Spinal muscular atrophy is an autosomal recessive motor neuron disease that is caused by mutation of the survival motor neuron gene (SMN1) but all patients retain a nearly identical copy, SMN2. The disease severity correlates inversely with increased SMN2 copy. Currently, the most promising therapeutic strategy for spinal muscular atrophy is induction of SMN2 gene expression by histone deacetylase inhibitors. Polyphenols are known for protection against oxidative stress and degenerative diseases. Among our candidate prodrug library, we found that (E )-resveratrol, which is one of the polyphenolic compounds, inhibited histone deacetylase activity in a concentration-dependent manner and half-maximum inhibition was observed at 650 microM. Molecular docking studies showed that (E )-resveratrol had more favorable free energy of binding (-9.09 kcal/mol) and inhibition constant values (0.219 microM) than known inhibitors. To evaluate the effect of (E )-resveratrol on SMN2 expression, spinal muscular atrophy type I fibroblast cell lines was treated with (E )-resveratrol. The level of full-length SMN2 mRNA and protein showed 1.2- to 1.3-fold increase after treatment with 100 microM (E )-resveratrol in only one cell line. These results indicate that response to (E )-resveratrol treatment is variable among cell lines. This data demonstrate a novel activity of (E )-resveratrol and that it could be a promising candidate for the treatment of spinal muscular atrophy.

Exercise studies in neuromuscular diseases like spinal muscular atrophy (SMA), a devastating disease caused by survival of motor neuron 1 ( SMN1) gene mutations, are drawing attention due to its beneficial effects. In this study, we presented a constructed arm cycling exercise protocol and evaluated the benefits on SMA patients. Five SMA type II patients performed 12 weeks of supervised arm cycling exercise. The physical functions were evaluated together with the SMN2 copy numbers, SMN protein levels, insulin-like growth factor 1(IGF1) and binding protein 3 (IGFBP3) levels. The active cycling distance and duration of patients significantly improved. Significant changes could not have detected either SMN or IGF1 and IGFBP3 levels in response to exercise. The findings demonstrated that the patients tolerated the exercise protocol and gained a benefit from arm cycling but benefits could not be associated with SMN2 copy number, SMN protein level, IGF1, or IGFBP3 levels.

Cytoskeletal rearrangement during axon growth is mediated by guidance receptors and their ligands which act either as repellent, attractant or both. Regulation of the actin cytoskeleton is disturbed in Spinal Muscular Atrophy (SMA), a devastating neurodegenerative disease affecting mainly motoneurons, but receptor-ligand interactions leading to the dysregulation causing SMA are poorly understood. In this study, we analysed the role of the guidance receptor PlexinD1 in SMA pathogenesis. We showed that PlexinD1 is cleaved by metalloproteases in SMA and that this cleavage switches its function from an attractant to repellent. Moreover, we found that the PlexinD1 cleavage product binds to actin rods, pathological aggregate-like structures which had so far been described for age-related neurodegenerative diseases. Our data suggest a novel disease mechanism for SMA involving formation of actin rods as a molecular sink for a cleaved PlexinD1 fragment leading to dysregulation of receptor signaling.

Spinal muscular atrophy (SMA) is a devastating childhood disease primarily affecting lower motoneurons in the spinal cord. SMA is caused by the loss of functional survival of motoneuron (SMN) protein, leading to structural and functional alterations of the cytoskeleton in motoneurons and other cells. Loss of SMN results in impairments of microtubule architecture, but the underlying mechanisms are not completely understood. In this study, we mechanistically analyzed the effects of SMN deficiency on microtubules, demonstrating a reduced stability together with a reduction in alpha tubulin detyrosination. This was caused by increased levels of microtubule-associated protein 1B and tubulin tyrosine ligase, resulting in mitochondrial mislocalization in SMA. Our findings suggest that altered tubulin post-translational modifications and microtubule-associated proteins are involved in the pathomechanisms of SMA, such as an impaired axonal transport of mitochondria.

In the present study, we examined the impact of humor’s positive functions on the perception of a job’s meaningfulness. We argued that liberating and stress-relieving humor act as job resources enhancing job crafting to increase social and structural resources to experience meaningfulness. We hypothesized that crafting the job to increase structural and social resources would mediate the link between organizational humor functions (i.e., liberating and stress-relieving) and meaningfulness. We conducted a cross-sectional study among 200 Turkish employees from different occupations. Our results revealed that increasing structural resources mediated the relationship between liberating humor and meaningfulness, while this mediation was partially for stress-relieving humor. The mediating role of increasing social resources was partial and conditional for both types of organizational humor functions. The practical and theoretical implications have been discussed from a positive organizational scholarship perspective.

Introduction/Aims: Spinal muscular atrophy (SMA) is an inherited neuromuscular disease caused by survival motor neuron (SMN) protein deficiency. Insulin-like growth factor-I (IGF-I) is a myotrophic and neurotrophic factor that has been reported to be dysregulated in in vivo SMA model systems. However, detailed analyses of the IGF-I system in SMA patients are missing. In this study, we analyzed the components of the IGF-I system in serum and archived skeletal muscle biopsies of SMA patients. Methods: Serum IGF-I, IGF binding protein (IGFBP)-3, and IGFBP-5 levels were analyzed in 11 SMA patients and 13 healthy children by immunoradiometric and enzyme-linked immunosorbent assays. The expression of IGF-I, IGF-I receptor, and IGFBP-5 proteins was investigated by immunofluorescence analysis in the archived skeletal muscle biopsies of nine SMA patients, six patients with non-SMA-related neuromuscular disease and atrophic fibers in muscle biopsy, and four controls.Results: A significant decrease in IGF-I levels (mean ± SD: À1.39 ± 1.46 vs. 0.017 ± 0.83, p = .02) and increase in IGFBP-5 levels (mean ± SD: 2358.5 ± 1617.4 ng/mL vs. 1003.4 ± 274.3 ng/mL, p = .03) were detected in serum samples of SMA patients compared to healthy controls. Increased expression of IGF-I, IGF-I receptor, and IGFBP-5 was detected in skeletal muscle biopsies of SMA patients and non-SMA neuromuscular diseases, indicating atrophy-specific alterations in the pathway.Discussion: Our findings suggested that the components of the IGF-I system are altered in SMA patients at both the systemic and tissue-specific levels.

No abstract

Özet: Ökaryotik hücredeki biyolojik olayların açıklanabilmesi amacıyla primer hücrelere ulaşımın kısıtlı olduğu durumlarda hücre hatları kullanılmaktadır. Hücre hatları, primer hücreleri birebir yansıtmamalarına karşın hastalık modeli oluşturmak için sıklıkla ihtiyaç duyulan ve kullanılan hücrelerdir. Bu çalışmada genlerin fonksiyonunun baskılanması prensibine dayanan RNA interferans yöntemi iki farklı nöron benzeri hücre hatında uygulanmış, hücrelerin birbirlerine göre avantajları/dezavantajları, nörodejeneratif bir hastalık olan Spinal müsküler atrofi üzerinden karşılaştırılmıştır. In vitro SMA modeli oluşturmak üzere, nöron benzeri hücrelere farklılaştırılan PC12 ve NSC34 hücre hatlarında SMN gen ifadesi siRNA yöntemi ile baskılanmiş, baskılanma Western blot ve immünfloresan boyama yöntemleri ile gösterilmiştir.PC12 ve NSC34 hücre hatlarında SMN gen ifadesi %90'ın üzerinde baskılanabilmiş ve çalışmalar sırasında hücre hatlarının kültür, farklılaşma, transfeksiyon koşulları arasındaki farklar karşılaştırmalı olarak incelenmiştir. Elde ettiğimiz bulgular, ileride nöron benzeri PC12 ve NSC34 hücre hatları kullanılarak gerçekleştirilecek çalışmalar açısından yol gösterici olacaktır.