RDH12-associated retinal degeneration caused by a homozygous pathogenic variant of 146C>T and literature review

AIM:To describe the clinical,electrophysiological,and genetic features of an unusual case with an RDH12 homozygous pathogenic variant and reviewed the characteristics of the patients reported with the same variant.METHODS:The patient underwent a complete ophthalmologic examination including best-corrected visual acuity,anterior segment and dilated fundus,visual field,spectral-domain optical coherence tomography(OCT)and electroretinogram(ERG).The retinal disease panel genes were sequenced through chip capture high-throughput sequencing and Sanger sequencing was used to confirm the result.Then we reviewed the characteristics of the patients reported with the same variant.RESULTS:A 30-year male presented with severe early retinal degeneration who complained night blindness,decreased visual acuity,vitreous floaters and amaurosis fugax.The best corrected vision was 0.04 OD and 0.12 OS,respectively.The fundus photo and OCT showed bilateral macular atrophy but larger areas of macular atrophy in the left eye.Autofluorescence shows bilateral symmetrical hypo-autofluorescence.ERG revealed that the amplitudes of a-and b-wave were severely decreased.Multifocal ERG showed decreased amplitudes in the local macular area.A homozygous missense variant c.146C>T(chr14:68191267)was found.The clinical characteristics of a total of 13 patients reported with the same pathologic variant varied.CONCLUSION:An unusual patient with a homozygous pathogenic variant in the c.146C>T of RDH12 which causes late-onset and asymmetric retinal degeneration are reported.The clinical manifestations of the patient with multimodal retinal imaging and functional examinations have enriched our understanding of this disease.

Neutrophil peptide 1 accelerates the clearance of degenerative axons during Wallerian degeneration by activating macrophages after peripheral nerve crush injury

Macrophages play an important role in peripheral nerve regeneration,but the specific mechanism of regeneration is still unclear.Our preliminary findings indicated that neutrophil peptide 1 is an innate immune peptide closely involved in peripheral nerve regeneration.However,the mechanism by which neutrophil peptide 1 enhances nerve regeneration remains unclear.This study was designed to investigate the relationship between neutrophil peptide 1 and macrophages in vivo and in vitro in peripheral nerve crush injury.The functions of RAW 264.7 cells we re elucidated by Cell Counting Kit-8 assay,flow cytometry,migration assays,phagocytosis assays,immunohistochemistry and enzyme-linked immunosorbent assay.Axonal debris phagocytosis was observed using the CUBIC(Clear,Unobstructed Brain/Body Imaging Cocktails and Computational analysis)optical clearing technique during Wallerian degeneration.Macrophage inflammatory factor expression in different polarization states was detected using a protein chip.The results showed that neutrophil peptide 1 promoted the prolife ration,migration and phagocytosis of macrophages,and CD206 expression on the surfa ce of macrophages,indicating M2 polarization.The axonal debris clearance rate during Wallerian degeneration was enhanced after neutrophil peptide 1 intervention.Neutrophil peptide 1 also downregulated inflammatory factors interleukin-1α,-6,-12,and tumor necrosis factor-αin invo and in vitro.Thus,the results suggest that neutrophil peptide 1 activates macrophages and accelerates Wallerian degeneration,which may be one mechanism by which neutrophil peptide 1 enhances peripheral nerve regeneration.

Taurine: a promising nutraceutic in the prevention of retinal degeneration

Taurine is considered a non-essential amino acid because it is synthesized by most mammals.However,dietary intake of taurine may be necessary to achieve the physiological levels required for the development,maintenance,and function of certain tissues.Taurine may be especially important for the retina.The concentration of taurine in the retina is higher than that in any other tissue in the body and taurine deficiency causes retinal oxidative stress,apoptosis,and degeneration of photoreceptors and retinal ganglion cells.Low plasma taurine levels may also underlie retinal degeneration in humans and therefore,taurine administration could exert retinal neuroprotective effects.Taurine has antioxidant,anti-apoptotic,immunomodulatory,and calcium homeostasis-regulatory properties.This review summarizes the role of taurine in retinal health and disease,where it appears that taurine may be a promising nutraceutical.

Autophagy-targeting modulation to promote peripheral nerve regeneration

Nerve regeneration following traumatic peripheral nerve injuries and neuropathies is a complex process modulated by diverse factors and intricate molecular mechanisms.Past studies have focused on factors that stimulate axonal outgrowth and myelin regeneration.However,recent studies have highlighted the pivotal role of autophagy in peripheral nerve regeneration,particularly in the context of traumatic injuries.Consequently,autophagy-targeting modulation has emerged as a promising therapeutic approach to enhancing peripheral nerve regeneration.Our current understanding suggests that activating autophagy facilitates the rapid clearance of damaged axons and myelin sheaths,thereby enhancing neuronal survival and mitigating injury-induced oxidative stress and inflammation.These actions collectively contribute to creating a favorable microenvironment for structural and functional nerve regeneration.A range of autophagyinducing drugs and interventions have demonstrated beneficial effects in alleviating peripheral neuropathy and promoting nerve regeneration in preclinical models of traumatic peripheral nerve injuries.This review delves into the regulation of autophagy in cell types involved in peripheral nerve regeneration,summarizing the potential drugs and interventions that can be harnessed to promote this process.We hope that our review will offer novel insights and perspectives on the exploitation of autophagy pathways in the treatment of peripheral nerve injuries and neuropathies.

Long noncoding RNA H19 regulates degeneration and regeneration of injured peripheral nerves

Our previous studies have shown that long noncoding RNA(lncRNA)H19 is upregulated in injured rat sciatic nerve during the process of Wallerian degeneration,and that it promotes the migration of Schwann cells and slows down the growth of dorsal root ganglion axons.However,the mechanism by which lncRNA H19 regulates neural repair and regeneration after peripheral nerve injury remains unclear.In this study,we established a Sprague-Dawley rat model of sciatic nerve transection injury.We performed in situ hybridization and found that at 4–7 days after sciatic nerve injury,lncRNA H19 was highly expressed.At 14 days before injury,adeno-associated virus was intrathecally injected into the L4–L5 foramina to disrupt or overexpress lncRNA H19.After overexpression of lncRNA H19,the growth of newly formed axons from the sciatic nerve was inhibited,whereas myelination was enhanced.Then,we performed gait analysis and thermal pain analysis to evaluate rat behavior.We found that lncRNA H19 overexpression delayed the recovery of rat behavior function,whereas interfering with lncRNA H19 expression improved functional recovery.Finally,we examined the expression of lncRNA H19 downstream target SEMA6D,and found that after lncRNA H19 overexpression,the SEMA6D protein level was increased.These findings suggest that lncRNA H19 regulates peripheral nerve degeneration and regeneration through activating SEMA6D in injured nerves.This provides a new clue to understand the role of lncRNA H19 in peripheral nerve degeneration and regeneration.

Role of transforming growth factor-βin peripheral nerve regeneration

Injuries caused by trauma and neurodegenerative diseases can damage the peripheral nervous system and cause functional deficits.Unlike in the central nervous system,damaged axons in peripheral nerves can be induced to regenerate in response to intrinsic cues after reprogramming or in a growth-promoting microenvironment created by Schwann cells.However,axon regeneration and repair do not automatically result in the restoration of function,which is the ultimate therapeutic goal but also a major clinical challenge.Transforming growth factor(TGF)is a multifunctional cytokine that regulates various biological processes including tissue repair,embryo development,and cell growth and differentiation.There is accumulating evidence that TGF-βfamily proteins participate in peripheral nerve repair through various factors and signaling pathways by regulating the growth and transformation of Schwann cells;recruiting specific immune cells;controlling the permeability of the blood-nerve barrier,thereby stimulating axon growth;and inhibiting remyelination of regenerated axons.TGF-βhas been applied to the treatment of peripheral nerve injury in animal models.In this context,we review the functions of TGF-βin peripheral nerve regeneration and potential clinical applications.

Hydrogen sulfide controls peripheral nerve degeneration and regeneration:a novel therapeutic strategy for peripheral demyelinating disorders or nerve degenerative diseases

After peripheral nerve injury, the process of Wallerian degeneration is initiated in the distal stump of injured nerves. Wallerian degeneration in peripheral nerves involves axonal degeneration and degradation of the myelin sheath in Schwann cells. This provides the necessary conditions for axonal regeneration and remyelination. After nerve injury, macrophages are also recruited to the distal nerve stump and, together with Schwann cells, play a role in the clearance of myelin debris.

Retinal detachment repair through multifocal intraocular lens-overcoming visualization challenge of the peripheral retina

Sir Nicholas Harold Lloyd Ridley has revolutionized the practice of ophthalmology by performing the firstintraocular lens （IOL） implantation in 1949. His scientific achievement was acknowledged thirty years later, which led to US Food and Drug Administration approval in 1981. Although the basic principles of IOL implantation have not changed since, many efforts have been invested in perfecting IOL design during the past decades.

Systemic epigallocatechin gallate protects against retinal degeneration and hepatic oxidative stress in the P23H-1 rat

Retinitis pigmentosa(RP) is a group of inherited retinal disorders that lead to photoreceptor loss.RP has been reported to be related to oxidative stress,autophagy,and inflammation.(-)-Epigallocatechin gallate(EGCG),the most abundant catechin-based flavonoid in green tea leaves,has significant antioxidant,anti-carcinogenic,antimicrobial,and neuroprotective properties.EGCG,given its low molecular weight and hydrophilic properties,can cross the blood-retinal barrier and is able to reach different ocular tissues such as the lens,cornea,and retina.EGCG has been shown to provide retinal protection against ischemia;sodium nitroprusside-,N-methyl-D-aspartate-,lipopolysaccharide-,light-,sodium iodate-,or H2 O2-induced damage and diabetic retinopathy.This suggests that systemic EGCG administration has the potential to protect against retinal degenerative or neurodegenerative diseases such as RP.The aim of this work was to investigate whether EGCG can protect against RP progression in the animal P23 H line 1,the model of RP.Albino P23 H rats were crossed with pigmented Long Evans rats to produce offspring exhibiting the clinical features of RP.Pigmented P23 H rats were treated via intraperitoneal injection with saline or EGCG at a dose of 25 mg/kg every week from P100 to P160 and then compared to wild-type Long Evans rats.Rats treated with EGCG showed better visual and retinal electrical function with increased contrast sensitivity and b-wave values compared with those observed in P23 H rats treated with vehicle.EGCG reduced lipid peroxidation and increased total antioxidant capacity and catalase and superoxide dismutase activities.No differences were observed in visual acuity,nitrate levels,nitrite levels or glutathione S-transferase activity.In conclusion,EGCG not only reduced the loss of visual function in P23 H rats but also improved the levels of antioxidant enzymes and reduced oxidative damage.This study was approved by the Institutional Animal Care and Use Committee(CEICA) from the University of Zaragoza under project license PI12/14 on July 11,2014.

Effect of rotary motion on Fos protein expression in the vestibular-related nucleus population in a mouse model of rapid retinal degeneration

BACKGROUND： Previous studies on integration mechanisms of visual and vestibular information in the central nervous system have focused on the vestibular system. Due to the lack of an appropriate animal model, few studies have addressed the visual system with regard to visual and vestibular information. OBJECTIVE： To investigate Fos protein expression differences of vestibular-related nucleus populations in a mouse model of rapid retinal degeneration and normal wild-type Kunming mice following rotary motion, and to verify integration regions of visual and vestibular information in the central nervous system. DESIGN, TIME AND SETTING： A randomized, controlled in vitro study was performed at the Key Laboratory of Aerospace Medicine of Ministry of Education, China from March 2008 to February 2009. MATERIALS： A rotary stimulation device was re-fit to an electric, rotating chair produced by the School of Aerospace Medicine, the Fourth Military Medical University. METHODS： A total of 12 rapid retinal degeneration mice and 12 normal wild-type male Kunming mice were randomly assigned to experimental and control subgroups, respectively （n = 6）. Mice in the experimental group were exposed to rotary motion at a speed of 180°/s, 3 minutes per cycle, in an alternating clockwise/counterclockwise movement. Mice in the control group were not exposed to rotary motion. MAIN OUTCOME MEASURES： Differences in the number of Fos-positive neurons were determined in the vestibular nucleus, prepositus hypoglossal nucleus, inferior olive subnucleus beta, Kooy cap of the inferior olive medial nucleus, and the flocculus and paraflocculus of the cerebellum in rapid retinal degeneration mice and normal wild-type Kunming mice. RESULTS： The number of Fos-positive neurons was reduced in the prepositus hypoglossal nucleus and the Kooy cap of the inferior olive medial nucleus in the rapid retinal degeneration mice following 30 minutes of rotary motion in the experimental group, compared with the normal wild-type Kunming mice （P 〈 0.01）. There was no significant difference in Fos protein expression in the vestibular nucleus, inferior olive subnucleus beta, and the flocculus and paraflocculus of the cerebellum between the rapid retinal degeneration mice and normal wild-type Kunming mice. CONCLUSION： Visual information affected neuronal activation in the prepositus hypoglossal nucleus and the Kooy cap of the inferior olive medial nucleus in mice following rotary motion. The prepositus hypoglossal nucleus and the dorsal cap of Kooy of inferior olive medial nucleus were shown to be key integration regions of visual information and vestibular information in the central nervous system.

Tweaking the immune system as an adjuvant for the treatment of retinal degenerations

Blinding diseases such as photoreceptor degenerations are debilitating conditions that severely impair daily lives of affected patients.This group of diseases are amenable to photoreceptor replacement therapies and recent transplantation studies provided proof-of-principle for functional recovery at the retinal and behavioral level,though the actual mechanism of repair still needs further investigations.The immune system responds in several ways upon photoreceptor engraftment,resulting in T-cell and macrophage infiltrations and,consequently,decrease in graft survival.Most studies on the role of the immune system suggest a detrimental effect in a therapeutic setting.Conversely,the opposite idea wherein the immune system can be activated towards a protective state was also explored in other experimental paradigms.Here,Neves and colleagues explored the potential of cross-species studies and,to a certain extent,the concept of a protective immune system in retinal degeneration and therapy.Mesencephalic astrocyte-derived neurotrophic factor(MANF)was identified in this study as a novel factor that,by modulating the immune system,can slow down photoreceptor degeneration and improve transplantation outcome.

Comparative study of microarray and experimental data on Schwann cells in peripheral nerve degeneration and regeneration: big data analysis

A Schwann cell has regenerative capabilities and is an important cell in the peripheral nervous system.This microarray study is part of a bioinformatics study that focuses mainly on Schwann cells. Microarray data provide information on differences between microarray-based and experiment-based gene expression analyses. According to microarray data, several genes exhibit increased expression(fold change) but they are weakly expressed in experimental studies(based on morphology, protein and mRNA levels). In contrast, some genes are weakly expressed in microarray data and highly expressed in experimental studies;such genes may represent future target genes in Schwann cell studies. These studies allow us to learn about additional genes that could be used to achieve targeted results from experimental studies. In the current big data study by retrieving more than 5000 scientific articles from PubMed or NCBI, Google Scholar, and Google, 1016(up-and downregulated) genes were determined to be related to Schwann cells. However,no experiment was performed in the laboratory; rather, the present study is part of a big data analysis. Our study will contribute to our understanding of Schwann cell biology by aiding in the identification of genes.Based on a comparative analysis of all microarray data, we conclude that the microarray could be a good tool for predicting the expression and intensity of different genes of interest in actual experiments.

Ascorbic acid accelerates Wallerian degeneration after peripheral nerve injury

Wallerian degeneration occurs after peripheral nerve injury and provides a beneficial microenvironment for nerve regeneration.Our previous study demonstrated that ascorbic acid promotes peripheral nerve regeneration,possibly through promoting Schwann cell proliferation and phagocytosis and enhancing macrophage proliferation,migration,and phagocytosis.Because Schwann cells and macrophages are the main cells involved in Wallerian degeneration,we speculated that ascorbic acid may accelerate this degenerative process.To test this hypothesis,400 mg/kg ascorbic acid was administered intragastrically immediately after sciatic nerve transection,and 200 mg/kg ascorbic acid was then administered intragastrically every day.In addition,rat sciatic nerve explants were treated with 200μM ascorbic acid.Ascorbic acid significantly accelerated the degradation of myelin basic protein-positive myelin and neurofilament 200-positive axons in both the transected nerves and nerve explants.Furthermore,ascorbic acid inhibited myelin-associated glycoprotein expression,increased c-Jun expression in Schwann cells,and increased both the number of macrophages and the amount of myelin fragments in the macrophages.These findings suggest that ascorbic acid accelerates Wallerian degeneration by accelerating the degeneration of axons and myelin in the injured nerve,promoting the dedifferentiation of Schwann cells,and enhancing macrophage recruitment and phagocytosis.The study was approved by the Southern Medical University Animal Care and Use Committee(approval No.SMU-L2015081)on October 15,2015.

Early cyclosporin A treatment retards axonal degeneration in an experimental peripheral nerve injection injury model

Injury to peripheral nerves during injections of therapeutic agents such as penicillin G potas-sium is common in developing countries. It has been shown that cyclosporin A, a powerful immunosuppressive agent, can retard Wallerian degeneration after peripheral nerve crush injury. However, few studies are reported on the effects of cyclosporin A on peripheral nerve drug in-jection injury. This study aimed to assess the time-dependent efifcacy of cyclosporine-A as an immunosuppressant therapy in an experimental rat nerve injection injury model established by penicillin G potassium injection. The rats were randomly divided into three groups based on the length of time after nerve injury induced by cyclosporine-A administration （30 minutes, 8 or 24 hours）. The compound muscle action potentials were recorded pre-injury, early post-injury （within 1 hour） and 4 weeks after injury and compared statistically. Tissue samples were taken from each animal for histological analysis. Compared to the control group, a significant im-provement of the compound muscle action potential amplitude value was observed only when cyclosporine-A was administered within 30 minutes of the injection injury （P 〈 0.05）; at 8 or 24 hours after cyclosporine-A administration, compound muscle action potential amplitude was not changed compared with the control group. Thus, early immunosuppressant drug therapy may be a good alternative neuroprotective therapy option in experimental nerve injection injury induced by penicillin G potassium injection.

Insensitivity of PI3K/Akt/GSK3 signaling in peripheral blood mononuclear cells of age-related macular degeneration patients

Our recent studies with cultured retinal pigment epithelium cells suggested that overexpression of interleukin 17 receptor C（IL-17RC）,a phenomenon observed in peripheral blood and chorioretinal tissues with age-related macular degeneration（AMD）,was associated with altered activation of phosphatidylinositide 3-kinase（PI3K）,Akt,and glycogen synthase kinase 3（GSK3）.We wondered whether or not altered PI3 K,Akt,and GSK3 activities could be detected in peripheral blood mononuclear cells（PBMC） obtained from AMD patients.In the patients＇ PBMC,absent or reduced serine-phosphorylation of GSK3α or GSK3β was observed,which was accompanied with increased phosphorylation of GSK3 substrates（e.g.CCAAT enhancer binding protein a,insulin receptor substrate 1,and TAU）,indicative of enhanced GSK3 activation.In addition,decreased protein mass of PI3K85α and tyrosinephosphorylation of PI3K50α was present in PBMC of the AMD patients,suggesting impaired PI3 K activation.Moreover,abnormally lowered molecular weight forms of Akt and GSK3 were detected in PBMC of the AMD patients.These data demonstrate that despite the presence of high levels of IL-17 RC,Wnt-3a and vascular endothelial growth factor,the PI3K/Akt/GSK3 signaling pathway is insensitive to these stimuli in PBMC of the AMD patients.Thus,measurement of PI3K/Akt/GSK3 expression and activity in PBMC may serve as a surrogate biomarker for AMD.

Effect of peripheral nerve on the neurite growth from retinal explants in culture

The effect of peripheral nerve (PN) on neurite outgrowth from retinal explants of adult hamsters was examined. Cultures of retinal explants, and co-cultures of retinal explants and PN were performed using chick retinal basement membrane (BM) as substrate. The presence of PN increases the number and length of neurite outgrowth. In addition, a high proportion of neurites situated close to PN tend to grow towards it. Since there was no contact between retinal ex-plants and PN, we suggest that PN might secrete diffusible substances to attract the neurites to grow towards it.

Role of microtubule dynamics in Wallerian degeneration and nerve regeneration after peripheral nerve injury

Wallerian degeneration,the progressive disintegration of distal axons and myelin that occurs after peripheral nerve injury,is essential for creating a permissive microenvironment for nerve regeneration,and involves cytoskeletal reconstruction.However,it is unclear whether microtubule dynamics play a role in this process.To address this,we treated cultured sciatic nerve explants,an in vitro model of Wallerian degeneration,with the microtubule-targeting agents paclitaxel and nocodazole.We found that paclitaxel-induced microtubule stabilization promoted axon and myelin degeneration and Schwann cell dedifferentiation,whereas nocodazole-induced microtubule destabilization inhibited these processes.Evaluation of an in vivo model of peripheral nerve injury showed that treatment with paclitaxel or nocodazole accelerated or attenuated axonal regeneration,as well as functional recovery of nerve conduction and target muscle and motor behavior,respectively.These results suggest that microtubule dynamics participate in peripheral nerve regeneration after injury by affecting Wallerian degeneration.This study was approved by the Animal Care and Use Committee of Southern Medical University,China(approval No.SMUL2015081) on October 15,2015.

Bone marrow-derived mononuclear stem cells in the treatment of retinal degenerations

Retinal degenerative diseases affecting the outer retina in its many forms(inherited,acquired or induced)are characterized by photoreceptor loss,and represent currently a leading cause of irreversible vision loss in the world.At present,there are very few treatments capable of preventing,recovering or reversing photoreceptor degeneration or the secondary retinal remodeling,which follows photoreceptor loss and can also cause the death of other retinal cells.Thus,these diseases are nowadays one of the greatest challenges in the field of ophthalmological research.Bone marrow derived-mononuclear stem cell transplantation has shown promising results for the treatment of photoreceptor degenerations.These cells may have the potential to slow down photoreceptor loss,and therefore should be applied in the early stages of photoreceptor degenerations.Furthermore,because of their possible paracrine effects,they may have a wide range of clinical applications,since they can potentially impact on several retinal cell types at once and photoreceptor degenerations can involve different cells and/or begin in one cell type and then affect adjacent cells.The intraocular injection of bone marrow derived-mononuclear stem cells also enhances the outcomes of other treatments aimed to protect photoreceptors.Therefore,it is likely that future investigations may combine bone marrow derived-mononuclear stem cell therapy with other systemic or intraocular treatments to obtain greater therapeutic effects in degenerative retinal diseases.

NLRP3 and autophagy in retinal ganglion cell inflammation in age-related macular degeneration:potential therapeutic implications

Retinal degenerative diseases were a large group of diseases characterized by the primary death of retinal ganglion cells(RGCs).Recent studies had shown an interaction between autophagy and nucleotide-binding oligomerization domain-like receptor 3(NLRP3)inflammasomes,which may affect RGCs in retinal degenerative diseases.The NLRP3 inflammasome was a protein complex that,upon activation,produces caspase-1,mediating the apoptosis of retinal cells and promoting the occurrence and development of retinal degenerative diseases.Upregulated autophagy could inhibit NLRP3 inflammasome activation,while inhibited autophagy can promote NLRP3 inflammasome activation,which leaded to the accelerated emergence of drusen and lipofuscin deposition under the neurosensory retina.The activated NLRP3 inflammasome could further inhibit autophagy,thus forming a vicious cycle that accelerated the damage and death of RGCs.This review discussed the relationship between NLRP3 inflammasome and autophagy and its effects on RGCs in age-related macular degeneration,providing a new perspective and direction for the treatment of retinal diseases.

Müller cells are activated in response to retinal outer nuclear layer degeneration in rats subjected to simulated weightlessness conditions

A microgravity environment has been shown to cause ocular damage and affect visual acuity,but the underlying mechanisms remain unclear.Therefore,we established an animal model of weightlessness via tail suspension to examine the pathological changes and molecular mechanisms of retinal damage under microgravity.After 4 weeks of tail suspension,there were no notable alterations in retinal function and morphology,while after 8 weeks of tail suspension,significant reductions in retinal function were observed,and the outer nuclear layer was thinner,with abundant apoptotic cells.To investigate the mechanism underlying the degenerative changes that occurred in the outer nuclear layer of the retina,proteomics was used to analyze differentially expressed proteins in rat retinas after 8 weeks of tail suspension.The results showed that the expression levels of fibroblast growth factor 2(also known as basic fibroblast growth factor)and glial fibrillary acidic protein,which are closely related to Müller cell activation,were significantly upregulated.In addition,Müller cell regeneration and Müller cell gliosis were observed after 4 and 8 weeks,respectively,of simulated weightlessness.These findings indicate that Müller cells play an important regulatory role in retinal outer nuclear layer degeneration during weightlessness.