Role of neurofilament aggregation in motor neuron disease

Lin, Hong; Schlaepfer, William W.

doi:10.1002/ana.20965

Cited by 27 publications

(20 citation statements)

References 85 publications

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“…Cytoskeletal proteins impact variably on tissue survival. Loss of neurofilaments like the microtubule-associated proteins ( Map2 ) for example, prevents neurotoxic protein aggregates disrupting axonal transport, whilst vimentin up-regulation reduces the protracted release from macrophages of toxic reactive oxygen species (ROS) [37,38,40,41]. A reduction in Ca2+ ATPase activity in the injured tissue causes a neurotoxic increase in intracellular calcium and up-regulation of genes modulating cell cycle mostly resulting in neuronal death.…”

Section: Introductionmentioning

confidence: 99%

“…Acute or chronic traumatisms may accelerate this process of abnormal protein deposition, leading to the premature surfacing of neurodegenerative conditions. Trauma to the neuroaxis can also enhance the level of protein aggregation, a process that causes the appearance of the histological hallmarks of idiopathic and genetically induced neurodegenerative disorders [40,70,71]. The spectrum of protein aggregates observed in neurodegenerative disorders whose expression could be conditioned by trauma includes beta amyloid and phosphorylated tau proteins normally observed within neurofibrillary tangles in Alzheimer's disease [72], alpha-synuclein within Lewy bodies found in Parkinson's disease [73], neurofilaments in bunina and spheroids bodies typical of ALS neuropathology and prion protein in Prion disease [71].…”

Section: Introductionmentioning

confidence: 99%

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Spinal cord trauma and the molecular point of no return

Yip

Malaspina

2012

Mol Neurodegeneration

123

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A mechanical trauma to the spinal cord can be followed by the development of irreversible and progressive neurodegeneration, as opposed to a temporary or partially reversible neurological damage. An increasing body of experimental and clinical evidence from humans and animal models indicates that spinal cord injury may set in motion the development of disabling and at times fatal neuromuscular disorders, whose occurrence is not normally associated with any major environmental event. This outcome appears to be dependent on the co-occurrence of a particular form of mechanical stress and of a genetically-determined vulnerability. This increased vulnerability to spinal cord injury may depend on a change of the nature and of the timing of activation of a number of neuroprotective and neurodestructive molecular signals in the injured cord. Among the main determinants, we could mention an altered homeostasis of lipids and neurofilaments, an earlier inflammatory response and the failure of the damaged tissue to rein in oxidative damage and apoptotic cell death. These changes could force injured tissue beyond a point of no return and precipitate an irreversible neurodegenerative process. A better knowledge of the molecular signals activated in a state of increased vulnerability to trauma can inform future treatment strategies and the prediction of the neurological outcome after spinal cord injury.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Spinal cord trauma and the molecular point of no return

Yip

Malaspina

2012

Mol Neurodegeneration

123

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“…Ribonucleoproteins (RNPs) that bind NF mRNAs have a major role in directing their expression (Lin and Schlaepfer, 2006;Szaro and Strong, 2010). One such RNP, hnRNP K, binds all three NF triplet RNAs (Thyagarajan and Szaro, 2004;Thyagarajan and Szaro, 2008).…”

Section: Introductionmentioning

confidence: 99%

hnRNP K post-transcriptionally co-regulates multiple cytoskeletal genes needed for axonogenesis

Liu

Szaro

2011

Development

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SUMMARYThe RNA-binding protein, hnRNP K, is essential for axonogenesis. Suppressing its expression in Xenopus embryos yields terminally specified neurons with severely disorganized microtubules, microfilaments and neurofilaments, raising the hypothesis that hnRNP K post-transcriptionally regulates multiple transcripts of proteins that organize the axonal cytoskeleton. To identify downstream candidates for this regulation, RNAs that co-immunoprecipitated from juvenile brain with hnRNP K were identified on microarrays. A substantial number of these transcripts were linked to the cytoskeleton and to intracellular localization, trafficking and transport. Injection into embryos of a non-coding RNA bearing multiple copies of an hnRNP K RNA-binding consensus sequence found within these transcripts largely phenocopied hnRNP K knockdown, further supporting the idea that it regulates axonogenesis through its binding to downstream target RNAs. For further study of regulation by hnRNP K of the cytoskeleton during axon outgrowth, we focused on three validated RNAs representing elements associated with all three polymers -Arp2, tau and an -internexin-like neurofilament. All three were co-regulated post-transcriptionally by hnRNP K, as hnRNP K knockdown yielded comparable defects in their nuclear export and translation but not transcription. Directly knocking down expression of all three together, but not each one individually, substantially reproduced the axonless phenotype, providing further evidence that regulation of axonogenesis by hnRNP K occurs largely through pleiotropic effects on cytoskeletal-associated targets. These experiments provide evidence that hnRNP K is the nexus of a novel post-transcriptional regulatory module controlling the synthesis of proteins that integrate all three cytoskeletal polymers to form the axon.KEY WORDS: Microtubule associated protein tau, Actin-related protein 2, -Internexin, Xenopus laevis hnRNP K post-transcriptionally co-regulates multiple cytoskeletal genes needed for axonogenesis

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“…48 A mechanical insult to CNS tissue in the elderly leads to an acceleration of the neurodegenerative process of protein aggregation in the neurons, which causes irreversible neurological damage. 1,16,17,48 We hypothesize that because of the changes in compliance of the thoracic cage, the thoracic spine and neural tissues are protected less in older vehicle occupants than in younger occupants. To the best of our knowledge, the increased likelihood of thoracolumbar neurological injury in the elderly after an MVC has not been reported previously.…”

Section: Discussionmentioning

confidence: 99%

Incidence and mechanism of neurological deficit after thoracolumbar fractures sustained in motor vehicle collisions

Mukherjee¹,

Beck²,

Yoganandan

et al. 2016

SPI

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OBJECT To determine the incidence of and assess the risk factors associated with neurological injury in motor vehicle occupants who sustain fractures of the thoracolumbar spine. METHODS In this study, the authors queried medical, vehicle, and crash data elements from the Crash Injury Research and Engineering Network (CIREN), a prospectively gathered multicenter database compiled from Level I trauma centers. Subjects had fractures involving the T1–L5 vertebral segments, an Abbreviated Injury Scale (AIS) score of ≥ 3, or injury to 2 body regions with an AIS score of ≥ 2 in each region. Demographic parameters obtained for all subjects included age, sex, height, body weight, and body mass index. Clinical parameters obtained included the level of the injured vertebra and the level and type of spinal cord injury. Vehicular crash data included vehicle make, seatbelt type, and usage and appropriate use of the seatbelt. Crash data parameters included the principal direction of force, change in velocity on impact (ΔV), airbag deployment, and vehicle rollover. The authors performed a univariate analysis of the incidence and the odds of sustaining spinal neurological injury associated with major thoracolumbar fractures with respect to the demographic, clinical, and crash parameters. RESULTS Neurological deficit associated with thoracolumbar fracture was most frequent at extremes of age; the highest rates were in the 0- to 10-year (26.7% [4 of 15]) and 70- to 80-year (18.4% [7 of 38]) age groups. Underweight occupants (OR 3.52 [CI 1.055–11.7]) and obese occupants (OR 3.27 [CI 1.28–8.31]) both had higher odds of sustaining spinal cord injury than occupants with a normal body mass index. The highest risk of neurological injury existed in crashes in which airbags deployed and the occupant was not restrained by a seatbelt (OR 2.35 [CI 0.087–1.62]). Reduction in the risk of neurological injuries occurred when 3-point seatbelts were used correctly in conjunction with the deployment of airbags (OR 0.34 [CI 1.3–6.6]) compared with the occupants who were not restrained by a seatbelt and for whom airbags were not deployed. Crashes with a ΔV greater than 50 km/hour had a significantly higher risk of spinal cord injury (OR 3.45 [CI 0.136–0.617]) than those at lower ΔV values. CONCLUSIONS Deployment of airbags was protective against neurological injury only when used in conjunction with 3-point seatbelts. Vehicle occupants who were either obese or underweight, very young or elderly, and those in crashes with a ΔV greater than 50 km/hour were at higher risk of thoracolumbar neurological injury. Neurological injury at thoracic and lumbar levels was associated with multiple factors, including the incidence of fatality, occupant factors such as age and body habitus, energy at impact, and direction of impact. Current vehicle safety technologies are geared toward a normative body morphology and need to be reevaluated for various body morphologies and torso compliances to lower the risk of neurological injury resulting from thoracolumbar fractures.

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Role of neurofilament aggregation in motor neuron disease

Cited by 27 publications

References 85 publications

Spinal cord trauma and the molecular point of no return

Spinal cord trauma and the molecular point of no return

hnRNP K post-transcriptionally co-regulates multiple cytoskeletal genes needed for axonogenesis

Incidence and mechanism of neurological deficit after thoracolumbar fractures sustained in motor vehicle collisions

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