Association and R01NS079339 from the National Institutes of Neurological Disease and Stroke of the National Institutes of Health
文摘While the peripheral nervous system has the capacity to regenerate following a nerve injury,it is often at a slow rate and results in unsatisfactory recovery,leaving patients with reduced function.Many regeneration associated genes have been identified over the years,which may shed some insight into how we can manipulate this intrinsic regenerative ability to enhance repair following peripheral nerve injuries.Our lab has identified the membrane bound protease beta-site amyloid precursor protein-cleaving enzyme 1（BACE1）,or beta secretase,as a potential negative regulator of peripheral nerve regeneration.When beta secretase activity levels are abolished via a null mutation in mice,peripheral regeneration is enhanced following a sciatic nerve crush injury.Conversely,when activity levels are greatly increased by overexpressing beta secretase in mice,nerve regeneration and functional recovery are impaired after a sciatic nerve crush injury.In addition to our work,many substrates of beta secretase have been found to be involved in regulating neurite outgrowth and some have even been identified as regeneration associated genes.In this review,we set out to discuss BACE1 and its substrates with respect to axonal regeneration and speculate on the possibility of utilizing BACE1 inhibitors to enhance regeneration following acute nerve injury and potential uses in peripheral neuropathies.
