Diabetes mellitus is independently associated with more severe cognitive impairment in Parkinson disease

BackgroundThere is increasing interest in interactions between metabolic syndromes and neurodegeneration. Diabetes mellitus (DM) contributes to cognitive impairment in the elderly but its effect in Parkinson disease (PD) is not well studied.ObjectiveTo investigate effects of comorbid DM on cognition in PD independent from PD-specific primary neurodegenerations.MethodsCross-sectional study. Patients with PD (n = 148); age 65.6 ± 7.4 years, Hoehn and Yahr stage 2.4 ± 0.6, with (n = 15) and without (n = 133) comorbid type II DM, underwent [¹¹C]methyl-4-piperidinyl propionate (PMP) acetylcholinesterase (AChE) PET imaging to assess cortical cholinergic denervation, [¹¹C]dihydrotetrabenazine (DTBZ) PET imaging to assess nigrostriatal denervation, and neuropsychological assessments. A global cognitive Z-score was calculated based on normative data. Analysis of covariance was performed to determine cognitive differences between subjects with and without DM while controlling for nigrostriatal denervation, cortical cholinergic denervation, levodopa equivalent dose and education covariates.ResultsThere were no significant differences in age, gender, Hoehn and Yahr stage or duration of disease between diabetic and non-diabetic PD subjects. There was a non-significant trend toward lower years of education in the diabetic PD subjects compared with non-diabetic PD subjects. PD diabetics had significantly lower mean (±SD) global cognitive Z-scores (−0.98 ± 1.01) compared to the non-diabetics (−0.36 ± 0.91; F = 7.78, P = 0.006) when controlling for covariate effects of education, striatal dopaminergic denervation, and cortical cholinergic denervation (total model F = 8.39, P < 0.0001).ConclusionDiabetes mellitus is independently associated with more severe cognitive impairment in PD likely through mechanisms other than disease-specific neurodegenerations.     

Genetically determined neuropathy (CMT 1A) accompanied by immune dysfunction: a case report

Peripheral Myelin Protein 22 (PMP22) is mostly expressed in Schwann cells where it is essential in the compaction of myelin. The duplication of the PMP22 gene results in a hereditary demyelinating neuropathy of the Charcot–Marie–Tooth type 1A (CMT1A). So far there are only a few case reports suggesting that dysimmune mechanisms may take part in the pathophysiology of this disease. We describe three siblings carrying the duplication of the PMP22 gene, with a significant reduction of serum immunoglobulin G levels in all three cases and sural nerve vasculitis in the two women, which supports the proposition, that immune dysfunction may accompany this disease in some cases.     

Clinical,genetic and electrophysiologic correlation in hereditary neuropathy with liability to pressure palsies with involvement of PMP22 gene at chromosome 17p11.2

Clinical and electrophysiological studies were performed in affected and unaffected individuals from five unrelated families segregating hereditary neuropathy with liability to pressure palsies (HNPP) as an autosomal dominant trait. A molecular lesion at the HNPP locus in chromosome 17p11.2 was previously confirmed in all families. In four families the HNPP 1.5Mb was demonstrated. In the fifth family the mutation was a point mutation involving the 5′ donor splicing site of the first intron of PMP22 gene. Clinical variability between and within families was observed. Susceptibility to minimal traumas was also variable. We mention certain peculiarities such as painless brachial plexus neuropathy, conduction block lasting more than 9 years, slimmer's paralysis as the unique clinical manifestation of the disease, and diagnostic problems in asymptomatic individuals. There is a genetic and electrophysiological correlation in affected individuals with HNPP.     

Visualization and quantitation of peroxisomes using fluorescent nanocrystals: treatment of rats and monkeys with fibrates and detection in the liver.

Peroxisome proliferation in the liver is a well-documented response that occurs in some species upon treatment with hypolipidemic drugs, such as fibrates. Typically, liver peroxisome proliferation has been estimated by direct counting via electron microscopy, as well as by gene expression, enzyme activity, and immunolabeling. We have developed a novel method for the immunofluorescent labeling of peroxisomes, using an antibody to the 70-kDa peroxisomal membrane protein (PMP70) coupled with fluorescent nanocrystals, Quantum Dots. This method is applicable to standard formalin-fixed, paraffin-embedded tissues. Using this technique, a dose-dependent increase in PMP70 labeling was evident in formalin-fixed liver sections from fenofibrate-treated rats. In formalin-fixed liver sections from cynomolgus monkeys given ciprofibrate, quantitative image analysis showed a statistically significant increase in PMP70 labeling compared to control; the increase in hepatic PMP70 protein levels was corroborated by immunoblotting using total liver protein. An increase in hepatic peroxisome number in ciprofibrate-treated monkeys was confirmed by electron microscopy. An advantage of the Quantum Dot/PMP70 method is that a single common protocol can be used to label peroxisomes from several different species, and many of the common problems that arise with immunolabeling, such as fading and low signal strength, are eliminated.     

The molecular genetics of myelination: An update

Recent molecular genetic studies have provided new insights into the structure and function of 2 of the major integral membrane proteins of myelin—the proteolipid protein (PLP) and protein zero (P_o)—and have uncovered a third such protein—PMP22/gas3. The rumpshaker mouse has been shown to carry a point mutation in the PLP gene that uncouples a deleterious effect on CNS myelin assembly, which these mice exhibit, from oligodendrocyte degeneration and cell death, which they do not. The developmental importance of the P_o protein in PNS myelination has been dramatically demonstrated by the analysis of loss-of-function mutations engineered through the expression of antisense RNA and through the insertional inactivation of the P_o gene by homologous recombination in embryonic stem cells and the generation of P_o-deficient mice. The cloned promoter of the P_o gene has been shown to drive quantitative, Schwann cell-specific expression of heterologous genes in transgenic mice. The PMP22/gas3 gene, previously cloned from fibroblast cell lines, has been found to encode an axonally regulated Schwann cell protein that is assembled into PNS myelin. Importantly, this gene appears to be the target of mutations that result in the Trembler alleles in mice, and in Charcot-Marie-Tooth disease Type 1a, the most common inherited peripheral neuropathy in humans.     

腓骨肌萎缩症分子突变研究现状

腓骨肌萎缩症(charcot marie tooth disease,CMT)是一组高发病率的周围神经系统的单基因遗传病,具有临床和遗传异质性。可分为CMT1型,CMT2型,CMTX型和CMT4型。近些年随着分子遗传学和分子生物学的快速发展,已经发现了很多CMT的相关致病基因。主要包括外周髓鞘蛋白22基因、髓鞘蛋白零蛋白基因、间隙连接蛋白-32基因、驱动蛋白1B基因、Ras相关蛋白7基因、小分子热休克蛋白27基因等。本文就CMT相关致病基因研究现状作一综述。     

一个Charcot-Marie-Tooth病家系的分子遗传学分析

目的 鉴定一个Charcot-Marie-Tooth病(CMT)家系的致病突变.方法 根据家族史、临床表现和肌电图检查结果判断家系CMT分型.采集16名家系成员外周血,提取基因组DNA.针对CMT1的6个亚型,选择微卫星标记进行连锁分析.针对PMP22基因重复突变,采用实时定量PCR检测家系成员.结果 本家系疾病呈常染色体显性遗传.患者均有青少年发病、缓慢进展的下肢无力症状.部分患者经查体发现下肢腱反射减弱、痛触觉减弱,下肢神经传导速度均小于30 m/s,提示为CMT1型.通过连锁分析排除了CMT1A、CMT1E以外的其他4个亚型,证实患者基因组内PMP22基因存在重复突变.结论 此家系患者表型为CMT1A,其致病突变为染色体17p11.2区域内PMP22基因的重复.     

Identification of Alu elements mediating a partial PMP22 deletion

Hereditary neuropathy with liability to pressure palsies (HNPP) is most frequently caused by deletion of a 1.4-Mb region in chromosome 17p11.2-12 including the peripheral myelin protein 22 (PMP22) gene. Smaller deletions partially affecting the PMP22 gene are less frequently observed. We identified in a HNPP patient a deletion of the 5′ region of PMP22 including non-coding exon 1, coding exons 2 and 3, whereas, exons 4 and 5 were present. PMP22 exon 3- and 4-specific qPCR resulted in a deletion of one exon 3 allele but in the presence of 2 exon 4 alleles. SNP analysis revealed the presence of heterozygosity for PMP22 coding exons 4 and 5. Finally, MLPA specific for the CMT1A region defined this deletion for the entire 5′ region of PMP22 (exons 1, 2 and 3). These partial HNPP deletions may be missed by other techniques, e.g., STR marker analysis. Alu elements have been reported to mediate non-allelic recombination events. Bioinformatic analysis revealed 12 Alu elements flanking in close neighbourhood the estimated 40-kb deletion region as candidates for recombination events. PCR primers were designed to identify a breakpoint-spanning product including the respective Alu elements. PCR-driven identification of a junction fragment was successful with AluJo–AluSq and AluYb9–AluSq specific primer pairs comprising the same intronic region of PMP22. Sequence analysis of these breakpoint-overlapping PCR fragments revealed a 29-bp motif including a chi-like sequence (GCTGG) present both in the AluYb9 and the AluSq element. These data confirm that low-copy repeats (LCRs) mediate non-allelic homologous recombinations (NAHR).     

Eicosapentaenoic acid improves hepatic steatosis independent of PPARα activation through inhibition of SREBP-1 maturation in mice

Eicosapentaenoic acid (EPA) in fish oil is known to improve hepatic steatosis. However, it remains unclear whether such action of EPA is actually caused by peroxisome proliferator-activated receptor α (PPARα) activation. To explore the contribution of PPARα to the effects of EPA itself, male wild-type and Ppara-null mice were fed a saturated fat diet for 16 weeks, and highly (>98%)-purified EPA was administered in the last 12 weeks. Furthermore, the changes caused by EPA treatment were compared to those elicited by fenofibrate (FF), a typical PPARα activator. A saturated fat diet caused macrovesicular steatosis in both genotypes. However, EPA ameliorated steatosis only in wild-type mice without PPARα activation, which was evidently different from numerous previous observations. Instead, EPA inhibited maturation of sterol-responsive element-binding protein (SREBP)-1 in the presence of PPARα through down-regulation of SREBP cleavage-activating protein and site-1 protease. Additionally, EPA suppressed fatty acid uptake and promoted hydrolysis of intrahepatic triglycerides in a PPARα-independent manner. These effects were distinct from those of fenofibrate. Although fenofibrate induced NAPDH oxidase and acyl-coenzyme A oxidase and significantly increased hepatic lipid peroxides, EPA caused PPARα-dependent induction of superoxide dismutases, probably contributing to a decrease in the lipid peroxides. These results firstly demonstrate detailed mechanisms of steatosis-ameliorating effects of EPA without PPARα activation and ensuing augmentation of hepatic oxidative stress.