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Increasing evidence has solidified the involvement of α-synuclein (α-Syn) and neurotoxins in the pathogenesis of Parkinson's disease (PD), suggesting a combination of genetic and environmental influences. 2,3,5,4′-Tetrahydroxystilbene-2-O-β-D-glucoside (TSG) is one of the main active components extracted from Polygonum multiflorum. The purpose of the present study was to investigate the effects of TSG on α-Syn aggregation, mitochondrial dysfunction, oxidative stress, and apoptosis in vitro. A53T mutant α-synuclein-transfected cells (A53T AS cells) plus MPP+ exposure were used as a complex cell model of PD. The expression of proteins was determined by Western blot assay. Flow cytometry was utilized to measure mitochondrial membrane potential and apoptosis. The results showed that MPP+ exposure for 24 h induced more severe damage in A53T AS cells than in vector control cells. Pretreatment of TSG for 24 h significantly increased the cell viability; decreased lactate dehydrogenase leakage; inhibited α-Syn over-expression and aggregation; elevated mitochondrial membrane potential; decreased reactive oxygen species, Bax/Bcl-2 ratio, and caspase-3 activity; and inhibited apoptosis in A53T AS cells exposed to MPP+. These results suggest that TSG may be an attractive candidate for PD therapy. [ABSTRACT FROM AUTHOR]

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Mutations in parkin ( PARK2) and Pink1 ( PARK6) are responsible for autosomal recessive forms of early onset Parkinson's disease (PD). Attributed to the failure of neurons to clear dysfunctional mitochondria, loss of gene expression leads to loss of nigrostriatal neurons. The Pink1/parkin pathway plays a role in the quality control mechanism aimed at eliminating defective mitochondria, and the failure of this mechanism results in a reduced lifespan and impaired locomotor ability, among other phenotypes. Inhibition of parkin or Pink1 through the induction of stable RNAi transgene in the Ddc-Gal4-expressing neurons results in such phenotypes to model PD. To further evaluate the effects of the overexpression of the Bcl-2 homologue Buffy, we analysed lifespan and climbing ability in both parkin-RNAi- and Pink1-RNAi-expressing flies. In addition, the effect of Buffy overexpression upon parkin-induced developmental eye defects was examined through GMR-Gal4-dependent expression. Curiously, Buffy overexpression produced very different effects: the parkin-induced phenotypes were enhanced, whereas the Pink1-enhanced phenotypes were suppressed. Interestingly, the overexpression of Buffy along with the inhibition of parkin in the neuron-rich eye results in the suppression of the developmental eye defects. [ABSTRACT FROM AUTHOR]

Mutations in High temperature requirement A2 (HtrA2), also designated PARK13, which lead to the loss of its protease activity, have been associated with Parkinson's disease (PD). HtrA2 is a mitochondrial protease that translocates to the cytosol upon the initiation of apoptosis where it participates in the abrogation of inhibitors of apoptosis (IAP) inhibition of caspases. Here, we demonstrate that the loss of the HtrA2 function in the dopaminergic neurons of Drosophila melanogaster results in PD-like phenotypes, and we attempt to restore the age-dependent loss in locomotor ability by co-expressing the sole pro-survival Bcl-2 homologue Buffy. The inhibition of HtrA2 in the dopaminergic neurons of Drosophila resulted in shortened lifespan and impaired climbing ability, and the overexpression of Buffy rescued the reduction in lifespan and the age-dependent loss of locomotor ability. In supportive experiments, the inhibition of HtrA2 in the Drosophila eye results in eye defects, marked by reduction in ommatidia number and increased disruption of the ommatidial array; phenotypes that are suppressed by the overexpression of Buffy. [ABSTRACT FROM AUTHOR]

Parkinsonian-pyramidal syndrome (PPS) is an early onset form of Parkinson's disease (PD) that shows degeneration of the extrapyramidal region of the brain to result in a severe form of PD. The toxic protein build-up has been implicated in the onset of PPS. Protein removal is mediated by an intracellular proteasome complex: an E3 ubiquitin ligase, the targeting component, is essential for function. FBXO7 encodes the F-box component of the SCF E3 ubiquitin ligase linked to familial forms of PPS. The Drosophila melanogaster homologue nutcracker ( ntc) and a binding partner, PI31, have been shown to be active in proteasome function. We show that altered expression of either ntc or PI31 in dopaminergic neurons leads to a decrease in longevity and locomotor ability, phenotypes both associated with models of PD. Furthermore, expression of ntc-RNAi in an established α-synuclein-dependent model of PD rescues the phenotypes of diminished longevity and locomotor control. [ABSTRACT FROM AUTHOR]

Increasing evidence suggests that motor rehabilitation may delay Parkinson's disease (PD) progression. Moreover, parallel treatments in animals up-regulate brain-derived neurotrophic factor (BDNF). Thus, we investigated the effect of a motor rehabilitation protocol on PD symptoms and BDNF serum levels. Motor rehabilitation training consisted of a cycle of 20 days/month of physiotherapy divided in 3 daily sessions. Clinical data were collected at the beginning, at the end, and at 90 days follow-up. BDNF serum levels were detected by ELISA at 0, 7, 14, 21, 30, and 90 days. The follow-up period had a duration of 60 days (T30-T90). The results showed that at the end of the treatment (day 30), an improvement in extrapyramidal signs (UPDRS III; UPDRS III - Gait and Balance items), motor (6 Minute Walking Test), and daily living activities (UPDRS II; PDQ-39) was observed. BDNF levels were increased at day 7 as compared with baseline. After that, no changes in BDNF were observed during the treatment and in the successive follow-up. This study demonstrates that motor rehabilitation training is able to ameliorate PD symptoms and to increase temporarily BDNF serum levels. The latter effect may potentially contribute to the therapeutic action. [ABSTRACT FROM AUTHOR]

The study of the genes that are related to the pathogenesis of Parkinson's disease (PD) will improve our understanding of the mechanisms that underlie the development of PD. α-Synuclein is a major protein component of Lewy bodies, which are characteristic structures of PD pathology. Mutations in α-synuclein are closely related to the early onset of autosomal dominant PD. Transgenic flies with mutant α-synuclein (A53T) display neurodegenerative changes that include movement dysfunctions and a loss of dopaminergic neurons in the brain. In the present study, we measured reactive oxygen species (ROS) levels in α-synuclein transgenic flies by monitoring the fluorescence levels of redox-sensitive indicators based on GFP (roGFP) in flies co-expressing roGFP and mutant α-synuclein. We found that the ROS levels were significantly increased in the mutant α-synuclein flies. The elevations in ROS levels were also proportionate to the behavioral disorders and the losses of dopaminergic neurons. We also found that CDDO-Me inhibited the increases in ROS levels in the A53T flies and improved the neurodegenerative changes by activating the Nrf2/antioxidant response element signaling pathway. Selective expression of the Nrf2 homologous gene cncC in the dopaminergic neurons effectively protected against the neurodegenerative phenotype of the A53T α-synuclein flies, compared to the flies that expressed cncC in all neurons. These results indicate that the reductions in oxidative stress that are mediated by the activation of the antioxidant signaling pathway can effectively attenuate the neurotoxicity caused by mutations in α-synuclein. [ABSTRACT FROM AUTHOR]

Previous studies have indicated that non-SMC condensin I complex, subunit D2 (NCAPD2), an important protein in chromosome condensation, gene polymorphisms are associated with Alzheimer's disease. But no study has shown the relationship between NCAPD2 polymorphisms and Parkinson's disease. Here, we conducted a case-control study to investigate the relationship between NCAPD2 polymorphisms and the risk of Parkinson's disease in a Han Chinese population. Two single nuclear polymorphisms (SNPs) of NCAPD2 (rs7311174 and rs2072374) showed significant p values ( p = 0.046 and p = 0.043, respectively) in 265 patients and 267 controls. Further analysis showed an effect of age and gender on the relationship between the two SNPs and the risk for Parkinson's disease. The A allele of rs7311174 and the T allele of rs2072374 were protective in the male patients ( p = 0.016 and p = 0.019, respectively). The frequencies of the T allele of rs7311174 and the C allele of rs2072374 were significantly associated with late-onset Parkinson's disease ( p = 0.048 and p = 0.044, respectively). This research demonstrates a positive relationship between the NCAPD2 gene and the risk for Parkinson's disease in a Han Chinese population and provides a potential genetic marker for sporadic Parkinson's disease. [ABSTRACT FROM AUTHOR]

Clinically, Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the development of tremors and rigidity that is found primarily in patients over the age of 50. At the cellular level, it is clear that the pathology of PD results from the progressive loss of dopaminergic neurons in the substantia nigra. Several lines of evidence have implicated oxidative stress as a contributing factor to the depletion of dopaminergic neurons in PD. Under conditions of oxidative stress, the neurotransmitter dopamine can be oxidized to form neurotoxic quinone and semiquinone products. While dopaquinones are known to be extremely reactive towards sulfhydryl groups of many cellular substrates, mounting evidence suggests that their toxic effects can be quenched by intrinsic antioxidant mechanisms (e.g., glutathione). However, to respond appropriately to differing levels of oxidative stress, cells require a mechanism to regulate an appropriate response. This manuscript proposes metallothionein as a major cellular sensor of oxidized dopamine stress and metallothionein-mediated Zn2+ mobilization as an effecter signal that is used by the cell to manage oxidized dopamine as an intrinsic neurotoxin. Cliniquement, la maladie de Parkinson (MP) est un trouble neurodégénératif caractérisé par le développement de tremblements et de rigidité musculaire, qui touche principalement les personnes de plus de 50 ans. Au niveau cellulaire, on sait que la pathologie de la MP est liée à la perte progressive de neurones dopaminergiques dans la substance noire. Plusieurs études ont clairement identifié le stress oxydatif comme un facteur contribuant à la dégénérescence des neurones dopaminergiques dans la MP. Dans des conditions de stress oxydatif, le neurotransmetteur dopamine peut s’oxyder pour former des quinones et des semiquinones neurotoxiques. On sait que les dopaquinones réagissent fortement aux groupements sulfhydryl de nombreux substrats cellulaires, mais de plus en plus de données autorisent à penser que leurs effets toxiques pourraient être amortis par des mécanismes antioxydants (ex. glutathion). Toutefois, pour répondre adéquatement aux divers niveaux de stress oxydatif, les cellules ont besoin d’un mécanisme de régulation. Le présent article présente la métallothionéine (MT) comme un capteur cellulaire majeur du stress induit par la dopamine oxydée, et la mobilisation du Zn2+ véhiculée par la MT comme un signal effecteur qui serait utilisé par la cellule pour traiter la dopamine oxydée comme une neurotoxine intrinsèque. [ABSTRACT FROM AUTHOR]

1,2,3,4-tetrahydroisoquinoline (TIQ) is endogenously present in the human brain, and some of its derivatives are thought to contribute to the induction of Parkinson's disease (PD)-like signs in rodents and primates. In contrast, the endogenous TIQ derivative 1-methyl-TIQ (1-MeTIQ) is reported to be neuroprotective. In the present study, we compared the effects of artificially modified 1-MeTIQ derivatives (loading an N -propyl, N -propenyl, N -propargyl, or N -butynyl group) on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD-like signs in mice. In a behavioral study, MPTP-induced bradykinesia was significantly decreased by all compounds. However, only 1-Me- N -propargyl-TIQ showed an inhibitory effect by blocking the MPTP-induced reduction in striatal dopamine content and the number of nigral tyrosine hydroxylase-positive cells. Western blot analysis showed that 1-Me- N -propargyl-TIQ and 1-Me- N -butynyl-TIQ potently prevented the MPTP-induced decrease in dopamine transporter expression, whereas 1-MeTIQ and 1-Me- N -propyl-TIQ did not. These results suggest that although loading an N -propargyl group on 1-MeTIQ clearly enhanced neuroprotective effects, other N -functional groups showed distinct pharmacological properties characteristic of their functional groups. Thus, the number of bonds and length of the N -functional group may contribute to the observed differences in effect.

Parkinson's disease (PD) is a neurodegenerative disease accompanied by a low expression level of cerebral hypoxia-inducible factor (HIF-1α). Hence, activating the hypoxia-signaling pathway may be a favorable therapeutic approach for curing PD. This study explored the efficacy of hydralazine, a well-known antihypertensive agent, for restoring the impaired HIF-1 signaling in PD, with the aid of 6-hydroxydopamine (6-OHDA)-exposed SH-SY5Y cells. The cytotoxicity of hydralazine and 6-OHDA on the SH-SY5Y cells were evaluated by MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] and apoptosis detection assays. The activities of malondialdehyde, nitric oxide (NO), ferric reducing antioxidant power (FRAP), and superoxide dismutase (SOD) were also measured. Expression levels of HIF-1α and its downstream genes at the protein level were assessed by Western blotting. Hydralazine showed no toxic effects on SH-SY5Y cells, at the concentration of ≤50 μmol/L. Hydralazine decreased the levels of apoptosis, malondialdehyde, and NO, and increased the activities of FRAP and SOD in cells exposed to 6-OHDA. Furthermore, hydralazine up-regulated the protein expression levels of HIF-1α, vascular endothelial growth factor, tyrosine hydroxylase, and dopamine transporter in the cells also exposed to 6-OHDA, by comparison with the cells exposed to 6-OHDA alone. In summary, hydralazine priming could attenuate the deleterious effects of 6-OHDA on SH-SY5Y cells by increasing cellular antioxidant capacity, as well as the protein levels of HIF-1α and its downstream target genes.

Molecular hydrogen (H 2 ) showed protection against various kinds of oxidative-stress-related diseases. First, it was reported that the mechanism of therapeutic effects of H 2 was antioxidative effect due to inhibition of the most cytotoxic reactive oxygen species, hydroxy radical (•OH). However, after chronic administration of H 2 in drinking water, oxidative-stress-induced nerve injury is significantly attenuated even in the absence of H 2 . It suggests indirect signaling of H 2 and gastrointestinal tract is involved. Indirect effects of H 2 could be tested by giving H 2 water only before nerve injury, as preconditioning. For example, preconditioning of H 2 for certain a period (∼7 days) in Parkinson's disease model mice shows significant neuroprotection. As the mechanism of indirect effect, H 2 in drinking water induces ghrelin production and release from the stomach via β1-adrenergic receptor stimulation. Released ghrelin circulates in the body, being transported across the blood-brain barrier, activates its receptor, growth-hormone secretagogue receptor. H 2 -induced upregulation of ghrelin mRNA is also shown in ghrelin-producing cell line, SG-1. These observations help with understanding the chronic effects of H 2 and raise intriguing preventive and therapeutic options using H 2 .

The presence of postganglionic sympathetic denervation is well established in Parkinson's disease (PD). Denervation at cardiac and blood vessel sites may lead to abnormal cardiovascular and hemodynamic responses to exercise. The aim of the present investigation was to examine how heart rate (HR) and hemodynamics are affected by an exercise test in PD patients without orthostatic hypotension. Thirty individuals without orthostatic hypotension, 14 individuals with PD, and 16 age-matched healthy controls performed an exercise test on a cycle ergometer. Heart rate, blood pressure, and other hemodynamic variables were measured in a fasted state during supine rest, active standing, exercise, and supine recovery. Peak HR and percent of age-predicted maximum HR (HR max ) achieved were significantly blunted in PD ( p < 0.05, p < 0.01). HR remained significantly elevated in PD during recovery compared with controls ( p = 0.03, p < 0.05). Systolic, diastolic, and mean arterial pressures were significantly lower at multiple time-points during active standing in PD compared with controls. Systemic vascular resistance index (SVRI) decreased significantly at the onset of exercise in PD, and remained significantly lower during exercise and the first minute of supine recovery. End diastolic volume index (EDVI) was significantly lower in PD during supine rest and recovery. Our results indicate for the first time that normal hemodynamics are disrupted during orthostatic stress and exercise in PD. Despite significant differences in EDVI at rest and during recovery, and SVRI during exercise, cardiac index was unaffected. Our finding of significantly blunted HR max and HR recovery in PD patients has substantial implications for exercise prescription and recovery guidelines.

Although the pathogenesis of Parkinson's disease (PD) remains unclear, mutations in leucine-rich repeat kinase 2 (Lrrk2) are among the major causes of familial PD. Most of these mutations disrupt Lrrk2 kinase and (or) GTPase domain function, resulting in neuronal degeneration. However, the signal pathways underlying Lrrk2-induced neuronal degeneration are not fully understood. There is an expanding body of evidence that suggests a link between Lrrk2 function and MAP kinase (MAPK) cascades. To further investigate this link in vivo, genetic RNAi screens of the MAPK pathways were performed in a Drosophila model to identify genetic modifier(s) that can suppress G2019S-Lrrk2-induced PD-like phenotypes. The results revealed that the knockdown of hemipterous (hep, or JNKK) increased fly survival time, improved locomotor function, and reduced loss of dopaminergic neurons in G2019S-Lrrk2 transgenic flies. Expression of the dominant-negative allele of JNK (JNK-DN), a kinase that is downstream of hep in G2019S-Lrrk2 transgenic flies, elicited a similar effect. Moreover, treatment with the JNK inhibitor SP600125 partially reversed the G2019S-Lrrk2-induced loss of dopaminergic neurons. These results indicate that the hep pathway plays an important role in Lrrk2-linked Parkinsonism in flies. These studies provide new insights into the molecular mechanisms underlying Lrrk2-linked PD pathogenesis and aid in identifying potential therapeutic targets.