A new alpha-synuclein missense variant (Thr72Met) in two Turkish families with Parkinson's disease

IntroductionMissense variants and multiplications of the alpha-synuclein gene (SNCA) are established as rare causes of autosomal dominant forms of Parkinson's Disease (PD).MethodsTwo families of Turkish origins with PD were studied; the SNCA coding region was analyzed by Sanger sequencing, and by whole exome sequencing (WES) in the index patient of the first and the second family, respectively. Co-segregation studies and haplotype analysis across the SNCA locus were carried out. Functional studies included in vitro thioflavin-T aggregation assay and in silico structural modelling of the alpha-synuclein (α-syn) protein.ResultsWe identified a novel heterozygous SNCA variant, c.215C > T (p.Thr72Met), segregating with PD in a total of four members in the two families. A shared haplotype across the SNCA locus was found among variant carriers, suggestive of a common ancestor. We next showed that the Thr72Met α-syn displays enhanced aggregation in-vitro, compared to the wild-type species. In silico analysis of a tetrameric α-syn structural model revealed that Threonine 72 lies in the tetrameric interface, and substitution with the much larger methionine residue could potentially destabilize the tetramer.ConclusionWe present clinical, genetic, and functional data supporting a causative role of the SNCA c.215C > T (p.Thr72Met) variant in familial PD. Testing for this variant in patients with PD, especially of Turkish origin, might detect additional carriers. Further functional analyses might offer new insights into the shared biochemical properties of the PD-causing SNCA missense variants, and how they lead to neurodegeneration.     

PP2A Ligand ITH12246 Protects against Memory Impairment and Focal Cerebral Ischemia in Mice

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A Study of Ser217Leu and Ala541Thr Polymorphism in the Men Afflicted with Prostate Cancer and in the Men being Suspicious of Prostate Cancer

Background and objective: Prostate cancer is one of the most widespread cancers among men throughout the world. In addition, it is the second cause of death after lung cancer. Occurrence of the prostate cancer is variable in various regions of the world. Solely, there are three known risk factors for the prostate cancer, including: Age, inheritance and ethnic origin. ELAC2 protein is a phosphodiesterase enzyme encoded by ELAC2 gene in human. This gene is placed on chromosome 17, and it is believed that product of the mentioned gene is an endonuclease contributed in puberty of mitochondrion’s tRNA. From clinical viewpoint, variables of ELAC2 gene such as Ser217Leu and Ala541Thr Missense mutations which are accompanied by hereditary prostate cancer (HPC2).Objective of this study is to investigate Ser217Leu (rs4792311) and Ala541Thr (rs5030739) polymorphisms in the individuals with prostate cancer or those who are suspicious of prostate cancer with family past record/history. Study method: In this study conducted by case-control method in 2018, 102 men with prostate cancer and 98 men being suspicious of prostate cancer out of 10 families referred to shahid Rajaei Hospital in Tonekabon county to study and check were investigated. After collection of data using questionnaire, sampling from individuals and performance of the rest steps, study of polymorphism was carried out by PCR sequencing technique, and the results were analyzed by Chromas software. Finding: Of the total studied 102 individuals, 44 individuals (43.1%) were homozygote for Ser217Leu mutation, 36 individuals (35.2%) were heterozygote and 22 individuals (21.5%) lacked Missense mutation. for Ala541Thr mutation, 18 ones (17.6%) were heterozygote and 84 ones (82.3%) lacked Missense mutation. For Ser217Leu mutation, out of 98 suspicious individuals, 21 individuals (21.4%) were homozygote. 6 individuals (6.1%) were heterozygote and 71 individuals (72.4%) lacked the mutation. For Ala541Thr mutation, 15 ones (15.3%) were homozygote and 84 ones (84.6%) lacked the studied mutation. Conclusion: Results of this research showed that, in the individuals with the prostate cancer, there is a relationship between Ser217Leu and Ala541Thr polymorphism of ELAC2 gene and/with prostate cancer, and the suspicious individuals gotten involved in the mutation must take action to prevent this cancer.     

RhoA和肌球蛋白轻链在肝纤维化大鼠肝组织中的表达

目的观察Rho/Rho激酶信号转导通路关键信号分子RhoA和磷酸化肌球蛋白轻链[p-MLC(Thr18/Ser19)]在大鼠肝纤维化组织中的表达规律。方法HE及Masson三色染色观察肝病理组织学变化;用Western blot检测RhoA、p-MLC(Thr18/Ser19)蛋白的表达;RT-PCR方法检测RhoAmRNA的表达。结果随着肝纤维化的进展,RhoA、p-MLC(Thr18/Ser19)蛋白表达明显增加,RhoAmRNA基因表达也逐渐加强。RhoA和p-MLC(Thr18/Ser19)分别与α-平滑肌肌动蛋白(α-SMA)呈显著正相关。结论Rho/Rho激酶信号转导通路在肝纤维化形成过程中发生变化。     

Severe dysplasminogenemia due to homozygous PLG Ala620Thr variant in a Korean woman without a history of venous thromboembolism: A case report and literature review

Rationale:Plasminogen plays an important role in fibrinolysis and is encoded by the PLG gene. The missense variant PLG Ala620Thr is the major cause of dysplasminogenemia in East Asian countries, including Korea. Although dysplasminogenemia was first reported in a Japanese patient with recurrent venous thromboembolism (VTE), subsequent studies have not demonstrated any clear association between the PLG Ala620Thr variant and the risk of VTE. To the best of our knowledge, this is the first report of a homozygous PLG Ala620Thr variant case from Korea.Patient concerns:Here, we report a Korean family with PLG Ala620Thr mutation. The proband was a 34-year-old man who presented with multiple thrombotic arterial embolism and cardiac myxoma.Interventions:Laboratory workup, including coagulation profile and PLG gene sequencing, was carried out for the affected family.Diagnosis and Outcome:The proband carried a heterozygous PLG Ala620Thr variant with decreased plasminogen activity of 65%. His 53-year-old mother, who had no reported history of VTE, was homozygous for the PLG Ala620Thr variant with decreased plasminogen activity of just 25%. Decreased plasminogen activity indicates dysplasminogenemia.Lessons:We believe that this clinically silent homozygous case supports the previous findings that isolated PLG Ala620Thr variant does not confer a significant risk of VTE.     

Ser/Thr蛋白激酶信号转导系统——抗结核药物筛选的新靶点

最近的研究表明,Ser/Thr蛋白激酶不只存在于真核生物中,而且也存在于结核分枝杆菌体内.它们构成结核分枝杆菌的信号转导系统,与结核分枝杆菌在宿主体内和体外的生存密切相关.因此,这一信号转导系统可能成为研制新型抗结核药物的靶点.本文就Ser/Thr蛋白激酶信号转导系统及相关蛋白激酶的特征与功能进行了综述.     

TAFI polymorphisms at amino acids 147 and 325 are not risk factors for cerebral infarction

Thrombin-activatable fibrinolysis inhibitor (TAFI) was reported as an anaphylatoxin-inactivating enzyme generated by proteolytic cleavage of its zymogen, and is the same enzyme as that first designated by our group as procarboxypeptidase R (proCPR). Its level in plasma appears to influence vascular disease. In addition, TAFI activity is strongly influenced by genetic polymorphism, especially at amino acids 147 and 325. We investigated whether these TAFI polymorphisms would act as a risk factor for cerebral infarction (CI) by examining 253 samples in which the diagnosis was cliniconeuropathologically confirmed. We found little that was statistically significant in terms of these polymorphisms among patients with no vascular problems or in a population-based control group. In the present study of an elderly Japanese group, our samples revealed a lower percentage of the Ile allele at Thr/Ile-325 compared with western counterparts. Although patients with severe infarcts had a lower percentage of the Ile allele (10%) at amino acid position 325 compared with the slightly and moderately affected patients and the population-based control group (15-18%), no statistical significance was found. None of our results showed any statistical correlation between TAFI polymorphisms and CI.     

Sarcolipin and phospholamban as regulators of cardiac sarcoplasmic reticulum Ca2+ ATPase

The cardiac sarcoplasmic reticulum calcium ATPase (SERCA2a) plays a critical role in maintaining the intracellular calcium homeostasis during cardiac contraction and relaxation. It has been well documented over the years that altered expression and activity of SERCA2a can lead to systolic and diastolic dysfunction. The activity of SERCA2a is regulated by two structurally similar proteins, phospholamban (PLB) and sarcolipin (SLN). Although, the relevance of PLB has been extensively studied over the years, the role SLN in cardiac physiology is an emerging field of study. This review focuses on the advances in the understanding of the regulation of SERCA2a by SLN and PLB. In particular, it highlights the similarities and differences between the two proteins and their roles in cardiac patho-physiology.     

GIGYF2 Asn56Ser and Asn457Thr mutations in Parkinson disease patients

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Immunolocalization of phospho-Arg-directed protein kinase-substrate in hypoxic kidneys using in vivo cryotechnique

Protein kinases (PKs) phosphorylate proteins at active regions for signal transduction. In this study, normal and hypoxic mouse kidneys were prepared using an “in vivo cryotechnique” (IVCT) and examined immunohistochemically with specific antibodies against phospho-(Ser/Thr) PKA/C substrate (P-PK-S) and phospho-(Ser/Thr) Akt substrate (P-Akt-S) to capture their time-dependent regulation in vivo. Left kidneys were cryofixed with IVCT under normal blood circulation and after varying hypoxic intervals, followed by freeze-substitution with acetone containing paraformaldehyde. Deparaffinized sections were immunostained for P-PK-S, Na⁺/HCO₃ ⁻ cotransporter NBC1, and a membrane skeletal protein, 4.1B. The P-PK-S was diffusely immunolocalized in the cytoplasm of the proximal tubules in normal kidneys, whereas NBC1 and 4.1B were detected at the basal striations of S1 and S2 segments of the proximal tubule. After 10 or 30 s hypoxia, P-PK-S was still immunolocalized in the cytoplasm of kidneys, but it was detected at the basal striations after 1 or 2 min hypoxia. The immunolocalization of P-Akt-S was the same as P-PK-S in the normal and hypoxic kidneys. Immunoblotting analyses of the kidney tissues under normal or hypoxic condition clearly identified the same 40-kDa bands. The IVCT is useful for time-dependent analysis of the immunodistribution of P-PK-S and P-Akt-S.