Neurites of neurons under acute or chronic stress form bundles of filaments (rods) containing 1∶1 cofilin∶actin, which impair transport and synaptic function. Rods contain disulfide cross-linked cofilin and are induced by treatments resulting in oxidative stress. Rods form rapidly (5–30 min) in >80% of cultured hippocampal or cortical neurons treated with excitotoxic levels of glutamate or energy depleted (hypoxia/ischemia or mitochondrial inhibitors). In contrast, slow rod formation (50% of maximum response in ∼6 h) occurs in a subpopulation (∼20%) of hippocampal neurons upon exposure to soluble human amyloid-β dimer/trimer (Aβd/t) at subnanomolar concentrations. Here we show that proinflammatory cytokines (TNFα, IL-1β, IL-6) also induce rods at the same rate and within the same neuronal population as Aβd/t. Neurons from prion (PrPC)-null mice form rods in response to glutamate or antimycin A, but not in response to proinflammatory cytokines or Aβd/t. Two pathways inducing rod formation were confirmed by demonstrating that NADPH-oxidase (NOX) activity is required for prion-dependent rod formation, but not for rods induced by glutamate or energy depletion. Surprisingly, overexpression of PrPC is by itself sufficient to induce rods in over 40% of hippocampal neurons through the NOX-dependent pathway. Persistence of PrPC-dependent rods requires the continuous activity of NOX. Removing inducers or inhibiting NOX activity in cells containing PrPC-dependent rods causes rod disappearance with a half-life of about 36 min. Cofilin-actin rods provide a mechanism for synapse loss bridging the amyloid and cytokine hypotheses for Alzheimer disease, and may explain how functionally diverse Aβ-binding membrane proteins induce synaptic dysfunction.
Filament bundles (rods) of cofilin and actin (1:1) form in neurites of stressed neurons where they inhibit synaptic function. Live-cell imaging of rod formation is hampered by the fact that overexpression of a chimera of wild type cofilin with a fluorescent protein causes formation of spontaneous and persistent rods, which is exacerbated by the photostress of imaging. The study of rod induction in living cells calls for a rod reporter that does not cause spontaneous rods. From a study in which single cofilin surface residues were mutated, we identified a mutant, cofilinR21Q, which when fused with monomeric Red Fluorescent Protein (mRFP) and expressed several fold above endogenous cofilin, does not induce spontaneous rods even during the photostress of imaging. CofilinR21Q-mRFP only incorporates into rods when they form from endogenous proteins in stressed cells. In neurons, cofilinR21Q-mRFP reports on rods formed from endogenous cofilin and induced by all modes tested thus far. Rods have a half-life of 30–60 min upon removal of the inducer. Vesicle transport in neurites is arrested upon treatments that form rods and recovers as rods disappear. CofilinR21Q-mRFP is a genetically encoded rod reporter that is useful in live cell imaging studies of induced rod formation, including rod dynamics, and kinetics of rod elimination.
Background: Management of ankle pain in dancers can be challenging because of the repetitive stress and complex demands placed on this region. Despite the prevalence of ankle injuries in this population, literature on surgical outcomes and return to dance is limited. Purpose: To retrospectively evaluate the efficacy and functional outcomes after surgical excision of a symptomatic os trigonum in dancers. Study Design: Case series; Level of evidence, 4. Methods: Between June 2006 and June 2016, a total of 44 dancers underwent surgical excision of a symptomatic os trigonum at a single institution and by a single surgeon. All patients presented with symptoms of posterior ankle impingement syndrome and subsequently failed nonsurgical treatment. Clinical analysis was conducted using various pre- and postoperative patient-reported outcome questionnaires, including the Veterans RAND 12-Item Health Survey (VR-12), Foot Function Index–Revised (FFI-R), and visual analog scale (VAS) for pain, as well as subjective patient satisfaction. Results: A total of 44 patients (54 ankles; mean age, 18.2 years) were retrospectively evaluated at a mean follow-up of 33.4 months. The VR-12 Physical Health score improved from a mean score of 37.8 ± 11.9 to 51.2 ± 10.5 ( P < .001). The cumulative FFI-R score improved from 46.45 ± 13.8 to 31.2 ± 9.7 ( P = .044), with the subcategory of “activity limitation” representing the highest-scoring FFI-R subcategory at 65.28 ± 13.4 preoperatively and improving to 34.47 ± 12.4 at follow-up ( P < .001). The mean VAS score for subjective pain improved significantly from 5.39 ± 2.84 to 1.73 ± 2.10 ( P < .00044). Conclusion: Overall, the findings of the present study demonstrate that dancers of varying style and level improved significantly according to various clinical measures. Patients included in this study reported that they returned to their previous level of dance upon completion of physical therapy and maintained thriving postoperative careers, which for several meant dancing at the professional level.
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