Macrophage Migration Inhibitory Factor as a Chaperone Inhibiting Accumulation of Misfolded SOD1

SummaryMutations in superoxide dismutase (SOD1) cause amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by loss of motor neurons and accompanied by accumulation of misfolded SOD1 onto the cytoplasmic faces of intracellular organelles, including mitochondria and the endoplasmic reticulum (ER). Using inhibition of misfolded SOD1 deposition onto mitochondria as an assay, a chaperone activity abundant in nonneuronal tissues is now purified and identified to be the multifunctional macrophage migration inhibitory factor (MIF), whose activities include an ATP-independent protein folding chaperone. Purified MIF is shown to directly inhibit mutant SOD1 misfolding. Elevating MIF in neuronal cells suppresses accumulation of misfolded SOD1 and its association with mitochondria and the ER and extends survival of mutant SOD1-expressing motor neurons. Accumulated MIF protein is identified to be low in motor neurons, implicating correspondingly low chaperone activity as a component of vulnerability to mutant SOD1 misfolding and supporting therapies to enhance intracellular MIF chaperone activity

Percutaneous endoscopic lumbar discectomy: clinical and quality of life outcomes with a minimum 2 year follow-up

<p>Abstract</p> <p>Background</p> <p>Percutaneous endoscopic lumbar discectomy is a relatively new technique. Very few studies have reported the clinical outcome of percutaneous endoscopic discectomy in terms of quality of life and return to work.</p> <p>Method</p> <p>55 patients with percutaneous endoscopic lumbar discectomy done from 2002 to 2006 had their clinical outcomes reviewed in terms of the North American Spine Score (NASS), Medical Outcomes Study Short Form-36 scores (SF-36) and Pain Visual Analogue Scale (VAS) and return to work.</p> <p>Results</p> <p>The mean age was 35.6 years, the mean operative time was 55.8 minutes and the mean length of follow-up was 3.4 years. The mean hospital stay for endoscopic discectomy was 17.3 hours. There was significant reduction in the severity of back pain and lower limb symptoms (NASS and VAS, p < 0.05) at 6 months and 2 years. There was significant improvement in all aspects of the Quality of Life (SF-36, p < 0.05) scores except for general health at 6 months and 2 years postoperation. The recurrence rate was 5% (3 patients). 5% (3 patients) subsequently underwent lumbar fusion for persistent back pain. All patients returned to their previous occupation after surgery at a mean time of 24.3 days.</p> <p>Conclusion</p> <p>Percutaneous endoscopic lumbar discectomy is associated with improvement in back pain and lower limb symptoms postoperation which translates to improvement in quality of life. It has the advantage that it can be performed on a day case basis with short length of hospitalization and early return to work thus improving quality of life earlier.</p

CK2 Phosphorylation of Schistosoma mansoni HMGB1 Protein Regulates Its Cellular Traffic and Secretion but Not Its DNA Transactions

parasite resides in mesenteric veins where fecundated female worms lay hundred of eggs daily. Some of the egg antigens are trapped in the liver and induce a vigorous granulomatous response. High Mobility Group Box 1 (HMGB1), a nuclear factor, can also be secreted and act as a cytokine. Schistosome HMGB1 (SmHMGB1) is secreted by the eggs and stimulate the production of key cytokines involved in the pathology of schistosomiasis. Thus, understanding the mechanism of SmHMGB1 release becomes mandatory. Here, we addressed the question of how the nuclear SmHMGB1 can reach the extracellular space. eggs of infected animals and that SmHMGB1 that were localized in the periovular schistosomotic granuloma were phosphorylated.We showed that secretion of SmHMGB1 is regulated by phosphorylation. Moreover, our results suggest that egg-secreted SmHMGB1 may represent a new egg antigen. Therefore, the identification of drugs that specifically target phosphorylation of SmHMGB1 might block its secretion and interfere with the pathogenesis of schistosomiasis

Mutant TDP-43 within motor neurons drives disease onset but not progression in amyotrophic lateral sclerosis

10.1007/s00401-017-1698-6Acta Neuropathologica1336907-92

Mutant TDP-43 within motor neurons drives disease onset but not progression in amyotrophic lateral sclerosis.

Mutations in TDP-43 cause amyotrophic lateral sclerosis (ALS), a fatal paralytic disease characterized by degeneration and premature death of motor neurons. The contribution of mutant TDP-43-mediated damage within motor neurons was evaluated using mice expressing a conditional allele of an ALS-causing TDP-43 mutant (Q331K) whose broad expression throughout the central nervous system mimics endogenous TDP-43. TDP-43Q331K mice develop age- and mutant-dependent motor deficits from degeneration and death of motor neurons. Cre-recombinase-mediated excision of the TDP-43Q331K gene from motor neurons is shown to delay onset of motor symptoms and appearance of TDP-43-mediated aberrant nuclear morphology, and abrogate subsequent death of motor neurons. However, reduction of mutant TDP-43 selectively in motor neurons did not prevent age-dependent degeneration of axons and neuromuscular junction loss, nor did it attenuate astrogliosis or microgliosis. Thus, disease mechanism is non-cell autonomous with mutant TDP-43 expressed in motor neurons determining disease onset but progression defined by mutant acting within other cell types

Full-endoscopic technique for anterior cervical discectomy and interbody fusion: 5-year follow-up results of 67 cases

With minimally invasive technique becoming more popular, endoscopic operations such as arthroscopy or laparoscopy have become the standard of care in several other areas. In this study, we evaluated the 5-year follow-up outcomes of anterior cervical (Ahn et al. in Photomed Laser Surg 23:362–368, 2005) discectomy and interbody fusion (ACDF) performed via endoscopic approach. Sixty-seven patients who underwent anterior cervical discectomy and cage fusion performed using endoscopic technique were followed for at least 5 years. We reviewed the clinical and radiographic records of these patients. The postoperative radiographic measures accessed were the anterior intervertebral height (AIH) and the lordosis angle (LDA). Clinical outcomes were determined using the previously validated Japanese Orthopaedic Association (JOA) and the pain visual analog scale (VAS). Patients included had a minimal follow-up period of 5 years and based on the outcomes criteria (JOA, VAS), 86.6% of patients reported excellent or good results. The AIH increased on average 18.7% of the original height (p < 0.01), and the LDA were more physiologic at final follow-up. Of the 67 cases, there was no segmental instability, and the bone fusion rate was 100%. One patient required revision open ACDF due to adjacent segment disc herniation 6 years postoperatively. There were no intraoperative complications, dysphasia or esophageal injury in this study group. It indicated endoscopic technique for ACDF can obtain satisfactory results in patients with cervical disc herniation, cervical myelopathy, or radiculopathy. Compared with a traditional approach, this technique may be associated with less morbidity while improving cosmesis and postoperative recovery. Prospective randomized control trials are needed to directly compare these two procedures

ALS-linked TDP-43 mutations produce aberrant RNA splicing and adult-onset motor neuron disease without aggregation or loss of nuclear TDP-43

Transactivating response region DNA binding protein (TDP-43) is the major protein component of ubiquitinated inclusions found in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) with ubiquitinated inclusions. Two ALS-causing mutants (TDP-43(Q331K) and TDP-43(M337V)), but not wild-type human TDP-43, are shown here to provoke age-dependent, mutant-dependent, progressive motor axon degeneration and motor neuron death when expressed in mice at levels and in a cell type-selective pattern similar to endogenous TDP-43. Mutant TDP-43-dependent degeneration of lower motor neurons occurs without: (i) loss of TDP-43 from the corresponding nuclei, (ii) accumulation of TDP-43 aggregates, and (iii) accumulation of insoluble TDP-43. Computational analysis using splicing-sensitive microarrays demonstrates alterations of endogenous TDP-43–dependent alternative splicing events conferred by both human wild-type and mutant TDP-43(Q331K), but with high levels of mutant TDP-43 preferentially enhancing exon exclusion of some target pre-mRNAs affecting genes involved in neurological transmission and function. Comparison with splicing alterations following TDP-43 depletion demonstrates that TDP-43(Q331K) enhances normal TDP-43 splicing function for some RNA targets but loss-of-function for others. Thus, adult-onset motor neuron disease does not require aggregation or loss of nuclear TDP-43, with ALS-linked mutants producing loss and gain of splicing function of selected RNA targets at an early disease stage

Therapeutic AAV9-mediated Suppression of Mutant SOD1 Slows Disease Progression and Extends Survival in Models of Inherited ALS

Mutations in superoxide dismutase 1 (SOD1) are linked to familial amyotrophic lateral sclerosis (ALS) resulting in progressive motor neuron death through one or more acquired toxicities. Involvement of wild-type SOD1 has been linked to sporadic ALS, as misfolded SOD1 has been reported in affected tissues of sporadic patients and toxicity of astrocytes derived from sporadic ALS patients to motor neurons has been reported to be reduced by lowering the synthesis of SOD1. We now report slowed disease onset and progression in two mouse models following therapeutic delivery using a single peripheral injection of an adeno-associated virus serotype 9 (AAV9) encoding an shRNA to reduce the synthesis of ALS-causing human SOD1 mutants. Delivery to young mice that develop aggressive, fatal paralysis extended survival by delaying both disease onset and slowing progression. In a later-onset model, AAV9 delivery after onset markedly slowed disease progression and significantly extended survival. Moreover, AAV9 delivered intrathecally to nonhuman primates is demonstrated to yield robust SOD1 suppression in motor neurons and glia throughout the spinal cord and therefore, setting the stage for AAV9-mediated therapy in human clinical trials