C-terminal domain small phosphatase 1 (CTDSP1) regulates growth factor expression and axonal regeneration in peripheral nerve tissue

AbstractPeripheral Nerve Injury (PNI) represents a major clinical and economic burden. Despite the ability of peripheral neurons to regenerate their axons after an injury, patients are often left with motor and/or sensory disability and may develop chronic pain. Successful regeneration and target organ reinnervation require comprehensive transcriptional changes in both injured neurons and support cells located at the site of injury. The expression of most of the genes required for axon growth and guidance and for synapsis formation is repressed by a single master transcriptional regulator, the Repressor Element 1 Silencing Transcription factor (REST). Sustained increase of REST levels after injury inhibits axon regeneration and leads to chronic pain. As targeting of transcription factors is challenging, we tested whether modulation of REST activity could be achieved through knockdown of carboxy-terminal domain small phosphatase 1 (CTDSP1), the enzyme that stabilizes REST by preventing its targeting to the proteasome. To test whether knockdown of CTDSP1 promotes neurotrophic factor expression in both support cells located at the site of injury and in peripheral neurons, we transfected mesenchymal progenitor cells (MPCs), a type of support cells that are present at high concentrations at the site of injury, and dorsal root ganglion (DRG) neurons with REST or CTDSP1 specific siRNA. We quantified neurotrophic factor expression by RT-qPCR and Western blot, and brain-derived neurotrophic factor (BDNF) release in the cell culture medium by ELISA, and we measured neurite outgrowth of DRG neurons in culture. Our results show that CTDSP1 knockdown promotes neurotrophic factor expression in both DRG neurons and the support cells MPCs, and promotes DRG neuron regeneration. Therapeutics targeting CTDSP1 activity may, therefore, represent a novel epigenetic strategy to promote peripheral nerve regeneration after PNI by promoting the regenerative program repressed by injury-induced increased levels of REST in both neurons and support cells.

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C-terminal domain small phosphatase 1 (CTDSP1) regulates growth factor expression and axonal regeneration

10.21203/rs.3.rs-74126/v1 ◽

2020 ◽

Author(s):

Noreen M Gervasi ◽

Alexander Dimitchev ◽

Desraj M. Clark ◽

Marvin Dingle ◽

Alexander V. Pisarchik ◽

...

Keyword(s):

Cell Culture ◽

Chronic Pain ◽

Growth Factor ◽

Peripheral Nerve ◽

Neurotrophic Factor ◽

Culture Medium ◽

Axon Regeneration ◽

Cell Culture Medium ◽

Drg Neurons ◽

Factor Expression

Abstract Background: Peripheral Nerve Injury (PNI) represents a major clinical and economic burden. Despite the ability of peripheral neurons to regenerate their axons after an injury, patients are often left with motor and/or sensory disability and may develop chronic pain. Successful regeneration and target organ reinnervation require comprehensive transcriptional changes in both injured neurons and support cells located at the site of injury. The expression of most of the genes required for axon growth and guidance and for synapsis formation is repressed by a single master transcriptional regulator, the Repressor Element 1 Silencing Transcription factor (REST). Sustained increase of REST levels after injury inhibits axon regeneration and leads to chronic pain. REST is stabilized by the Carboxy-terminal domain small phosphatase 1 (CTDSP1), which prevents REST targeting to the proteasome. Here, we explore whether knockdown of CTDSP1 promotes neurotrophic factor expression in mesenchymal progenitor cells (MPCs), a type of support cells that can be harvested from the site of injury during surgical debridement, and in dorsal root ganglion (DRG) neurons. In addition, we explore whether CTDSP1 knockdown supports DRG neurite regeneration. Methods: Cultured human MPCs or rat DRG neurons were transfected with REST or CTDSP1 specific siRNA. Neurotrophic factor expression was analyzed by RT-qPCR and Western Blot. Brain-derived Neurotrophic Factor (BDNF) in cell culture medium was quantified by ELISA. Axon regeneration was quantified measuring the length of the longest neurite of a neuron. Results: Knockdown of REST or CTDSP1 in MPCs results in increased expression of BDNF and nerve growth factor (NGF). In addition, knockdown of CTDSP1 leads to increased release of BDNF in cell culture medium from MPCs and to reduced levels of REST protein. Finally, knockdown of CTDSP1 in DRG neurons results in increased levels of BDNF and increased DRG neurite growth rate.Conclusions: CTDSP1 knockdown promotes neurotrophic factor expression in both DRG neurons and the support cells MPCs. In addition, it promotes DRG neuron regeneration. Therapeutics targeting CTDSP1 activity may represent a novel epigenetic strategy to promote peripheral nerve regeneration after PNI by promoting the regenerative program repressed by injury-induced increased levels of REST in both neurons and support cells.

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Polyaniline promotes peripheral nerve regeneration by enhancement of the brain-derived neurotrophic factor and ciliary neurotrophic factor expression and activation of the ERK1/2/MAPK signaling pathway

Molecular Medicine Reports ◽

10.3892/mmr.2017.7534 ◽

2017 ◽

Vol 16 (5) ◽

pp. 7534-7540 ◽

Cited By ~ 15

Author(s):

Lin Fan ◽

Yan Xiong ◽

Zhen Fu ◽

Dingfeng Xu ◽

Lei Wang ◽

...

Keyword(s):

Peripheral Nerve ◽

Nerve Regeneration ◽

Signaling Pathway ◽

Neurotrophic Factor ◽

Peripheral Nerve Regeneration ◽

Brain Derived Neurotrophic Factor ◽

Mapk Signaling ◽

Ciliary Neurotrophic Factor ◽

Factor Expression ◽

The Brain

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Remodeling of myelinated fibers and internal capillaries in distal peripheral nerves following aerobic exercise in aged rats

Journal of Applied Physiology ◽

10.1152/japplphysiol.00257.2018 ◽

2018 ◽

Vol 125 (4) ◽

pp. 1051-1061 ◽

Cited By ~ 2

Author(s):

Masahiro Sakita ◽

Shinichiro Murakami ◽

Hidemi Fujino ◽

Satoshi Hayashi ◽

Kazuyoshi Kameyama ◽

...

Keyword(s):

Vascular Endothelial Growth Factor ◽

Growth Factor ◽

Peripheral Nerve ◽

Aerobic Exercise ◽

Neurotrophic Factor ◽

Peripheral Nerves ◽

Nerve Tissue ◽

Vascular Endothelial ◽

Myelinated Fibers ◽

Endothelial Growth Factor

The aim of this study was to determine whether aerobic exercise (AE) in old age contributes to improving the morphologies of myelinated fibers (MFs) in peripheral nerves as well as capillaries. Furthermore, we investigated whether such processes are associated with complementary activity of brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF) in the circulating blood and peripheral nerve tissue. Fourteen male Wistar rats (age: 95 wk) were randomly divided into moderate AE ( n = 8) and sedentary (SED; n = 6) groups. Rats in the AE group performed treadmill running for 1 h per day for 2 wk, following which the bilateral tibial nerves of the two groups were removed to examine MF and capillary structure. Levels of BDNF and VEGF in the serum and peripheral nerves were analyzed via enzyme-linked immunosorbent assay. Myelin thickness, axon diameter, and capillary luminal diameter were significantly larger in the AE group than in the SED group ( P < 0.0001). Levels of serum BDNF and VEGF were significantly lower and higher, respectively, in the AE group than in the SED group ( P < 0.001). Conversely, BDNF and VEGF levels in tibial nerve tissue were significantly higher, respectively, and lower in the AE group than in the SED group ( P < 0.001). In conclusion, our study indicates that regular AE induces enlargement of the capillaries and thickens the myelin in aged peripheral nerves, likely via a complementary process involving BDNF and VEGF. NEW & NOTEWORTHY Accumulating evidence indicates that age-related sarcopenia is accompanied by the degeneration of myelinated fibers (MFs) in peripheral nerves. Our study indicates that regular aerobic exercise contributes to increased thickness of the myelin surrounding MFs and enlargement of the capillaries, likely via a complementary process involving brain-derived neurotrophic factor and vascular endothelial growth factor. Our findings demonstrate that regular, moderate-intensity aerobic exercise may help to prevent and reverse peripheral nerve regression in older adults.

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Neurotrophic factor expression in denervated motor and sensory Schwann cells: Relevance to specificity of peripheral nerve regeneration

Experimental Neurology ◽

10.1016/j.expneurol.2014.01.012 ◽

2014 ◽

Vol 254 ◽

pp. 99-108 ◽

Cited By ~ 32

Author(s):

Tessa Gordon

Keyword(s):

Peripheral Nerve ◽

Nerve Regeneration ◽

Schwann Cells ◽

Neurotrophic Factor ◽

Peripheral Nerve Regeneration ◽

Factor Expression

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Autoantibody screening in Guillain–Barré syndrome

Journal of Neuroinflammation ◽

10.1186/s12974-021-02301-0 ◽

2021 ◽

Vol 18 (1) ◽

Author(s):

Cinta Lleixà ◽

Lorena Martín-Aguilar ◽

Elba Pascual-Goñi ◽

Teresa Franco ◽

Marta Caballero ◽

...

Keyword(s):

Peripheral Nerve ◽

Motor Neurons ◽

Prognostic Value ◽

Nerve Tissue ◽

Guillain Barre Syndrome ◽

Drg Neurons ◽

Guillain Barré Syndrome ◽

Ganglioside Antibodies ◽

Human Motor ◽

Guillain Barré

Abstract Background Guillain–Barré syndrome (GBS) is an acute inflammatory neuropathy with a heterogeneous presentation. Although some evidences support the role of autoantibodies in its pathogenesis, the target antigens remain unknown in a substantial proportion of GBS patients. The objective of this study is to screen for autoantibodies targeting peripheral nerve components in Guillain–Barré syndrome. Methods Autoantibody screening was performed in serum samples from all GBS patients included in the International GBS Outcome study by 11 different Spanish centres. The screening included testing for anti-ganglioside antibodies, anti-nodo/paranodal antibodies, immunocytochemistry on neuroblastoma-derived human motor neurons and murine dorsal root ganglia (DRG) neurons, and immunohistochemistry on monkey peripheral nerve sections. We analysed the staining patterns of patients and controls. The prognostic value of anti-ganglioside antibodies was also analysed. Results None of the GBS patients (n = 100) reacted against the nodo/paranodal proteins tested, and 61 (61%) were positive for, at least, one anti-ganglioside antibody. GBS sera reacted strongly against DRG neurons more frequently than controls both with IgG (6% vs 0%; p = 0.03) and IgM (11% vs 2.2%; p = 0.02) immunodetection. No differences were observed in the proportion of patients reacting against neuroblastoma-derived human motor neurons. Reactivity against monkey nerve tissue was frequently detected both in patients and controls, but specific patterns were only detected in GBS patients: IgG from 13 (13%) patients reacted strongly against Schwann cells. Finally, we confirmed that IgG anti-GM1 antibodies are associated with poorer outcomes independently of other known prognostic factors. Conclusion Our study confirms that (1) GBS patients display a heterogeneous repertoire of autoantibodies targeting nerve cells and structures; (2) gangliosides are the most frequent antigens in GBS patients and have a prognostic value; (3) further antigen-discovery experiments may elucidate other potential antigens in GBS.

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