Nogo-A is known to restrict plasticity in the adult central nervous system,and signalling through its cognate receptors modulates synaptic spine architecture and excitatory glutamate transmission via restricting synap...Nogo-A is known to restrict plasticity in the adult central nervous system,and signalling through its cognate receptors modulates synaptic spine architecture and excitatory glutamate transmission via restricting synaptic glutamate receptor levels and their delivery to the post-synaptic compartments.A recent report now indicates that Nogo-A,signaling through Sphingosine-1-Phosphate Receptor 2,also strengthens inhibitory gamma amino acid butyric acid(GABA)ergic transmission by limiting the diffusion dynamics of GABAA receptors.This reciprocal modulation of excitatory and inhibitory signaling via neurotransmitter receptor dynamics by Nogo-A likely plays important pathophysiological roles in synaptic plasticity during development and injury.展开更多
Highlight Semaphorin 3A is a classically known axonal guidance cue that mediates axonal growth cone repulsion and collapse.Recent works,however,suggest that it may have the apparently diametrically opposite activity o...Highlight Semaphorin 3A is a classically known axonal guidance cue that mediates axonal growth cone repulsion and collapse.Recent works,however,suggest that it may have the apparently diametrically opposite activity of promoting neuronal regeneration.展开更多
Environmental enrichment is known to be beneficial for cognitive improvement.In many animal models of neurological disorders and brain injury,EE has also demonstrated neuroprotective benefits in neurodegenerative dise...Environmental enrichment is known to be beneficial for cognitive improvement.In many animal models of neurological disorders and brain injury,EE has also demonstrated neuroprotective benefits in neurodegenerative diseases and in improving recovery after stroke or traumatic brain injury.The exact underlying mechanism for these phenomena has been unclear.Recent findings have now indicated that neuronal activity elicited by environmental enrichment induces Ca2+influx in dorsal root ganglion neurons results in lasting enhancement of CREB-binding protein-mediated histone acetylation.This,in turn,increases the expression of pro-regeneration genes and promotes axonal regeneration.This mechanism associated with neuronal activity elicited by environmental enrichment-mediated pathway is one of several epigenetic mechanisms which modulate axon regeneration upon injury that has recently come to light.The other prominent mechanisms,albeit not yet directly associated with environmental enrichment,include DNA methylation/demethylation and N6-methyladenosine modification of transcripts.In this brief review,I highlight recent work that has shed light on the epigenetic basis of environmental enrichment-based axon regeneration,and discuss the mechanism and pathways involved.I further speculate on the implications of the findings,in conjunction with the other epigenetic mechanisms,that could be harness to promote axon regeneration upon injury.展开更多
Cholesterol is biosynthesized by all animal cells. Beyond its metabolic role in steroidogenesis, it is enriched in the plasma membrane where it has key structural and regulatory functions. Cholesterol is thus presumab...Cholesterol is biosynthesized by all animal cells. Beyond its metabolic role in steroidogenesis, it is enriched in the plasma membrane where it has key structural and regulatory functions. Cholesterol is thus presumably important for post-injury axon regrowth, and this notion is supported by studies showing that impairment of local cholesterol reutilization impeded regeneration. However, several studies have also shown that statins, inhibitors of 3-hydroxy-3-methylglutaryl-Co A reductase, are enhancers of axon regeneration, presumably acting through an attenuation of the mevalonate isoprenoid pathway and consequent reduction in protein prenylation. Several recent reports have now shown that cholesterol depletion, as well as inhibition of cholesterol synthesis per se, enhances axon regeneration. Here, I discussed these findings and propose some possible underlying mechanisms. The latter would include possible disruptions to axon growth inhibitor signaling by lipid raft-localized receptors, as well as other yet unclear neuronal survival signaling process enhanced by cholesterol lowering or depletion.展开更多
Membrane trafficking processes are presumably vital for axonal regeneration after injury, but mechanistic understanding in this regard has been sparse. A recent loss-of-function screen had been carried out for factors...Membrane trafficking processes are presumably vital for axonal regeneration after injury, but mechanistic understanding in this regard has been sparse. A recent loss-of-function screen had been carried out for factors important for axonal regeneration by cultured cortical neurons and the results suggested that the activity of a number of Rab GTPases might act to restrict axonal regeneration. A loss of Rab27b, in particular, is shown to enhance axonal regeneration in vitro, as well as in C. elegans and mouse central nervous system injury models in vivo. Possible mechanisms underlying this new finding, which has important academic and translational implication, are discussed.展开更多
Amyotrophic lateral sclerosis（ALS）is a progressively fatal neuromuscular disorder classically characterized by loss of upper and lower motor neurons from the cortex to the spinal cord Diagnosed patients have a media...Amyotrophic lateral sclerosis（ALS）is a progressively fatal neuromuscular disorder classically characterized by loss of upper and lower motor neurons from the cortex to the spinal cord Diagnosed patients have a median survival of about 3 years and death usually results from eventual respiratory failure.展开更多
Mutations in genes encoding a key component of cytotoxic granules, or the machinery for their release, underlie the systemic hyperiflammatory symptoms of familial hemophagocytic lymphohistiocytosis (FHL), a typically ...Mutations in genes encoding a key component of cytotoxic granules, or the machinery for their release, underlie the systemic hyperiflammatory symptoms of familial hemophagocytic lymphohistiocytosis (FHL), a typically pediatric onset autosomal recessive disorder with five known genetic subtypes (FHL1 - 5). FHL1 mutations have been mapped to chromosome 9, while the respective genes mutated in FHL2 (PRF1), FHL3 (UNC13D/Munc13-4), FHL4 (STX11) and FHL5 (STXBP2/ Munc18b/Munc18-2) have been identified. Perforin gene mutation directly affected the cytolytic activity of the cytotoxic granules. All the other FHL mutations appear to affect some aspect of cytotoxic granule exocytosis, resulting in impaired target cell killing by cytolytic T lymphocytes (CTLs) and/or natural killer (NK) cells. Recent findings suggest that failure to kill and detach from target cells, and prolonged synapse connection time, promote cytokine hypersecretion by the defective CTLs and NKs, which in turn result in systemic inflammation. Deciphering the genetics of FHL has contributed towards our understanding of the cell biology of hyperinflammatory responses and hemophagocytic lymphohistiocytosis accompanying pathological conditions such as cancer and viral infections.展开更多
Regeneration research is more focused on translational values. However, lying at its very foundation is an understanding of how tissues and organs repair and renew themselves at the cellular level. The past decade has...Regeneration research is more focused on translational values. However, lying at its very foundation is an understanding of how tissues and organs repair and renew themselves at the cellular level. The past decade has witnessed paradigm changing advances in regenerative biology, many of these stems from novel insights into stemness, pluripotency, cell death and their related intra- and inter-cellular biochemical and molecular processes. Some of these new insights are highlighted in the paragraphs that follow. We now have a much better understanding of how regeneration occurs in lower organisms. We have also discovered tools and means of nuclear reprogramming to generate induced pluripotency and changes in cell fate in mammalian models. With further research, there is reasonable hope that various obstacles of regeneration in humans can be better understood and tackled. As regeneration research enters a new era, CellBio welcomes timely review articles and original papers on the theme of “The Cell Biology of Regeneration”.展开更多
Other than the respiratory chain components, most mitochondrial proteins are synthesized in the cytosol and imported into the mitochondria. Many mitochondrial proteins therefore have at least a transient cytosolic app...Other than the respiratory chain components, most mitochondrial proteins are synthesized in the cytosol and imported into the mitochondria. Many mitochondrial proteins therefore have at least a transient cytosolic appearance, and several have a dual mitochondrial-cytosol functional localization. However, recent work has revealed several proteins, one of which is a large protein complex, with dual mitochondrial and nuclear localizations. The enzyme fumarase which catalyzes the reversible hydration/dehydration of fumarate to malate is part of the mitochondria matrix tricarboxylic acid (TCA) cycle. It could, however, be recruited from the cytosol to the nucleus in response to DNA damage, where it is important for DNA repair. The pyruvate dehydrogenase complex (PDC) generates acetyl-CoA from pyruvate, and is recently shown to translocate from the mitochondrial matrix into the nuclear under mitogenic and stress conditions to generate acetyl–CoA within the nucleus. The mitochondrial monooxygenase CLK-1/COQ7 responsible for the synthesis of ubiquinone is most recently found to have a nuclear isoform with an uncleaved amino terminus, where it affects transcriptional changes associated with mitochondrial reactive oxygen species (ROS) generation. In this review, we highlight these unusual cases of nuclear localization of classically mitochondrial proteins, and discuss their possible functions in the nucleus.展开更多
Pyruvate is a key intermediate at the branchpoint of anaerobic and aerobic energy metabolism. Its transport into the mitochondrial matrix is necessary prior to its decarboxylation into acetyl-CoA, which feeds the redu...Pyruvate is a key intermediate at the branchpoint of anaerobic and aerobic energy metabolism. Its transport into the mitochondrial matrix is necessary prior to its decarboxylation into acetyl-CoA, which feeds the reducing equivalent-generating tricarboxylic acid (TCA) cycle. Although the existence of specific carrier transport of cytosolic pyruvate into the mitochondria has been inferred from a myriad of studies, the identities of the mitochondrial pyruvate carrier (MPC) were only confirmed very recently. Identification of the MPC facilitated several other recent advances. These include the finding of MPC’s inhibition by the insulin-sensitizing drug family thiazolidinediones, how cells respond flexibly to a reduction in MPC functionality, as well as insights into how changes in MPC levels affect oncogenic potential of cancer cells. These new findings, discussed here in this brief review, have important implications in therapeutic approaches towards metabolic disorders and cancer.展开更多
Damaged adult central nervous system axons have very limited regenerative capacity,if any.Other than an intrinsic deficiency（Liu et al.,2011）in axonal extension and guidance compared to embryonic neurons or peripher...Damaged adult central nervous system axons have very limited regenerative capacity,if any.Other than an intrinsic deficiency（Liu et al.,2011）in axonal extension and guidance compared to embryonic neurons or peripheral neurons,the injury site is also generally viewed to be non-permissive for axonal regrowth.In particular,展开更多
A neuron with injured or severed axon responds with attempts at axonal regrowth. In this regard, axonal regeneration of peripheral nerves occurs far more efficiently compared to central nervous system （CNS） neurons....A neuron with injured or severed axon responds with attempts at axonal regrowth. In this regard, axonal regeneration of peripheral nerves occurs far more efficiently compared to central nervous system （CNS） neurons. The latter typically could not form a proper growth cone, and any axonal regeneration in vivo is very limited. The adult CNS environment is not conducive for axonal regrowth. An extensive body of work has revealed mechanisms whereby the myelin-associated inhibitors and extracellular matrix chondroitin sulfate proteoglycans promote collapse of axonal growth cones or repel their advances （Lee and Zheng, 2012）. The intrinsic axonal regeneration capacity of an injured neuron is, however,展开更多
文摘Nogo-A is known to restrict plasticity in the adult central nervous system,and signalling through its cognate receptors modulates synaptic spine architecture and excitatory glutamate transmission via restricting synaptic glutamate receptor levels and their delivery to the post-synaptic compartments.A recent report now indicates that Nogo-A,signaling through Sphingosine-1-Phosphate Receptor 2,also strengthens inhibitory gamma amino acid butyric acid(GABA)ergic transmission by limiting the diffusion dynamics of GABAA receptors.This reciprocal modulation of excitatory and inhibitory signaling via neurotransmitter receptor dynamics by Nogo-A likely plays important pathophysiological roles in synaptic plasticity during development and injury.
文摘Highlight Semaphorin 3A is a classically known axonal guidance cue that mediates axonal growth cone repulsion and collapse.Recent works,however,suggest that it may have the apparently diametrically opposite activity of promoting neuronal regeneration.
基金supported by the National University of Singapore Graduate School for Integrative Sciences and Engineering(to BLT)
文摘Environmental enrichment is known to be beneficial for cognitive improvement.In many animal models of neurological disorders and brain injury,EE has also demonstrated neuroprotective benefits in neurodegenerative diseases and in improving recovery after stroke or traumatic brain injury.The exact underlying mechanism for these phenomena has been unclear.Recent findings have now indicated that neuronal activity elicited by environmental enrichment induces Ca2+influx in dorsal root ganglion neurons results in lasting enhancement of CREB-binding protein-mediated histone acetylation.This,in turn,increases the expression of pro-regeneration genes and promotes axonal regeneration.This mechanism associated with neuronal activity elicited by environmental enrichment-mediated pathway is one of several epigenetic mechanisms which modulate axon regeneration upon injury that has recently come to light.The other prominent mechanisms,albeit not yet directly associated with environmental enrichment,include DNA methylation/demethylation and N6-methyladenosine modification of transcripts.In this brief review,I highlight recent work that has shed light on the epigenetic basis of environmental enrichment-based axon regeneration,and discuss the mechanism and pathways involved.I further speculate on the implications of the findings,in conjunction with the other epigenetic mechanisms,that could be harness to promote axon regeneration upon injury.
文摘Cholesterol is biosynthesized by all animal cells. Beyond its metabolic role in steroidogenesis, it is enriched in the plasma membrane where it has key structural and regulatory functions. Cholesterol is thus presumably important for post-injury axon regrowth, and this notion is supported by studies showing that impairment of local cholesterol reutilization impeded regeneration. However, several studies have also shown that statins, inhibitors of 3-hydroxy-3-methylglutaryl-Co A reductase, are enhancers of axon regeneration, presumably acting through an attenuation of the mevalonate isoprenoid pathway and consequent reduction in protein prenylation. Several recent reports have now shown that cholesterol depletion, as well as inhibition of cholesterol synthesis per se, enhances axon regeneration. Here, I discussed these findings and propose some possible underlying mechanisms. The latter would include possible disruptions to axon growth inhibitor signaling by lipid raft-localized receptors, as well as other yet unclear neuronal survival signaling process enhanced by cholesterol lowering or depletion.
基金supported by the National University of Singapore Graduate School for Integrative Sciences and Engineering(to BLT)
文摘Membrane trafficking processes are presumably vital for axonal regeneration after injury, but mechanistic understanding in this regard has been sparse. A recent loss-of-function screen had been carried out for factors important for axonal regeneration by cultured cortical neurons and the results suggested that the activity of a number of Rab GTPases might act to restrict axonal regeneration. A loss of Rab27b, in particular, is shown to enhance axonal regeneration in vitro, as well as in C. elegans and mouse central nervous system injury models in vivo. Possible mechanisms underlying this new finding, which has important academic and translational implication, are discussed.
基金supported by the NUS Graduate School for Integrative Sciences and Engineering
文摘Amyotrophic lateral sclerosis（ALS）is a progressively fatal neuromuscular disorder classically characterized by loss of upper and lower motor neurons from the cortex to the spinal cord Diagnosed patients have a median survival of about 3 years and death usually results from eventual respiratory failure.
文摘Mutations in genes encoding a key component of cytotoxic granules, or the machinery for their release, underlie the systemic hyperiflammatory symptoms of familial hemophagocytic lymphohistiocytosis (FHL), a typically pediatric onset autosomal recessive disorder with five known genetic subtypes (FHL1 - 5). FHL1 mutations have been mapped to chromosome 9, while the respective genes mutated in FHL2 (PRF1), FHL3 (UNC13D/Munc13-4), FHL4 (STX11) and FHL5 (STXBP2/ Munc18b/Munc18-2) have been identified. Perforin gene mutation directly affected the cytolytic activity of the cytotoxic granules. All the other FHL mutations appear to affect some aspect of cytotoxic granule exocytosis, resulting in impaired target cell killing by cytolytic T lymphocytes (CTLs) and/or natural killer (NK) cells. Recent findings suggest that failure to kill and detach from target cells, and prolonged synapse connection time, promote cytokine hypersecretion by the defective CTLs and NKs, which in turn result in systemic inflammation. Deciphering the genetics of FHL has contributed towards our understanding of the cell biology of hyperinflammatory responses and hemophagocytic lymphohistiocytosis accompanying pathological conditions such as cancer and viral infections.
文摘Regeneration research is more focused on translational values. However, lying at its very foundation is an understanding of how tissues and organs repair and renew themselves at the cellular level. The past decade has witnessed paradigm changing advances in regenerative biology, many of these stems from novel insights into stemness, pluripotency, cell death and their related intra- and inter-cellular biochemical and molecular processes. Some of these new insights are highlighted in the paragraphs that follow. We now have a much better understanding of how regeneration occurs in lower organisms. We have also discovered tools and means of nuclear reprogramming to generate induced pluripotency and changes in cell fate in mammalian models. With further research, there is reasonable hope that various obstacles of regeneration in humans can be better understood and tackled. As regeneration research enters a new era, CellBio welcomes timely review articles and original papers on the theme of “The Cell Biology of Regeneration”.
文摘Other than the respiratory chain components, most mitochondrial proteins are synthesized in the cytosol and imported into the mitochondria. Many mitochondrial proteins therefore have at least a transient cytosolic appearance, and several have a dual mitochondrial-cytosol functional localization. However, recent work has revealed several proteins, one of which is a large protein complex, with dual mitochondrial and nuclear localizations. The enzyme fumarase which catalyzes the reversible hydration/dehydration of fumarate to malate is part of the mitochondria matrix tricarboxylic acid (TCA) cycle. It could, however, be recruited from the cytosol to the nucleus in response to DNA damage, where it is important for DNA repair. The pyruvate dehydrogenase complex (PDC) generates acetyl-CoA from pyruvate, and is recently shown to translocate from the mitochondrial matrix into the nuclear under mitogenic and stress conditions to generate acetyl–CoA within the nucleus. The mitochondrial monooxygenase CLK-1/COQ7 responsible for the synthesis of ubiquinone is most recently found to have a nuclear isoform with an uncleaved amino terminus, where it affects transcriptional changes associated with mitochondrial reactive oxygen species (ROS) generation. In this review, we highlight these unusual cases of nuclear localization of classically mitochondrial proteins, and discuss their possible functions in the nucleus.
文摘Pyruvate is a key intermediate at the branchpoint of anaerobic and aerobic energy metabolism. Its transport into the mitochondrial matrix is necessary prior to its decarboxylation into acetyl-CoA, which feeds the reducing equivalent-generating tricarboxylic acid (TCA) cycle. Although the existence of specific carrier transport of cytosolic pyruvate into the mitochondria has been inferred from a myriad of studies, the identities of the mitochondrial pyruvate carrier (MPC) were only confirmed very recently. Identification of the MPC facilitated several other recent advances. These include the finding of MPC’s inhibition by the insulin-sensitizing drug family thiazolidinediones, how cells respond flexibly to a reduction in MPC functionality, as well as insights into how changes in MPC levels affect oncogenic potential of cancer cells. These new findings, discussed here in this brief review, have important implications in therapeutic approaches towards metabolic disorders and cancer.
基金supported by NUS Graduate School for Integrative Sciences and Engineering(NGS)
文摘Damaged adult central nervous system axons have very limited regenerative capacity,if any.Other than an intrinsic deficiency（Liu et al.,2011）in axonal extension and guidance compared to embryonic neurons or peripheral neurons,the injury site is also generally viewed to be non-permissive for axonal regrowth.In particular,
基金supported by the Graduate School for Integrative Sciences and Engineering,National University of Singapore
文摘A neuron with injured or severed axon responds with attempts at axonal regrowth. In this regard, axonal regeneration of peripheral nerves occurs far more efficiently compared to central nervous system （CNS） neurons. The latter typically could not form a proper growth cone, and any axonal regeneration in vivo is very limited. The adult CNS environment is not conducive for axonal regrowth. An extensive body of work has revealed mechanisms whereby the myelin-associated inhibitors and extracellular matrix chondroitin sulfate proteoglycans promote collapse of axonal growth cones or repel their advances （Lee and Zheng, 2012）. The intrinsic axonal regeneration capacity of an injured neuron is, however,
