Succinate dehydrogenase in Parkinson’s disease

Background

The prevalence of neurodegenerative disorders such as Parkinson’s disease (PD) is increased by age. Alleviation of their symptoms and protection of normal neurons against degeneration are the main aspects of the researches to establish novel therapeutic strategies. Many studies have shown that mitochondria as the most important organelles in the brain which show impairment in PD models. Succinate dehydrogenase (SDH) as a component of the oxidative phosphorylation system in mitochondria connects Krebs cycle to the electron transport chain. Dysfunction or inhibition of the SDH can trigger mitochondrial impairment and disruption in ATP generation. Excessive in lipid synthesis and induction of the excitotoxicity as inducers in PD are controlled by SDH activity directly and indirectly. On the other hand, mutation in subunits of the SDH correlates with the onset of neurodegenerative disorders. Therefore, SDH could behave as one of the main regulators in neuroprotection.

Objective

In this review we will consider contribution of the SDH and its related mechanisms in PD.

Methods

Pubmed search engine was used to find published studies from 1977 to 2016. “Succinate dehydrogenase”, “lipid and brain”, “mitochondria and Parkinson’s disease” were the main keywords for searching in the engine.

Results

Wide ranges of studies (59 articles) in neurodegenerative disorders especially Parkinson’s disease like genetics of the Parkinson’s disease, effects of the mutant SDH on cell activity and physiology and lipid alteration in neurodegenerative disorders have been used in this review.

Conclusion

Mitochondria as key organelles in the energy generation plays crucial roles in PD. ETC complex in this organelle consists four complexes which alteration in their activities cause ROS generation and ATP depletion. Most of complexes are encoded by mtDNA while complex II is the only part of the ETC which is encoded by nuclear genome. So, focusing on the SDH and related pathways which have important role in neuronal survival and SDH has a potential to further studies as a novel neuroprotective agent.

     

Thermal stability of α-glycerophosphate dehydrogenase in Drosophila

Thermal stability of -glycerophosphate dehydrogenase-1 (-Gpdh-1) in nine Drosophila species was studied at pH's ranging from 6.4 to 8.5. This was done by measuring the changes in the activity of enzymes during the heat denaturation process. In addition to temperature, the rate of denaturation is highly dependent on the pH of the incubation buffer. The results of this study show that the thermal stability of enzyme molecules is different in different species. This holds true also in the species in which the enzymes have been found to be identical by other means. The differences between species of the Drosophila virilis group are discussed.This study was supported by funds from the National Research Council of Sciences of Finland.     

3α-Hydroxysteroid dehydrogenase and 3β-hydroxysteroid dehydrogenase in the ovary of young Mongolian gerbils

Summary The ovaries of sexually mature, pregnant mare serum gonadotropin (PMSG) stimulated, 12 week old Mongolian gerbils were investigated morphologically and enzyme histochemically for the appearance of the 3-hydroxysteroid and the 3-hydroxysteroid dehydrogenase during the estrous cycle. Up to ovulation, on day 3 of the estrous cycle, the number of vesicular follicles increases continuously. Primarily atretic follicles can be seen on day 4. On day 5 corpora lutea appear, but they degenerate already by day 6.During the entire estrous cycle, 3-hydroxysteroid dehydrogenase and 3-hydroxysteroid dehydrogenase activity can be found in the theca of tertiary follicles and in the interstitial cells, whereas the theca of secondary follicles and the granulosa of healthy follicles do not exhibit any enzyme activity. The activity decreases from day 1 till day 6. The granulosa of atretic follicles and the cells of corpora lutea show only weak activity. It may be significant that the intensity of enzyme activity in the ovary and the estrogen level in the plasma are differently correlated to the estrous cycle.This investigation was supported by the Deutsche Forschungsgemeinschaft     

The so-called "testis-specific aldehyde dehydrogenase" corresponds to type 2 retinaldehyde dehydrogenase in the mouse

The distribution pattern of "testis-specific aldehyde dehydrogenase" in mouse tissues was investigated. Because of the broad substrate specificity and the high degree of sequence identity of the large aldehyde dehydrogenase family a specific detection of single isoforms is not possible by histochemical means. Therefore, the technique of native isoelectric focusing was used. Thus, the expression of four to five banded "testis-specific aldehyde dehydrogenase" in the mouse testis was confirmed. However, the activity of this enzyme with the same pattern of multiplicity was found not only in the testis but also in the uterus and in embryonic tissues. At 9.5 and 10.5 days of embryonic development the enzyme activity was restricted to tissues of the embryonic trunk and absent in extracts from cranial tissues. The tissue distribution as well as substrate specificity and isoelectric points indicate that the "testis-specific aldehyde dehydrogenase" corresponds to mouse type 2 retinaldehyde dehydrogenase.     

Immunocytochemical localization of 17β-hydroxysteroid dehydrogenase in porcine testis

Summary The immunocytochemical localization of 17-hydroxysteroid dehydrogenase (17-HSD) in porcine testes was examined by applying an indirect-immunofluorescence method using an antiporcine testicular 17-HSD antibody. Only the Leydig cells located in the interstitial tissue exhibited a positive immunoreaction for 17-HSD: the germ cells and Sertoli cells located in the seminiferous tubules were entirely negative. These results suggest that, in porcine testis, the biosynthesis of testicular testosterone, the final step of which is the conversion of androstenedione to testosterone, takes place in the Leydig cells.Supported by grants from the Ministry of Education, Science, and Culture, Japan     

Cell specific steroid inhibitions in histochemical steroid 3β-ol dehydrogenase activities in man

Summary Histochemical evidence is presented for the occurrence of specific steroid 3-ol dehydrogenase activities in steroidogenic cells of the human ovary, testes and adrenal. The enzymes in the cells of the corpus luteum and adrenal show similar dehydrogenase reactions with some steroid substrates and are inhibited by progesterone, a known physiologic steroid. Theca cells have an activity which is less readily demonstrated and apparently inhibited by both progesterone and DHA. The ovarian hilus cells and the interstitial cells of the testis contain steroid dehydrogenase activity which is inhibited by DHA and not by progesterone. The cellular specificity suggests that the type of activity plays a major role in determining the type of hormone production. The specificity of the steroid inhibitors suggests the possibility of intracellular feedback mechanisms which control the amount of hormone produced.Supported by USPHS Grant No. AMO 3806-07.     

Oxidative phosphorylation in a yeast mutant lacking α-ketoglutarate dehydrogenase activity

The effect of α-ketoglutarate deficiency on the oxidative phosphorylation in yeast mitochondria was studied. By determining the properties of electron transport and energy transduction systems of mutant mitochondria it was found that the lack of α-ketoglutarate dehydrogenase activity in mitochondria does not result in any functional defect in the oxidative phosphorylation system.     

Induction of isoenzymes of alcohol dehydrogenase in “flor” yeast

Summary Two isoenzymes of alcohol dehydrogenase (adh I and adh II) from Saccharomyces cheresiensis have been differentiated by thermal treatment of the crude extracts. The effect of pH on the stability and the K _m for ethanol are different for the two isoenzymes.The proportions in which they are present depend on the carbon source used by the yeast: adh I is the major component in cells grown on glucose, and adh II in those grown on ethanol. Cells grown on glucose plus ethanol show high levels of both isoenzymes, indicating that the synthesis of adh I is subjected to nutritional induction by glucose, and that of adh II by ethanol.The physiological roles of the two isoenzymes are discussed in relation with the nutritional characteristics of S. cheresiensis.     

Δ5-3β-Hydroxysteroid dehydrogenase in differentiating chick gonads

Summary A histochemical technique for 3-hydroxysteroid-dehydrogenase was applied to chick embryonic gonads between the seventh and fourteenth day of incubation. Up to the sixth and seventh day, the undifferentiated gonads gave negative reactions. Eleven out of twenty-eight ovaries of eight days showed some reaction and all ovaries over that age a stronger reaction, which was localized in isolated groups of cells distributed between medullary lacunae. Testes were negative before the tenth day, showing after that time an atypical and possibly unspecific reaction consisting of a diffuse purple stain of testicular cords. Adrenal glands were positive at all ages. The interpretation of these facts is discussed in relation to the production of steroid hormones by the embryonic gonads and their possible role in sex differentiation.This work was supported by a grant from the Consejo Nacional de Investigaciones Científicas y Técnicas of Argentina. Dr. Narbaitz holds a research position of the same Institution.     

Effects of phthalates on 3β-hydroxysteroid dehydrogenase and 17β-hydroxysteroid dehydrogenase 3 activities in human and rat testes

The 3β-hydroxysteroid dehydrogenase (3β-HSD) and 17β-hydroxysteroid dehydrogenase 3 (17β-HSD3) are involved in the reactions that culminate in androgen biosynthesis in Leydig cells. Human and rat testis microsomes were used to investigate the inhibitory potencies on 3β-HSD and 17β-HSD3 activities of 14 different phthalates with various carbon numbers in the ethanol moiety. The results demonstrated that the half-maximal inhibitory concentrations (IC(50)s) of dipropyl (DPrP), dibutyl (DBP), dipentyl (DPP), bis(2-butoxyethyl) (BBOP) and dicyclohexyl (DCHP) phthalate were 123.0, 24.1, 25.5, 50.3 and 25.5μM for human 3β-HSD activity, and 62.7, 30.3, 33.8, 82.6 and 24.7μM for rat 3β-HSD activity, respectively. However, only BBOP and DCHP potently inhibited human (IC(50)s, 23.3 and 8.2μM) and rat (IC(50)s, 30.24 and 9.1μM) 17β-HSD3 activity. Phthalates with 1-2 or 7-8 carbon atoms in ethanol moieties had no effects on both enzyme activities even at concentrations up to 1mM. The mode of action of DCHP on 3β-HSD activity was competitive with the substrate pregnenolone but noncompetitive with the cofactor NAD+. The mode of action of DCHP on 17β-HSD3 activity was competitive with the substrate androstenedione but noncompetitive with the cofactor NADPH. In summary, our results showed that there are clear structure-activity responses for phthalates in the inhibition of both 3β-HSD and 17β-HSD3 activities. The length of carbon chains in the ethanol moieties of phthalates may determine the potency to inhibit these two enzymes.     

Genetics and ontogeny of α-glycerophosphate dehydrogenase isozymes in Drosophila melanogaster

-Glycerophosphate dehydrogenase (GPDH) occurs in Drosophila melanogaster in three isozymic forms. These are separable by starch gel electrophoresis and have been tentatively numbered 1, 2, and 3. GPDH-1 is most concentrated in the adult thorax and GPDH-3 in the abdomen; 1 and 3 are in approximately equal amounts in the head. GPDH-2 is relatively weak in all preparations. In larvae, only GPDH-3 is present. Purified GPDH-1 has optimal activity at pH 6.7–7.0. GPDH-3 at pH 7.5, and GPDH-2 is intermediate. Changes in total GPDH activity parallel larval growth, pupal histolysis, and differentiation of adult tissues. In the latter period the ratio of activity at pH 6.7 to pH 7.6 increases, reflecting the shift from GPDH-3 to GPDH-1. Two types of homozygous GPDH patterns which differ in the electrophoretic mobilities of all three isozymes have been found in inbred strains. In heterozygous adults six bands, the parental forms of GPDH-1 and GPDH-3 and hybrid forms of each, can be resolved. Analysis of F₂ and backcross progeny suggests that a single genetic locus affects all three isozymes. Heterozygous embryos have only the maternal form of GPDH-3 until just before they hatch as first instar larvae. At this stage they have maternal and paternal GPDH-3 plus an intermediate band.This project was supported in part by National Institutes of Health research grant GM-15597.     

Polymorphisms in the human X-linked pyruvate dehydrogenase E1α gene

Summary Pyruvate dehydrogenase E1 deficiency is an X-chromosome-linked disorder, often with fatal consequences. We have searched for genetically useful polymorphisms in or near this gene. No restriction fragment length polymorphisms were detected using a battery of 36 different restriction enzymes and probing with a fulllength cDNA fragment, or two single-copy genomic fragments located within intron 8, and 15 kb 3 of the coding region, respectively. The chemical cleavage method was then applied to the detection of base changes in or near the gene. One polymorphism was found in exon 8 of the coding region. However, no base changes were detected in intron 3 or in the part of intron 8 covered by fragment gB2. Three blocks of microsatellite DNA containing variable numbers of CA-repeats were isolated from the 5 end of the gene and characterized. Length polymorphisms in these microsatellite DNAs were analysed using the polymerase chain reaction. Although the three loci are tightly linked, the polymorphisms appear not to be in disequilibrium, making them useful markers in linkage studies of the pyruvate dehydrogenase E1 gene. Of 31 females analysed 12 (39%) were heterozygous for at least one length polymorphism of the three (CA)_n alleles.     

Genetics and physiological expression of β-hydroxy acid dehydrogenase in Drosophila

A mutant Had ^nl was induced in Drosophila melanogaster and found to be deficient in -hydroxy acid dehydrogenase. This mutation was utilized to study the genetics and physiological expression of Had ⁺. Had⁺ was mapped to the X chromosome at 54.4 and seems to be the structural gene for the enzyme. Enzyme activity in male and female flies indicates that the gene shows both dosage compensation independent from dose effect and differential activity during ontogeny. Electrophoretic mobility data indicate that the enzyme is a dimer which forms by random association of subunits. The fact that the mutant shows no detrimental effect implies that the enzyme is dispensable, at least under laboratory conditions. The biological and technical implications of this gene-enzyme system are discussed.This research was sponsored by the Energy Research and Development Administration under contract with the Union Carbide Corporation. J. E. T. was a postdoctoral investigator supported by USPHS Fellowship No. 1-F02-GM53673-01 during a portion of this work.     

Upregulation of 11β-hydroxysteroid dehydrogenase 1 in lymphoid organs during inflammation in the rat

Glucocorticoids exert anti-inflammatory and immunomodulatory effects that may be regulated in part by the activities of the glucocorticoid-activating and -inactivating enzymes, 11β-hydroxysteroid dehydrogenase type 1 (11HSD1) and type 2 (11HSD2), respectively. Previous studies have demonstrated that inflammatory bowel diseases in humans and experimental animals upregulate 11HSD1 and downregulate 11HSD2. We investigated whether proinflammatory cytokines modulate colonic 11HSDs as well as whether lymphoid organs exhibit any 11HSD response to inflammation. Colon tissue explants exposed to tumor necrosis factor α exhibited an upregulation of 11HSD1 mRNA whereas interleukin 1β downregulated 11HSD2 mRNA. Experimental colitis induced by the intracolonic administration of 2,4,6-trinitrobenzenesulfonic acid stimulated 11HSD1 activity not only in the colon but also in mesenteric lymph nodes and the spleen. Analysis of mRNA for 11HSD1 in colon-draining lymph nodes and the spleen showed that inflammation upregulates the expression of this enzyme in mobile lymphoid cells similar to the intraepithelial and lamina propria leukocytes isolated from the colon. It is inferred that inflammation stimulates the reactivation of glucocorticoids in lymphoid organs and in gut-associated lymphoid tissue.     

The increase in activity of glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase in skeletal muscles of rats after subcutaneous administration of N,N′-dimethyl-para-phenylenediamine

Summary After subcutaneous administration of N,N-dimethyl-para-phenylenediamine (DPPD) in rats, a myogenic myopathy was produced in the skeletal muscles. In this communication, the results of the application of various histochemical techniques for the localization of oxidoreductases, transferases, hydrolases and isomerases and biochemical techniques for the estimation of activities of oxidoreductases in the experimental skeletal muscles are presented. The most striking result was the activity of glucose-6-phosphate dehydrogenase and 6-phosphogluconate dehydrogenase which increased dramatically during the early phase of the muscle disease. The increase in activity of the pentose phosphate shunt enzymes was the first pathological alteration and was present as early as 8 h after a single injection of DPPD. Histochemical techniques for demonstration of activity of both enzymes are therefore highly suited for the detection of minor diseases and the early onset of major diseases of the neuromuscular system. Some glycolytic enzymes as well as some enzymes of the aerobic part of the metabolism showed an early decrease or increase in activity indicating a metabolic imbalance in the muscle fibres. There were more fibres with an intermediate pattern of the energy yielding enzymes in the experimental muscle specimens then in specimens from the control groups. The activity of the catabolic hydrolytic enzymes was strongly increased in pathological muscles. The aerobic muscles were more vulnerable to DPPD than the anaerobic muscles.     

Xanthine dehydrogenase and aldehyde oxidase in chicken liver: Molecular identity?

Evidence is presented to suggest that in chick liver, xanthine dehydrogenase and aldehyde oxidase activities are associated with only one protein species. The results of SDS electrophoresis of the purified material indicate a subunit MW of 120 000.     

The physiological significance of 11β-hydroxysteroid dehydrogenase in the rat lung

We have examined the interconversion of cortisone (E) and cortisol (F) in rat lung homogenate and microsomal fraction and in the isolated rat lung perfused with Krebs bicarbonate solution containing 4.5% albumin. In the perfused lung the apparent K_m was 5.1 μM E and the V_max was 9nmol·g⁻¹ · min⁻¹. The ability of the lung to reduce E to F was enhanced both by 7 days prior exposure of the rat to an ambient temperature of 2°C and by starvation of the rat for 3 days. The activity was inhibited by adrenalectomy and castration of 7 days duration. Whereas little steroid oxidation occurred in the perfused lung, preparations of lung homogenatcs and microsomal fraction readily reduced or oxidised the 11-position of the corticoid molecule depending on the preponderance of either NADPH or NADP, respectively. We conclude, that the predominance of the reductive reaction in the whole rat lung under physiological conditions reflects the very active pentose-phosphate shunt in the lung, which produces NADPH. We suggest that this ability of the lung to activate E to F may exert a fine control over the arterial concentrtion of unbound, physiologically active, 11-hydroxylated steroid.     

The distribution of monoamine oxidase and α-glycerophosphate dehydrogenase in pig brain

Activities of the enzymes monoamine oxidase (EC 1.4.3.4), alpha-glycerophosphate dehydrogenase (EC 1.1.99.5) and cytochrome oxidase (EC 1.9.3.1) were determined in homogenates and in the mitochondrial fraction prepared from individual regions of pig brain. The variation in the activity of alpha-glycerophosphate dehydrogenase paralleled that of cytochrome oxidase, but this was not the case with monoamine oxidase. The differences in the activities of the enzymes among homogenates of the various regions of the brain persisted in mitochondria prepared from these homogenates. The purification of these three enzymes paralleled each other when mitochondria were prepared, suggesting that the three enzymes are bound to the same particles.     

A urine-concentrating defect in 11β-hydroxysteroid dehydrogenase type 2 null mice

In aldosterone target tissues, 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2) is coexpressed with mineralocorticoid receptors (MR) and protects the receptor from activation by glucocorticoids. Null mutations in the encoding gene, HSD11B2, cause apparent mineralocorticoid excess, in which hypertension is thought to reflect volume expansion secondary to sodium retention. Hsd11b2(-/-) mice are indeed hypertensive, but impaired natriuretic capacity is associated with significant volume contraction, suggestive of a urine concentrating defect. Water turnover and the urine concentrating response to a 24-h water deprivation challenge were therefore assessed in Hsd11b2(-/-) mice and controls. Hsd11b2(-/-) mice have a severe and progressive polyuric/polydipsic phenotype. In younger mice (～2 mo of age), polyuria was associated with decreased abundance of aqp2 and aqp3 mRNA. The expression of other genes involved in water transport (aqp4, slc14a2, and slc12a2) was not changed. The kidney was structurally normal, and the concentrating response to water deprivation was intact. In older Hsd11b2(-/-) mice (>6 mo), polyuria was associated with a severe atrophy of the renal medulla and downregulation of aqp2, aqp3, aqp4, slc14a2, and slc12a2. The concentrating response to water deprivation was impaired, and the natriuretic effect of the loop diuretic bumetanide was lost. In older Hsd11b2(-/-) mice, the V2 receptor agonist desmopressin did not restore full urine concentrating capacity. We find that Hsd11b2(-/-) mice develop nephrogenic diabetes insipidus. Gross changes to renal structure are observed, but these were probably secondary to sustained polyuria, rather than of developmental origin.     

Encapsulation of lactate dehydrogenase in carbon nanotube doped alginate–chitosan capsules

Alginate–chitosan shell–core (AC) capsules doped with carbon nanotubes (CNTs) were prepared for lactate dehydrogenase (LDH, EC 1.1.1.27) encapsulation to convert pyruvic acid to lactic acid coupling with the oxidation of NADH to NAD⁺. LDH was entrapped within the liquid core of the capsules and the CNTs were incorporated in the alginate or chitosan matrices or both. The physical properties of the capsules and the immobilized LDH activity were investigated. The AC capsules doped with CNTs showed better mechanical strength than that without CNTs. The LDH loading efficiency of the AC capsules with CNTs (10 mg/mL) doped in both the shell and the core was 30.7% higher than that without CNTs. The optimal pH value for the bioconversion catalyzed by immobilized LDH was 7.0, lower than that by free LDH (7.5). The optimal temperature was 35 °C for both immobilized and free LDH. Operational stability of the immobilized LDH was greatly improved by doping CNTs in AC capsules. The results showed that this method was efficient for enzyme encapsulation in the biotechnology applications.