Spatial and temporal gene expression profiling of the contused rat spinal cord

Aimone, James B.; Leasure, J. Leigh; Perreau, Victoria M.; Thallmair, Michaela

doi:10.1016/j.expneurol.2004.05.042

Cited by 98 publications

(127 citation statements)

References 89 publications

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“…Such changes in the expression level of CKMT1 also seem to be involved in pathological scenarios of apoptotic induction. Transcriptional profiling has detected significant downregulation of CKMT1 mRNA in neurons after spinal cord contusion (Aimone et al, 2004), and in neurodegeneration following spinal cord root avulsion (Swanberg et al, 2006). In line with this, downregulation of CKMT1 expression by RNAi in N2A neuronal cells also resulted in apoptosis (data not shown).…”

Section: Research Articlesupporting

confidence: 55%

CKMT1 regulates the mitochondrial permeability transition pore in a process that provides evidence for alternative forms of the complex

Datler

Pazarentzos

Mahul‐Mellier

et al. 2014

Journal of Cell Science

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The permeability transition pore (PT-pore) mediates cell death through the dissipation of the mitochondrial membrane potential (DY m ). Because the exact composition of the PT-pore is controversial, it is crucial to investigate the actual molecular constituents and regulators of this complex. We found that mitochondrial creatine kinase-1 (CKMT1) is a universal and functionally necessary gatekeeper of the PT-pore, as its depletion induces mitochondrial depolarization and apoptotic cell death. This can be inhibited efficiently by bongkrekic acid, a compound that is widely used to inhibit the PT-pore. However, when the 'classical' PTpore subunits cyclophilin D and VDAC1 are pharmacologically inhibited or their expression levels reduced, mitochondrial depolarization by CKMT1 depletion remains unaffected. At later stages of drug-induced apoptosis, CKMT1 levels are reduced, suggesting that CKMT1 downregulation acts to reinforce the commitment of cells to apoptosis. A novel high-molecular-mass CKMT1 complex that is distinct from the known CKMT1 octamer disintegrates upon treatment with cytotoxic drugs, concomitant with mitochondrial depolarization. Our study provides evidence that CKMT1 is a key regulator of the PT-pore through a complex that is distinct from the classical PT-pore.

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Section: Research Articlesupporting

confidence: 55%

CKMT1 regulates the mitochondrial permeability transition pore in a process that provides evidence for alternative forms of the complex

Datler

Pazarentzos

Mahul‐Mellier

et al. 2014

Journal of Cell Science

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“…Therefore the transcriptome reflects not only the identity of the cell, but also the physiological/pathological state of that cell. Presumably, within the injured spinal cord at different time points postinjury, various pathological cellular events could be reflected by transcription programs of injured spinal cord segments (8). Unfortunately, the lack of powerful bioinformatics data processing capability had confounded previous attempts of using transcriptome analyses to study SCI (8); however, a recently developed novel analytical approach, weighted gene-coexpression network analysis (WGCNA), now allows the identification of cores of gene networks based on a pairwise Pearson correlation matrix of all expressed genes across samples (12,13).…”

Section: Significancementioning

confidence: 99%

“…The primary lesion includes the physical traumatic wounding of both white and gray matter, breakdown of the vasculature system, and acute immune reactions, which is followed by secondary lesions, such as demyelination, additional immune cell infiltration, inflammation, glial scar formation, impaired neurotransmission, and neuronal apoptosis (8). Secondary lesions are intermingled with intrinsic repair processes, including remyelination, reestablishment of the vasculature system, reactivation of presumptive endogenous neural stem/progenitor cells (NSCs), and axonal sprouting and growth (9).…”

mentioning

confidence: 99%

Transcriptome analyses reveal molecular mechanisms underlying functional recovery after spinal cord injury

Duan

Zhang

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

119

101

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Spinal cord injury (SCI) is considered incurable because axonal regeneration in the central nervous system (CNS) is extremely challenging, due to harsh CNS injury environment and weak intrinsic regeneration capability of CNS neurons. We discovered that neurotrophin-3 (NT3)-loaded chitosan provided an excellent microenvironment to facilitate nerve growth, new neurogenesis, and functional recovery of completely transected spinal cord in rats. To acquire mechanistic insight, we conducted a series of comprehensive transcriptome analyses of spinal cord segments at the lesion site, as well as regions immediately rostral and caudal to the lesion, over a period of 90 days after SCI. Using weighted gene coexpression network analysis (WGCNA), we established gene modules/ programs corresponding to various pathological events at different times after SCI. These objective measures of gene module expression also revealed that enhanced new neurogenesis and angiogenesis, and reduced inflammatory responses were keys to conferring the effect of NT3-chitosan on regeneration.S pinal cord injury (SCI) is a debilitating medical condition that often leads to permanent impairment of sensory and motor functions. SCI is considered almost incurable because axons in the central nervous system (CNS), unlike those in the peripheral nervous system (PNS), are believed not to regenerate. The innate ability of mature CNS neurons to regenerate is much weaker than that of PNS neurons (1). In addition, myelin debris in the injured CNS is more inhibitory toward axonal growth compared to that in the PNS (2). Moreover, the mode of immune cell infiltration and microglia activation are different in CNS versus PNS, resulting in a different cellular microenvironment, which crucially influences the outcome, i.e., PNS axons regenerate, while CNS axons do not (3).Over the years, SCI research has focused on ways to promote the long-distance growth of CNS motor axons, mainly by neutralizing inhibitory myelin components and/or changing the neuronal intrinsic program to enable better regeneration (4). Unfortunately, however, although numerous studies have been carried out following this line of strategy, no major breakthroughs translatable to therapy have been achieved. In recent years, efforts toward promoting long distance axonal growth have been complemented with alternative approaches aimed at using exogenous stem cells to generate local new neurons that form nascent relay neural networks to pass ascending and descending neurotransmission signals with or without long-distance axonal growth (5-7).SCI is a complex medical condition. The primary lesion includes the physical traumatic wounding of both white and gray matter, breakdown of the vasculature system, and acute immune reactions, which is followed by secondary lesions, such as demyelination, additional immune cell infiltration, inflammation, glial scar formation, impaired neurotransmission, and neuronal apoptosis (8). Secondary lesions are intermingled with intrinsic repair processes, including remyelina...

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“…These investigators attributed this asymmetry to vascular compromise in rostral regions; however, in the current study, we did not perform contrast enhanced MRI to evaluate this hypothesis. It is worth noting that asymmetry in the concentration and expression of various substances that can influence water diffusivity have been documented in rostral and caudal sections of the spinal cord after injury, including the levels of the neutrophil enzyme myeloperoxidase (42), expression of the angiogenic gene osteopontin (43), levels of N-acetyl aspartate (44), and expression of the water channel aquaporin-4 (45). These substances may have also played a role in the observed rostral-caudal asymmetry.…”

Section: Roi-based Analysismentioning

confidence: 99%

Ex vivo diffusion tensor imaging and quantitative tractography of the rat spinal cord during long‐term recovery from moderate spinal contusion

Ellingson

Kurpad

Schmit

2008

Magnetic Resonance Imaging

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Purpose: To characterize DTI metric changes throughout the length of the entire spinal cord from the acute through chronic stages of spinal cord injury (SCI). Materials and Methods:Ex vivo DTI was performed at 9.4 Tesla to examine changes in water diffusion throughout the entire spinal cord (7-cm) up to 25 weeks after injury in a rat model of contusive SCI. Animals were grouped according to recovery times after injury (2, 5, 15, 20, or 25 weeks), and various DTI metrics were evaluated including transverse and longitudinal apparent diffusion coefficient (tADC and lADC), mean diffusivity (MD), and fractional anisotropy (FA).Results: An overall decrease in lADC throughout the cord and decreases in MD remote from the lesion site were observed, along with an increase in tADC within fiber tracts throughout the recovery period. These trends were statistically significant at P Ͻ 0.05 and were found in both white and gray matter regions. tADC and lADC distributions in fiber bundles extracted using DTI tractography were well fit by an exponential model (R ϭ 0.998) with time constants of 4.6 and 3.3 days, respectively. Conclusion:Results from the current study support the hypothesis that the spinal cord undergoes continual changes during recovery from SCI.

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Spatial and temporal gene expression profiling of the contused rat spinal cord

Cited by 98 publications

References 89 publications

CKMT1 regulates the mitochondrial permeability transition pore in a process that provides evidence for alternative forms of the complex

CKMT1 regulates the mitochondrial permeability transition pore in a process that provides evidence for alternative forms of the complex

Transcriptome analyses reveal molecular mechanisms underlying functional recovery after spinal cord injury

Ex vivo diffusion tensor imaging and quantitative tractography of the rat spinal cord during long‐term recovery from moderate spinal contusion

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