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41.
Tetsuaki Arai Ian R. A. Mackenzie Masato Hasegawa Takashi Nonoka Kazhuhiro Niizato Kuniaki Tsuchiya Shuji Iritani Mitsumoto Onaya Haruhiko Akiyama 《Acta neuropathologica》2009,117(2):125-136
Phosphorylated and proteolytically cleaved TDP-43 is a major component of the ubiquitin-positive inclusions in the most common
pathological subtype of frontotemporal lobar degeneration (FTLD-U). Intracellular accumulation of TDP-43 is observed in a
subpopulation of patients with other dementia disorders, including Alzheimer’s disease (AD) and dementia with Lewy bodies
(DLB). However, the pathological significance of TDP-43 pathology in these disorders is unknown, since biochemical features
of the TDP-43 accumulated in AD and DLB brains, especially its phosphorylation sites and pattern of fragmentation, are still
unclear. To address these issues, we performed immunohistochemical and biochemical analyses of AD and DLB cases, using phosphorylation-dependent
anti-TDP-43 antibodies. We found a higher frequency of pathological TDP-43 in AD (36–56%) and in DLB (53–60%) than previously
reported. Of the TDP-43-positive cases, about 20–30% showed neocortical TDP-43 pathology resembling the FTLD-U subtype associated
with progranulin gene (PGRN) mutations. Immunoblot analyses of the sarkosyl-insoluble fraction from cases with neocortical TDP-43 pathology showed intense
staining of several low-molecular-weight bands, corresponding to C-terminal fragments of TDP-43. Interestingly, the band pattern
of these C-terminal fragments in AD and DLB also corresponds to that previously observed in the FTLD-U subtype associated
with PGRN mutations. These results suggest that the morphological and biochemical features of TDP-43 pathology are common between AD
or DLB and a specific subtype of FTLD-U. There may be genetic factors, such as mutations or genetic variants of PGRN underlying the co-occurrence of abnormal deposition of TDP-43, tau and α-synuclein. 相似文献
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Sara RollinsonJonathan D. Rohrer Julie van der ZeeKristel Sleegers Simon MeadSebastiaan Engelborghs John CollingePeter P. De Deyn David M.A. MannChristine Van Broeckhoven Stuart M. Pickering-Brown 《Neurobiology of aging》2011,32(4):754-755
Frontotemporal lobar degeneration (FTLD) is a highly familial neurodegenerative disease. It has been claimed that homozygosity of the SNP rs5848 located in the 3′UTR of progranulin increases risk for FTLD. We have attempted to replicate the association of rs5848 in three independent FTLD cohorts. No association of rs5848 with FTLD was observed in any individual cohort nor was any observed when the data was combined. These data argue that rs5848 is not a risk factor for FTLD. 相似文献
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Nermeen A. Fouad Maha H. Nassr Hanan M. Fathi Othman M. Zaki Ahmed A. Negm Soha H. Senara 《The Egyptian Rheumatologist》2019,41(2):93-97
Aim of the work
To determine the serum progranulin levels in rheumatoid arthritis (RA) patients and to study its relation with disease activity assessed clinically and by ultrasound (US).Patients and methods
The study included 52 RA patients and 19 age and sex matched controls. Disease activity score (DAS-28) and modified health assessment questionaire were assessed. Progranulin was measured by ELISA. Ultrasound examination was performed and the German US7 score (USS) recorded.Results
The patients mean age was 42.8?±?10.5?years; disease duration was 4.9?±?5.02?years; 47 females and 5 males with a mean DAS28 of 4.4?±?0.9 (3 in remission; 5 low activity; 31 moderate and 13 high). The mean serum progranulin level in patients (9.5?±?45.5?ng/ml) was significantly elevated compared to control (32.74?±?9.2?ng/ml) (p?<?0.0001). There was a significant difference in the progranulin levels and USS according to the grades of disease activity (p?<?0.0001 and p?=?0.037 respectively). The progranulin and USS significantly correlated with the DAS28 (r?=?0.64, r?=?0.58; p?<?0.0001 respectively) and erythrocyte sedimentation rate (p?<?0.0001). The progranulin and USS significantly correlated with each other (r?=?0.32, p?=?0.02). At a cut-off value 51.5?ng/ml, progranulin would discriminate between patients and control at sensitivity 96.2%, specificity 100% and accuracy 99%.Conclusion
Serum progranulin levels were higher in RA patients than age and sex matched controls. It significantly correlated with disease activity measured by DAS28, ESR and ultrasound activity measured by German US7 score. Serum progranulin levels may be a useful biomarker in RA disease. Ultrasound correlated with ESR and DAS28 in RA patients. 相似文献46.
Sarah Herdewyn Louis De Muynck Ludo Van Den Bosch Wim Robberecht Philip Van Damme 《Neurobiology of aging》2013
Motor neuron degeneration in amyotrophic lateral sclerosis (ALS) is familial in 10% of patients, with mutations in SOD1 and C9orf72 being the most frequent cause. There is convincing evidence for overlap between ALS and frontotemporal lobar degeneration at the genetic, pathological, and clinical level. Null mutations in progranulin (PGRN) are a frequent cause of familial frontotemporal lobar degeneration. PGRN exerts neurotrophic properties on motor neurons in vitro and in vivo. We therefore examined whether PGRN could affect disease progression in mutant SOD1 mice and rats, both established models for ALS. Overexpression of PGRN in mice and intracerebroventricular delivery of PGRN in rats did not affect onset or progression of motor neuron degeneration. 相似文献
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《Revue neurologique》2021,177(9):1082-1089
As per recent reports, there is an association between glucocerebrosidase (Gcase) enzyme and Parkinson's disease (PD). In addition, certain mutations in the Gcase gene (GBA) and the progranulin (PGRN) gene are found to be linked with the imbalance in the levels of Gcase enzyme. This imbalance or decrease or impairment in Gcase activity can lead to Gaucher disease, frontotemporal lobar degeneration (FTLD), dementia, etc. Recent evidences suggest that the drugs used to treat these diseases can be used for PD. The present review has focused on the therapeutic approaches used for diseases linked with Gcase enzyme, which can be used for PD. The review also considered possible target specific novel strategies, which may help to meet the unmet needs in the treatment of PD. 相似文献
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Xiao S Sato C Kawarai T Goodall EF Pall HS Zinman LH Robertson J Morrison K Rogaeva E 《Neurobiology of aging》2008,29(8):1279-1282
There is increasing evidence of a clinical, neuropathological and genetic overlap between frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). We conducted a case–control study using a UK dataset to test the hypothesis that polymorphisms in two FTD-related genes (GRN and FT74) are associated with increased susceptibility to ALS. We evaluated the majority of known genetic variability in IFT74 and GRN. The results revealed that the common variations in IFT74 and GRN neither constitute strong ALS risk factors nor modify the age-at-onset. However, the possibility of a modest risk effect remains to be assessed in large datasets. 相似文献
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目的研究颗粒蛋白前体(PGRN)在肥胖PCOS大鼠卵巢中的表达情况,初步探讨PGRN在PCOS发病中的作用。方法选择SPF级23日龄SD雌性大鼠38只,使用随机数字表随机分为3组:正常对照组(n=8)、PCOS组(DHEA组,n=15)及肥胖PCOS组(DHEA+HFD组,n=15)。采用脱氢表雄酮联合高脂饲料(DHEA+HFD)诱导肥胖PCOS大鼠。HE染色光镜下观察PCOS大鼠卵巢的病理结构改变。酶联免疫吸附法测定血清睾酮(T)、雌二醇(E2)及空腹血糖(FBG)、空腹胰岛素(FINS)含量等,比较各组间的水平差异。采用免疫组织化学法检测各组卵巢PGRN的表达水平及分布情况。结果造模结束时,DHEA+HFD组体重显著高于对照组(P<0.01)及DHEA组(P<0.05)。DHEA组及DHEA+HFD组的FINS、稳态模型评估的胰岛素抵抗指数(HOMA-IR)均显著高于对照组(P<0.05)。DHEA组及DHEA+HFD组的睾酮(T)、FSH水平均显著升高(P<0.01)。DHEA组及DHEA+HFD组卵巢组织光镜下均表现出典型的多囊样改变。免疫组化结果显示各组大鼠卵巢中均可见PGRN蛋白表达,主要分布于卵泡的颗粒细胞层及黄体;DHEA组PGRN表达水平显著高于对照组(P<0.01),DHEA+HFD组PGRN表达水平显著高于DHEA组及对照组(P<0.01)。结论 PGRN在卵巢颗粒细胞层有表达。其在PCOS大鼠和肥胖PCOS大鼠卵巢组织中的差异性表达,提示PGRN可能通过作用于局部卵泡微环境,参与PCOS肥胖及慢性代谢性炎症的发生。 相似文献