ON THE CONVERGENCE RATE OF A CLASS OF REACTION HYPERBOLIC SYSTEMS FOR AXONAL TRANSPORT

In this paper, we consider a class of reaction hyperbolic systems for axonal trans- port arising in neuroscience which can be regarded as hyperbolic systems with relaxation. We prove the BV entropy solutions of the hyperbolic systems converge toward to the unique entropy solution of the equilibrium equation at the optimal rate O（√δ） in L1 norm as the relaxation time δ tends to zero.

Receptor-mediated increase in rabies virus axonal transport

Rabies virus （RABV） of the rhabdoviridae family is a prototype neurotropic virus that causes a fatal disease, and is still a major risk mostly in developing countries. A key step in the RABV infection process is its arrival into the central nervous system （CNS）, for which it uses the cellular transport machinery. Neurons are irregular cells with a specialized anatomy, and often extend lengthy axons that may span over a meter long. In infected organisms, RABV virions enter the neuron periphery at the area of a bite and must overcome great distances in order to reach the peripheral neuron＇s cell body and from there,

Restoring axonal localization and transport of transmembrane receptors to promote repair within the injured CNS: a critical step in CNS regeneration

Each neuronal subtype is distinct in how it develops,responds to environmental cues,and whether it is capable of mounting a regenerative response following injury.Although the adult central nervous system（CNS） does not regenerate,several experimental interventions have been trialled with successful albeit limited instances of axonal repair.We highlight here some of these approaches including extracellular matrix（ECM） modification,cellular grafting,gene therapy-induced replacement of proteins,as well as application of biomaterials.We also review the recent report demonstrating the failure of axonal localization and transport of growth-promoting receptors within certain classes of mature neurons.More specifically,we discuss an inability of integrin receptors to localize within the axonal compartment of mature motor neurons such as in the corticospinal and rubrospinal tracts,whereas in immature neurons of those pathways and in mature sensory tracts such as in the optic nerve and dorsal column pathways these receptors readily localize within axons.Furthermore we assert that this failure of axonal localization contributes to the intrinsic inability of axonal regeneration.We conclude by highlighting the necessity for both combined therapies as well as a targeted approach specific to both age and neuronal subtype will be required to induce substantial CNS repair.

Soluble N-terminal fragment of mutant Huntingtin protein impairs mitochondrial axonal transport in cultured hippocampal neurons

Huntington＇s disease （HD） is an autosomal dominant, progressive, neurodegenerative disorder caused by an unstable expansion of CAG repeats （〉35 repeats） within exon 1 of the interesting transcript 15 （IT15） gene. This gene encodes a protein called Huntingtin （Htt）, and mutation of the gene results in a polyglutamine （polyQ） near the N-terminus of Htt. The N-terminal fragments of mutant Htt （mHtt）, which tend to aggregate, are sufficient to cause HD. Whether these aggregates are causal or protective for HD remains hotly debated. Dysfunctional mitochondrial axonal transport is associated with HD. It remains unknown whether the soluble or aggregated form of mHtt is the primary cause of the impaired mitochondrial axonal transport in HD pathology. Here, we investigated the impact of soluble and aggregated N-terminal fragments of mHtt on mitochondrial axonal transport in cultured hippocampal neurons. We found that the N-terminal fragment of mHtt formed aggregates in almost half of the transfected neurons. Overexpression of the N-terminal fragment of mHtt decreased the velocity of mitochondrial axonal transport and mitochondrial mobility in neurons regardless of whether aggregates were formed. However, the impairment of mitochondrial axonal transport in neurons expressing the soluble and aggregated N-terminal fragments of mHtt did not differ. Our findings indicate that both the soluble and aggregated N-terminal fragments of mHtt impair mitochondrial axonal transport in cultured hippocampal neurons. We predict that dysfunction of mitochondrial axonal transport is an early-stage event in the progression of HD, even before mHtt aggregates are formed.

Neuronal PPARαdeficiency-induced axonal mitochondrial transport defects underly isch⁃emic stroke pathology

OBJECTIVE Peroxisome proliferator activated receptor alpha(PPARα)is an important protective factor in neurovascular diseases such as ischemic stroke.Although PPARαexpression is higher in neurons than astrocytes and microglia,the pathophysiological functions of neuronal specific-PPARαin isch⁃emic stroke remains unknown.Here,we report that neuronal PPARαdeficiency is a key factor of neuronal injury.PPARαexpression markedly decreased in neurons after ischemic stroke.METHODS AND RESULTS Neuronal-specific PPARαknockout(NCKO)exacerbates neuronal damage and brain ischemic injury.PPARαdefi⁃ciency disrupts axonal microtubule organization and mitochondrial transport by decreasing the expression of dynein light chain Tctex-type 1(Dynlt1),which is implicated in cytoprotective role with damaged neurons.Furthermore,resto⁃ration of Dynlt1 expression in neurons of NCKO mice rescue mitochondrial transport disorder,cognitive deficits and brain ischemic injury asso⁃ciated with PPARαdeletion.CONCLUSION These results reveal a critical role for neuronal PPARαin ischemic brain injury by modulating axonal mitochondrial transportation.

76nt RNAs are transported axonally into regenerating axons and growth cones.What are they doing there?

Successful nerve regeneration requires not only that neurons reconstruct new axons distal to the site of injury,but also those growing axons must navigate through the neuropil to make appropriate synaptic connections with target cells.While this is an imposing task for the thousands of axons that may occupy a regenerating nerve in the peripheral nervous system or a tract inthe central nervous system, the billions of neurons in the developing brain must accomplish similar tasks making connections that number in the trillions. How do neurons do this？

The pathogenic mechanism of TAR DNA-binding protein 43(TDP-43)in amyotrophic lateral sclerosis

The onset of amyotrophic lateral sclerosis is usually characterized by focal death of both upper and/or lower motor neurons occurring in the motor cortex,basal ganglia,brainstem,and spinal cord,and commonly involves the muscles of the upper and/or lower extremities,and the muscles of the bulbar and/or respiratory regions.However,as the disease progresses,it affects the adjacent body regions,leading to generalized muscle weakness,occasionally along with memory,cognitive,behavioral,and language impairments;respiratory dysfunction occurs at the final stage of the disease.The disease has a complicated pathophysiology and currently,only riluzole,edaravone,and phenylbutyrate/taurursodiol are licensed to treat amyotrophic lateral sclerosis in many industrialized countries.The TAR DNA-binding protein 43 inclusions are observed in 97%of those diagnosed with amyotrophic lateral sclerosis.This review provides a preliminary overview of the potential effects of TAR DNAbinding protein 43 in the pathogenesis of amyotrophic lateral sclerosis,including the abnormalities in nucleoplasmic transport,RNA function,post-translational modification,liquid-liquid phase separation,stress granules,mitochondrial dysfunction,oxidative stress,axonal transport,protein quality control system,and non-cellular autonomous functions(e.g.,glial cell functions and prion-like propagation).

Collapsin response mediator protein-2 plays a major protective role in acute axonal degeneration

Axonal degeneration is a key pathological feature in many neurological diseases. It often leads to persistent deficits due to the inability of axons to regenerate in the central nervous system. Therefore therapeutic approaches should optimally both attenuate axonal degeneration and foster axonal regeneration. Compelling evidence suggests that collapsin response mediator protein-2（CRMP2） might be a molecular target fulfilling these requirements. In this mini-review, we give a compact overview of the known functions of CRMP2 and its molecular interactors in neurite outgrowth and in neurodegenerative conditions. Moreover, we discuss in detail our recent findings on the role of CRMP2 in acute axonal degeneration in the optic nerve. We found that the calcium influx induced by the lesion activates the protease calpain which cleaves CRMP2, leading to impairment of axonal transport. Both calpain inhibition and CRMP2 overexpression effectively protected the proximal axons against acute axonal degeneration. Taken together, CRMP2 is further characterized as a central molecular player in acute axonal degeneration and thus evolves as a promising therapeutic target to both counteract axonal degeneration and foster axonal regeneration in neurodegenerative and neurotraumatic diseases.

Rabs and axonal regeneration

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.

Bridging the gap:axonal fusion drives rapid functional recovery of the nervous system

Injuries to the central or peripheral nervous system frequently cause long-term disabilities because damaged neurons are unable to efficiently self-repair.This inherent deficiency necessitates the need for new treatment options aimed at restoring lost function to patients.Compared to humans,a number of species possess far greater regenerative capabilities,and can therefore provide important insights into how our own nervous systems can be repaired.In particular,several invertebrate species have been shown to rapidly initiate regeneration post-injury,allowing separated axon segments to re-join.This process,known as axonal fusion,represents a highly efficient repair mechanism as a regrowing axon needs to only bridge the site of damage and fuse with its separated counterpart in order to re-establish its original structure.Our recent findings in the nematode Caenorhabditis elegans have expanded the promise of axonal fusion by demonstrating that it can restore complete function to damaged neurons.Moreover,we revealed the importance of injury-induced changes in the composition of the axonal membrane for mediating axonal fusion,and discovered that the level of axonal fusion can be enhanced by promoting a neuron＇s intrinsic growth potential.A complete understanding of the molecular mechanisms controlling axonal fusion may permit similar approaches to be applied in a clinical setting.

Axonal mRNA localization and local translation in neurodegenerative diseases

The regulation of mRNA localization and local translation play vital roles in the maintenance of cellular structure and function.Many human neurodegenerative diseases,such as fragile X syndrome,amyotrophic lateral sclerosis,Alzheimer’s disease,and spinal muscular atrophy,have been characterized by pathological changes in neuronal axons,including abnormal mRNA translation,the loss of protein expression,or abnormal axon transport.Moreover,the same protein and mRNA molecules have been associated with variable functions in different diseases due to differences in their interaction networks.In this review,we briefly examine fragile X syndrome,amyotrophic lateral sclerosis,Alzheimer’s disease,and spinal muscular atrophy,with a focus on disease pathogenesis with regard to local mRNA translation and axon transport,suggesting possible treatment directions.

Linking axon transport to regeneration using in vitro laser axotomy

Spinal cord injury has devastating consequences because adult central nervous system （CNS） neurons do not regenerate their axons after injury. Two key reasons for axon regeneration fail- ure are extrinsic inhibitory factors and a low intrinsic capacity for axon regrowth. Research has therefore focused on overcom- ing extrinsic growth inhibition, and enhancing intrinsic regeneration capacity. Both of these issues will need to be addressed to enable optimal repair of the injured sp＋inal cord.

Regenerative peripheral nerve interface prevents neuroma formation after peripheral nerve transection

Neuroma formation after peripheral nerve transection often leads to severe neuropathic pain.Regenerative peripheral nerve interface has been shown to reduce painful neuroma in the clinic.However,no reports have investigated the underlying mechanisms,and no comparative animal studies on regenerative peripheral nerve interface and other means of neuroma prevention have been conducted to date.In this study,we established a rat model of left sciatic nerve transfection,and subsequently interfered with the model using the regenerative peripheral nerve interface or proximal nerve stump implantation inside a fully innervated muscle.Results showed that,compared with rats subjected to nerve stump implantation inside the muscle,rats subjected to regenerative peripheral nerve interface intervention showed greater inhibition of the proliferation of collagenous fibers and irregular regenerated axons,lower expressions of the fibrosis markerα-smooth muscle actin and the inflammatory marker sigma-1 receptor in the proximal nerve stump,lower autophagy behaviors,lower expressions of c-fos and substance P,higher expression of glial cell line-derived neurotrophic factor in the ipsilateral dorsal root ganglia.These findings suggested that regenerative peripheral nerve interface inhibits peripheral nerve injury-induced neuroma formation and neuropathic pain possibly via the upregulation of the expression of glial cell line-derived neurotrophic factor in the dorsal root ganglia and reducing neuroinflammation in the nerve stump.

What we know about axons in Parkinson’s disease

Tremendous research efforts have been made regarding the pathogenesis of Parkinson’s disease(PD).However,there are still no effective strategies to restore midbrain dopaminergic(mDA)innervation and prevent disease progression.One possibility is that we may have been neglecting the role of axons in mDA neuronal degeneration.This review first summarizes mDA axon development during the early stage of PD and discusses how axon guidance defects contribute to PD vulnerability.Furthermore,we review axonal transport dysregulation in the numerous PD-related genetic mutations,including Parkin,PINK1,DJ1,LRRK2 and SNCA.The evidence suggests that proper axonal transport is crucial for neuronal function and survival.Finally,advanced tools for axonal studies were evaluated,including light-sheet and super-resolution microscopy.These adapted microscopes have been used to help solve questions unanswered before.Overall,the role of axon terminals in the initiation of the degeneration cascade remains undeciphered,and more research in the related area may be conducted further to restore dopamine levels in the striatum to alleviate the motor complications of PD.

Basic mechanisms of peripheral nerve injury and treatment via electrical stimulation

Previous studies on the mechanisms of peripheral nerve injury(PNI)have mainly focused on the pathophysiological changes within a single injury site.However,recent studies have indicated that within the central nervous system,PNI can lead to changes in both injury sites and target organs at the cellular and molecular levels.Therefore,the basic mechanisms of PNI have not been comprehensively understood.Although electrical stimulation was found to promote axonal regeneration and functional rehabilitation after PNI,as well as to alleviate neuropathic pain,the specific mechanisms of successful PNI treatment are unclear.We summarize and discuss the basic mechanisms of PNI and of treatment via electrical stimulation.After PNI,activity in the central nervous system(spinal cord)is altered,which can limit regeneration of the damaged nerve.For example,cell apoptosis and synaptic stripping in the anterior horn of the spinal cord can reduce the speed of nerve regeneration.The pathological changes in the posterior horn of the spinal cord can modulate sensory abnormalities after PNI.This can be observed in cases of ectopic discharge of the dorsal root ganglion leading to increased pain signal transmission.The injured site of the peripheral nerve is also an important factor affecting post-PNI repair.After PNI,the proximal end of the injured site sends out axial buds to innervate both the skin and muscle at the injury site.A slow speed of axon regeneration leads to low nerve regeneration.Therefore,it can take a long time for the proximal nerve to reinnervate the skin and muscle at the injured site.From the perspective of target organs,long-term denervation can cause atrophy of the corresponding skeletal muscle,which leads to abnormal sensory perception and hyperalgesia,and finally,the loss of target organ function.The mechanisms underlying the use of electrical stimulation to treat PNI include the inhibition of synaptic stripping,addressing the excessive excitability of the dorsal root ganglion,alleviating neuropathic pain,improving neurological function,and accelerating nerve regeneration.Electrical stimulation of target organs can reduce the atrophy of denervated skeletal muscle and promote the recovery of sensory function.Findings from the included studies confirm that after PNI,a series of physiological and pathological changes occur in the spinal cord,injury site,and target organs,leading to dysfunction.Electrical stimulation may address the pathophysiological changes mentioned above,thus promoting nerve regeneration and ameliorating dysfunction.

Promoting axon regeneration in the central nervous system by increasing PI3-kinase signaling

Much research has focused on the PI3-kinase and PTEN signaling pathway with the aim to stimulate repair of the injured central nervous system.Axons in the central nervous system fail to regenerate,meaning that injuries or diseases that cause loss of axonal connectivity have life-changing consequences.In 2008,genetic deletion of PTEN was identified as a means of stimulating robust regeneration in the optic nerve.PTEN is a phosphatase that opposes the actions of PI3-kinase,a family of enzymes that function to generate the membrane phospholipid PIP_(3) from PIP_(2)(phosphatidylinositol(3,4,5)-trisphosphate from phosphatidylinositol(4,5)-bisphosphate).Deletion of PTEN therefore allows elevated signaling downstream of PI3-kinase,and was initially demonstrated to promote axon regeneration by signaling through mTOR.More recently,additional mechanisms have been identified that contribute to the neuron-intrinsic control of regenerative ability.This review describes neuronal signaling pathways downstream of PI3-kinase and PIP3,and considers them in relation to both developmental and regenerative axon growth.We briefly discuss the key neuron-intrinsic mechanisms that govern regenerative ability,and describe how these are affected by signaling through PI3-kinase.We highlight the recent finding of a developmental decline in the generation of PIP_(3) as a key reason for regenerative failure,and summarize the studies that target an increase in signaling downstream of PI3-kinase to facilitate regeneration in the adult central nervous system.Finally,we discuss obstacles that remain to be overcome in order to generate a robust strategy for repairing the injured central nervous system through manipulation of PI3-kinase signaling.

BDNF improves axon transportation and rescues visual function in a rodent model of acute elevation of intraocular pressure

Optic neuropathies lead to blindness;the common pathology is the degeneration of axons of the retinal ganglion cells. In this study, we used a rat model of retinal ischemia-reperfusion and a one-time intravitreal brain-derived neurotrophic factor(BDNF)injection;then we examined axon transportation function, continuity, physical presence of axons in different part of the optic nerve, and the expression level of proteins involved in axon transportation. We found that in the disease model, axon transportation was the most severely affected, followed by axon continuity, then the number of axons in the distal and proximal optic nerve. BDNF treatment relieved all reductions and significantly restored function. The molecular changes were more minor,probably due to massive gliosis of the optic nerve, so interpretation of protein expression data should be done with some caution.The process in this acute model resembles a fast-forward of changes in the chronic model of glaucoma. Therefore, impairment in axon transportation appears to be a common early process underlying different optic neuropathies. This research on effective intervention can be used to develop interventions for all optic neuropathies targeting axon transportation.

Microtubule acetylation dyshomeostasis in Parkinson’s disease

The inter-neuronal communication occurring in extensively branched neuronal cells is achieved primarily through the microtubule(MT)-mediated axonal transport system.This mechanistically regulated system delivers cargos(proteins,mRNAs and organelles such as mitochondria)back and forth from the soma to the synapse.Motor proteins like kinesins and dynein mechanistically regulate polarized anterograde(from the soma to the synapse)and retrograde(from the synapse to the soma)commute of the cargos,respectively.Proficient axonal transport of such cargos is achieved by altering the microtubule stability via post-translational modifications(PTMs)ofα-andβ-tubulin heterodimers,core components constructing the MTs.Occurring within the lumen of MTs,K40 acetylation ofα-tubulin viaα-tubulin acetyl transferase and its subsequent deacetylation by HDAC6 and SIRT2 are widely scrutinized PTMs that make the MTs highly flexible,which in turn promotes their lifespan.The movement of various motor proteins,including kinesin-1(responsible for axonal mitochondrial commute),is enhanced by this PTM,and dyshomeostasis of neuronal MT acetylation has been observed in a variety of neurodegenerative conditions,including Alzheimer’s disease and Parkinson’s disease(PD).PD is the second most common neurodegenerative condition and is closely associated with impaired MT dynamics and deregulated tubulin acetylation levels.Although the relationship between status of MT acetylation and progression of PD pathogenesis has become a chicken-and-egg question,our review aims to provide insights into the MT-mediated axonal commute of mitochondria and dyshomeostasis of MT acetylation in PD.The enzymatic regulators of MT acetylation along with their synthetic modulators have also been briefly explored.Moving towards a tubulin-based therapy that enhances MT acetylation could serve as a disease-modifying treatment in neurological conditions that lack it.

Protection of retinal ganglion cells against glaucomatous neuropathy by neurotrophin-producing,genetically modified neural progenitor cells in a rat model

OBJECTIVE: To investigate in vivo survival of retinal ganglion cells (RGCs) after partial blockage of optic nerve (ON) axoplasmic flow by sub-retinal space or vitreous cavity injection of brain-derived neural factor (BDNF) produced by genetically modified neural progenitor cells (NPCs). METHODS: Adult Sprague-Dawley (SD) rat RGCs were labeled with granular blue (GB) applied to their main targets in the brain. Seven days later, the left ON was intra-obitally crushed with a 40 g power forceps to partially block ON axoplasmic flow. Animals were randomized to three groups. The left eye of each rat received a sham injection, NPCs injection or an injection of genetically modified neural progenitors producing BDNF (BDNF-NPCs). Seven, 15 and 30 days after ON crush, retinas were examined under a fluorescence microscope. By calculating and comparing the average RGCs densities and RGC apoptosis density, RGC survival was estimated and the neuro-protective effect of transplanted cells was evaluated. RESULTS: Seven, 15 and 30 days after crush, in the intra-vitreous injection group, mean RGC densities had decreased to 1885 +/- 68, 1562 +/- 20, 1380 +/- 7 and 1837 +/- 46, 1561 +/- 58, 1370 +/- 16, respectively with sham injection or neural progenitors injection. However, RGCs density in the groups treated with intra-vitreous injection of BDNF-NPC was 2101 +/- 15, 1809 +/- 19 and 1625 +/- 34. Similar results were found in groups after sub-retinal injection. Higher densities were observed in groups treated with BDNF-NPCs. There were statistically significant differences among groups through nonparametric tests followed by the Mann-Whitely test. RGC apoptosis density in BDNF-NPC at each follow-up time was less than in other groups. CONCLUSIONS: A continuous supply of neurotrophic factors by the injection of genetically modified neural progenitors presents a highly effective approach to counteract optic neuropathy and RGC degeneration after partial ON axoplasmic flow blockage.

New perspectives on cytoskeletal dysregulation and mitochondrial mislocalization in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis(ALS)is a progressive neurodegenerative disease characterized by selective,early degeneration of motor neurons in the brain and spinal cord.Motor neurons have long axonal projections,which rely on the integrity of neuronal cytoskeleton and mitochondria to regulate energy requirements for maintaining axonal stability,anterograde and retrograde transport,and signaling between neurons.The formation of protein aggregates which contain cytoskeletal proteins,and mitochondrial dysfunction both have devastating effects on the function of neurons and are shared pathological features across several neurodegenerative conditions,including ALS,Alzheimer's disease,Parkinson's disease,Huntington's disease and Charcot-Marie-Tooth disease.Furthermore,it is becoming increasingly clear that cytoskeletal integrity and mitochondrial function are intricately linked.Therefore,dysregulations of the cytoskeletal network and mitochondrial homeostasis and localization,may be common pathways in the initial steps of neurodegeneration.Here we review and discuss known contributors,including variants in genetic loci and aberrant protein activities,which modify cytoskeletal integrity,axonal transport and mitochondrial localization in ALS and have overlapping features with other neurodegenerative diseases.Additionally,we explore some emerging pathways that may contribute to this disruption in ALS.