Pharmacologic treatment with OKN-007 reduces alpha-motor neuron loss in spinal cord of aging mice

The blood–spinal cord barrier (BSCB) regulates molecular exchange between blood and spinal cord. Pericytes are presumed to be important cellular constituents of the BSCB. However, the regional abundance and vascular functions of spinal cord pericytes have yet to be determined. Utilizing wild-type mice, we show that spinal cord pericyte capillary coverage and number compared with the brain regions are reduced most prominently in the anterior horn. Regional pericyte variations are highly correlated with: (1) increased capillary permeability to 350 Da, 40,000 Da, and 150,000 Da, but not 2,000,000 Da fluorescent vascular tracers in cervical, thoracic, and lumbar regions and (2) diminished endothelial zonula occludens-1 (ZO-1) and occludin tight junction protein expression. Pericyte-deficient mutations ( Pdgfrβ F7/F7 mice) resulted in additional pericyte reductions in spinal cord capillaries leading to overt BSCB disruption to serum proteins, accumulation in motor neurons of cyotoxic thrombin and fibrin and motor neuron loss. Barrier disruption in perciyte-deficient mice coincided with further reductions in ZO-1 and occludin. These data suggest that pericytes contribute to proper function of the BSCB at the capillary level. Regional reductions in spinal cord pericytes may provide a cellular basis for heightened spinal cord barrier capillary permeability and motor neuron loss.

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Lasting paraplegia caused by loss of lumbar spinal cord interneurons in rats: no direct correlation with motor neuron loss

Journal of Neurosurgery Spine ◽

10.3171/spi.2000.93.2.0266 ◽

2000 ◽

Vol 93 (2) ◽

pp. 266-275 ◽

Cited By ~ 3

Author(s):

Bassam Hadi ◽

Y. Ping Zhang ◽

Darlene A. Burke ◽

Christopher B. Shields ◽

David S. K. Magnuson

Keyword(s):

Spinal Cord ◽

Locomotor Activity ◽

Motor Neuron ◽

Motor Neurons ◽

Lumbar Spinal Cord ◽

Neuron Loss ◽

Content Type ◽

Motor Neuron Loss ◽

Lumbar Spinal ◽

Fine Print

Object. The aims of this study were to investigate further the role played by lumbar spinal cord interneurons in the generation of locomotor activity and to develop a model of spinal cord injury suitable for testing neuron replacement strategies. Methods. Adult rats received intraspinal injections of kainic acid (KA). Locomotion was assessed weekly for 4 weeks by using the Basso, Beattie, and Bresnahan (BBB) 21-point locomotor scale, and transcranial magnetic motor evoked potentials (MMEPs) were recorded in gastrocnemius and quadriceps muscles at 1 and 4 weeks. No changes in transcranial MMEP latency were noted following KA injection, indicating that the descending motor pathways responsible for these responses, including the alpha motor neurons, were not compromised. Rats in which KA injections included much of the L-2 segment (10 animals) showed severe locomotor deficits, with a mean BBB score of 4.5 ± 3.6 (± standard deviation). Rats that received lesions rostral to the L-2 segment (four animals) were able to locomote and had a mean BBB score of 14.6 ± 2.6. Three rats that received only one injection bilaterally centered at L-2 (three animals) had a mean BBB score of 3.2 ± 2. Histological examination revealed variable loss of motor neurons limited to the injection site. There was no correlation between motor neuron loss and BBB score. Conclusions. Interneuron loss centered on the L-2 segment induces lasting paraplegia independent of motor neuron loss and white matter damage, supporting earlier suggestions that circuitry critical to the generator of locomotor activity (the central pattern generator) resides in this area. This injury model may prove ideal for studies of neuron replacement strategies.

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Blood-spinal cord barrier leakage is independent of motor neuron pathology in ALS

10.1101/704270 ◽

2019 ◽

Author(s):

Sarah Waters ◽

Birger V. Dieriks ◽

Molly E. V. Swanson ◽

Yibin Zhang ◽

Natasha L. Grimsey ◽

...

Keyword(s):

Spinal Cord ◽

Motor Neuron ◽

Lower Motor Neuron ◽

Spinal Cord Tissue ◽

Thoracic Spinal Cord ◽

Neuron Loss ◽

Thoracic Spinal ◽

Potential Biomarker ◽

Motor Neuron Loss ◽

Blood Spinal Cord Barrier

AbstractBackgroundAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease involving progressive degeneration of upper and lower motor neurons. Both lower motor neuron loss and the deposition of phosphorylated TDP-43 inclusions display regional patterning along the spinal cord. The blood-spinal cord barrier (BSCB) ordinarily restricts entry into the spinal cord parenchyma of blood components that are neurotoxic, but in ALS there is evidence for barrier breakdown. Here we sought to examine whether BSCB breakdown, motor neuron loss, and TDP-43 proteinopathy display the same regional patterning across and along the spinal cord.MethodsWe measured cerebrospinal fluid (CSF) hemoglobin in living ALS patients (n=87 controls, n=236 ALS) as a potential biomarker of BSCB and blood-brain barrier leakage. We then immunostained cervical, thoracic, and lumbar post mortem spinal cord tissue (n=5 controls, n=13 ALS) and employed semi-automated imaging and analysis to quantify and map lower motor neuron loss and phosphorylated TDP-43 inclusion load against hemoglobin leakage.ResultsMotor neuron loss and TDP-43 proteinopathy were seen at all three levels of the ALS spinal cord, with most abundant TDP-43 deposition in the ventral grey (lamina IX) of the cervical and lumbar cord. In contrast, hemoglobin leakage was observed along the ALS spinal cord axis but was most severe in the dorsal grey and white matter in the thoracic spinal cord.ConclusionsOur data show that leakage of the blood-spinal cord barrier occurs during life but at end-stage its distribution is independent from the major motor neuron pathology and is unlikely to be a major contributor to pathogenesis in ALS.

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Dynamic changes of CX3CL1/CX3CR1 axis during microglial activation and motor neuron loss in the spinal cord of ALS mouse model

Translational Neurodegeneration ◽

10.1186/s40035-018-0138-4 ◽

2018 ◽

Vol 7 (1) ◽

Cited By ~ 9

Author(s):

Jingjing Zhang ◽

Yufei Liu ◽

Xinyao Liu ◽

Song Li ◽

Cheng Cheng ◽

...

Keyword(s):

Spinal Cord ◽

Mouse Model ◽

Motor Neuron ◽

Microglial Activation ◽

Dynamic Changes ◽

Neuron Loss ◽

Motor Neuron Loss

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Motor unit number index detects the effectiveness of surgical treatment in improving distal motor neuron loss in patients with incomplete cervical spinal cord injury

BMC Musculoskeletal Disorders ◽

10.1186/s12891-020-03567-w ◽

2020 ◽

Vol 21 (1) ◽

Author(s):

Jun Li ◽

Yancheng Zhu ◽

Yang Li ◽

Shisheng He ◽

Deguo Wang

Keyword(s):

Spinal Cord ◽

Spinal Cord Injury ◽

Surgical Treatment ◽

Motor Neuron ◽

Motor Unit ◽

Cervical Spinal Cord ◽

Cervical Spinal Cord Injury ◽

Neuron Loss ◽

Cord Injury ◽

Motor Neuron Loss

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Viral mediated knockdown of GATA6 in SMA iPSC-derived astrocytes prevents motor neuron loss and microglial activation

10.1101/2021.10.11.463972 ◽

2021 ◽

Author(s):

Reilly L Allison ◽

Emily Welby ◽

Guzal Khayrullina ◽

Barrington G Burnett ◽

Allison D Ebert

Keyword(s):

Spinal Cord ◽

Motor Neuron ◽

Motor Neurons ◽

Muscular Atrophy ◽

Genetic Disorder ◽

Neuron Loss ◽

Microglial Phagocytosis ◽

Lentiviral Infection ◽

Motor Neuron Loss ◽

Induced Pluripotent

Spinal muscular atrophy (SMA), a pediatric genetic disorder, is characterized by the profound loss of spinal cord motor neurons and subsequent muscle atrophy and death. Although the mechanisms underlying motor neuron loss are not entirely clear, data from our work and others support the idea that glial cells contribute to disease pathology. GATA6, a transcription factor that we have previously shown to be upregulated in SMA astrocytes, is negatively regulated by SMN and can increase the expression of the inflammatory regulator NFκB. In this study, we identified upregulated GATA6 as a contributor to increased activation, pro-inflammatory ligand production, and neurotoxicity in spinal-cord patterned astrocytes differentiated from SMA patient induced pluripotent stem cells. Reducing GATA6 expression in SMA astrocytes via lentiviral infection ameliorated these effects to healthy control levels. Additionally, we found that SMA astrocytes contribute to SMA microglial phagocytosis, which was again decreased by lentiviral-mediated knockdown of GATA6. Together these data identify a role of GATA6 in SMA astrocyte pathology and further highlight glia as important targets of therapeutic intervention in SMA.

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Blood-spinal cord barrier leakage is independent of motor neuron pathology in ALS

Acta Neuropathologica Communications ◽

10.1186/s40478-021-01244-0 ◽

2021 ◽

Vol 9 (1) ◽

Author(s):

Sarah Waters ◽

Molly E. V. Swanson ◽

Birger V. Dieriks ◽

Yibin B. Zhang ◽

Natasha L. Grimsey ◽

...

Keyword(s):

Spinal Cord ◽

Motor Neuron ◽

Lower Motor Neuron ◽

Spinal Cord Tissue ◽

Thoracic Spinal Cord ◽

Neuron Loss ◽

Thoracic Spinal ◽

Potential Biomarker ◽

Motor Neuron Loss ◽

Blood Spinal Cord Barrier

AbstractAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease involving progressive degeneration of upper and lower motor neurons. The pattern of lower motor neuron loss along the spinal cord follows the pattern of deposition of phosphorylated TDP-43 aggregates. The blood-spinal cord barrier (BSCB) restricts entry into the spinal cord parenchyma of blood components that can promote motor neuron degeneration, but in ALS there is evidence for barrier breakdown. Here we sought to quantify BSCB breakdown along the spinal cord axis, to determine whether BSCB breakdown displays the same patterning as motor neuron loss and TDP-43 proteinopathy. Cerebrospinal fluid hemoglobin was measured in living ALS patients (n = 87 control, n = 236 ALS) as a potential biomarker of BSCB and blood–brain barrier leakage. Cervical, thoracic, and lumbar post-mortem spinal cord tissue (n = 5 control, n = 13 ALS) were then immunolabelled and semi-automated imaging and analysis performed to quantify hemoglobin leakage, lower motor neuron loss, and phosphorylated TDP-43 inclusion load. Hemoglobin leakage was observed along the whole ALS spinal cord axis and was most severe in the dorsal gray and white matter in the thoracic spinal cord. In contrast, motor neuron loss and TDP-43 proteinopathy were seen at all three levels of the ALS spinal cord, with most abundant TDP-43 deposition in the anterior gray matter of the cervical and lumbar cord. Our data show that leakage of the BSCB occurs during life, but at end-stage disease the regions with most severe BSCB damage are not those where TDP-43 accumulation is most abundant. This suggests BSCB leakage and TDP-43 pathology are independent pathologies in ALS.

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