Differential Alterations in Metabolism and Proteolysis-Related Proteins in Human Parkinson's Disease Substantia Nigra.

Parkinson's disease is the most common neurodegenerative disorder after Alzheimer's disease, with the majority of cases being sporadic or "idiopathic". The aetiology of the sporadic form is still unknown, but there is a broad consensus that Parkinson's disease involves multiple pathways. In previous human post-mortem studies investigating substantia nigra of parkinsonian subjects, gene expression alterations in various metabolic pathways including protein folding, trafficking, aggregation, ubiquitination and oxidative stress were found. These studies revealed transcriptomic dysregulation of various genes, amongst others Skp1A and PSMC4 (part of ubiquitin-proteasome system), HSC70 (belonging to the chaperone family) and ALDH1A1 (an enzyme involved in the catabolism of dopamine). To investigate whether these alterations are manifested at the protein level, we performed immunohistochemical analysis in the substantia nigra of Parkinson's disease and compared them to Alzheimer's disease and non-neurological post-mortem controls. We were able to confirm cell-specific reductions in the protein content of ALHD1A1 and Skp1A in the dopaminergic neurons of the substantia nigra of Parkinsonian patients compared to Alzheimer's and control subjects. Furthermore, we observed particular distribution for HSC70 and PSMC4 in the cytoplasm and accumulation within Lewy body in the dopaminergic neurons of the substantia nigra in Parkinson patients. These findings, together with previous evidence, suggest a malfunction of the ubiquitin-proteasome and possible autophagy systems as major players in protein misfolding and aggregation in Parkinson's disease. Nevertheless, this needs further proof, possibly with trajectory time line.

DJ-1 deficiency triggers microglia sensitivity to dopamine toward a pro-inflammatory phenotype that is attenuated by rasagiline.

DJ-1 is an oxidative stress sensor that localizes to the mitochondria when the cell is exposed to oxidative stress. DJ-1 mutations that result in gene deficiency are linked to increased risk of Parkinson's disease (PD). Activation of microglial stress conditions that are linked to PD may result in neuronal death. We postulated that DJ-1 deficiency may increase microglial neurotoxicity. We found that down-regulation of DJ-1 in microglia using an shRNA approach increased cell sensitivity to dopamine as measured by secreted pro-inflammatory cytokines such as IL-1ß and IL-6. Furthermore, we discovered that DJ-1-deficient microglia had increased monoamine oxidase activity that resulted in elevation of intracellular reactive oxygen species and nitric oxide leading to increased dopaminergic neurotoxicity. Rasagaline, a monoamine oxidase inhibitor approved for treatment of PD, reduced the microglial pro-inflammatory phenotype and significantly reduced neurotoxicity. Moreover, we discovered that DJ-1-deficient microglia have reduced expression of triggering receptor expressed on myeloid cells 2 (TREM2), previously suggested as a risk factor for pro-inflammation in neurodegenerative diseases. Further studies of DJ-1-mediated cellular pathways in microglia may contribute useful insights into the development of PD providing future avenues for therapeutic intervention

Effects of novel neuroprotective and neurorestorative multifunctional drugs on iron chelation and glucose metabolism.

Iron accumulation and iron-related oxidative stress are involved in several pathological conditions and provide a rationale for the development of iron chelators as novel promising therapeutic strategies. Thus, we have recently synthesized multifunctional non-toxic, brain permeable iron chelating compounds, M30 and HLA20, possessing the neuroprotective N-propargyl moiety of the anti-Parkinsonian drug, monoamine oxidase (MAO)-B inhibitor, rasagiline and the antioxidant-iron chelating moiety of an 8-hydroxyquinoline derivative of the iron chelator, VK28. Here, we examined the hepatic regulatory effects of these novel compounds using two experimental approaches: chelation activity and glucose metabolism parameters. The present study demonstrated that M30 and HLA20 significantly decreased intracellular iron content and reduced ferritin expression levels in iron-loaded hepatoma Hep3B cells. In electron microscopy analysis, M30 was shown to reduce the electron-dense deposits of siderosomes by ~30 %, as well as down-regulate cytosolic ferritin particles observed in iron-overloaded cells. In vivo studies demonstrated that M30 administration (1 mg/kg, P.O. three times a week) reduced hepatic ferritin levels; increased hepatic insulin receptor and glucose transporter-1 levels and improved glucose tolerance in C57BL/6 mice and in a mouse model of type-2 diabetes, the ob/ob (leptin(-/-)). The results clearly indicate that the novel multifunctional drugs, especially M30, display significant capacity of chelating intracellular iron and regulating glucose metabolism parameters. Such effects can have therapeutic significance in conditions with abnormal local or systemic iron metabolism, including neurological diseases.

In the rush for green gold: Can green tea delay age-progressive brain neurodegeneration?

It is evident that brain aging engages changes in biological systems linked to synaptic function and cell metabolism and in the capacity to cope with different stresses that are either idiopathic in nature, or subject to environmental insults. In a substantial segment of the aging population there is a pathological transition to cognitive and behavioral dysfunction and thus, age constitutes the primary risk factor for Alzheimer's disease and other neurodegenerative disorders. To address the etiological complexity of aging and age-associated conditions, a new paradigm gaining increasing acceptance considers the use of multi-targeted ligands or combination of drugs to modulate several targets at once. During the past years intensive efforts are dedicated to the implementation of life style habits such as exercise and dietary compounds/supplements in combination with symptomatic treatment drugs to improve age-related cognitive decline and to attenuate motor and neurological dysfunction in neurodegenerative diseases. The catechin polyphenols constituents of green tea, which were for long time regarded merely as dietary antioxidants, have caught our and other scientist's attention because of their diverse pharmacological activities, which have been allied to a possible beneficial action on brain health. This review will elaborate on the impact of nutritional supplementation on brain function in general, and provide a compilation of the most updated literature on epidemiology, clinical and animal studies with green tea polyphenols in age-associated cognitive decline and in fighting neurodegenerative diseases. To conclude, a future perspective on the utility and assigned patents with green tea constituents will be presented.

A molecular signature in blood identifies early Parkinson's disease.

BACKGROUND: The search for biomarkers in Parkinson's disease (PD) is crucial to identify the disease early and monitor the effectiveness of neuroprotective therapies. We aim to assess whether a gene signature could be detected in blood from early/mild PD patients that could support the diagnosis of early PD, focusing on genes found particularly altered in the substantia nigra of sporadic PD. RESULTS: The transcriptional expression of seven selected genes was examined in blood samples from 62 early stage PD patients and 64 healthy age-matched controls. Stepwise multivariate logistic regression analysis identified five genes as optimal predictors of PD: p19 S-phase kinase-associated protein 1A (odds ratio [OR] 0.73; 95% confidence interval [CI] 0.60-0.90), huntingtin interacting protein-2 (OR 1.32; CI 1.08-1.61), aldehyde dehydrogenase family 1 subfamily A1 (OR 0.86; 95% CI 0.75-0.99), 19 S proteasomal protein PSMC4 (OR 0.73; 95% CI 0.60-0.89) and heat shock 70-kDa protein 8 (OR 1.39; 95% CI 1.14-1.70). At a 0.5 cut-off the gene panel yielded a sensitivity and specificity in detecting PD of 90.3 and 89.1 respectively and the area under the receiving operating curve (ROC AUC) was 0.96. The performance of the five-gene classifier on the de novo PD individuals alone composing the early PD cohort (n = 38), resulted in a similar ROC with an AUC of 0.95, indicating the stability of the model and also, that patient medication had no significant effect on the predictive probability (PP) of the classifier for PD risk. The predictive ability of the model was validated in an independent cohort of 30 patients at advanced stage of PD, classifying correctly all cases as PD (100% sensitivity). Notably, the nominal average value of the PP for PD (0.95 (SD = 0.09)) in this cohort was higher than that of the early PD group (0.83 (SD = 0.22)), suggesting a potential for the model to assess disease severity. Lastly, the gene panel fully discriminated between PD and Alzheimer's disease (n = 29). CONCLUSIONS: The findings provide evidence on the ability of a five-gene panel to diagnose early/mild PD, with a possible diagnostic value for detection of asymptomatic PD before overt expression of the disorder.

From anti-Parkinson's drug rasagiline to novel multitarget iron chelators with acetylcholinesterase and monoamine oxidase inhibitory and neuroprotective properties for Alzheimer's disease.

Alzheimer's disease (AD) is a multifactorial syndrome involving a complex array of different, while related, factors in its progression. Accordingly, novel approaches that can simultaneously modulate several disease-related targets hold great promise for the effective treatment of AD. This review describes the development of novel hybrid molecules with multimodal activity, including: i) M30, the brain permeable selective monoamine oxidase (MAO)-A and -B inhibitor with chelating and neuroprotective activity; ii) HLA20, a brain permeable metal chelator with neuroprotective activity; iii) HLA20A, an acetylcholinesterase (AChE) inhibitor with site-activated chelating and neuroprotective activity; iv) M30D, an AChE and MAO-A and -B inhibitor with site-activated chelating and neuroprotective activity; and v) analogs of the neuroprotective aminoacid peptide, NAPVSIPQ. HLA20A and M30D act as pro-chelators and can be activated to liberate their respective active chelators HLA20 and M30 through pseudo inhibition of AChE. We first discuss the knowledge and structure-based strategy for the rational design of these novel compounds. Then, we review our recent studies on these drug candidates, regarding their wide range in vitro and in vivo activities, with emphasis on antioxidant-chelating potency and AchE and MAO-A and -B inhibitory activity, as well as neuroprotective/neurorescue effects. Finally, we discuss the diverse molecular mechanisms of action of these compounds with relevance to AD, including modulation of amyloid-ß and amyloid-ß protein precursor expression/processing; induction of cell cycle arrest; inhibition of neuronal death markers; and upregulation of neurotrophic factors, as well as activation of protein kinase signaling pathways.

Genetic reduction of the E3 ubiquitin ligase element, SKP1A and environmental manipulation to emulate cardinal features of Parkinson's disease.

AIMS: To assess whether reduction of Skp1 will increase the vulnerability of dopaminergic neurons to genetic/environmental factors known to play a role in the pathological process of PD. METHODS: Short hairpin RNA lentiviruses infection of substantia nigra (SN)-derived cell-line (SN4741) and mice intranigral injection. RESULTS: We have knocked down the expression of SKP1A, an E3 ubiquitin ligase element, found significantly decreased in human SN in patients with PD. The deficiency of SKP1A in SN4741 cells closely recapitulated cardinal features of the dopamine (DA) neuron pathology of human PD, such as decreased expression of DA phenotypic markers and cell cycle aberrations. Moreover, the knocked down cells displayed a lethal phenotype in differentiated cells exhibiting proteinaceous round inclusions, which were almost identical in composition to human Lewy bodies. Knock down of SKP1A rendered SN4741 cells especially sensitive to genetic reduction of the DA metabolizing enzyme, aldehyde dehydrogenase 1 and exposure to external Stressors implicated in PD pathology. CONCLUSION: Future studies should contemplate intrinsic and environmental manipulations in Skp1-deficient animals to emulate the motor and non-motor disabilities, the progressive nature of PD, and striatal-nigral and adjacent areas pathology. This model may provide a reliable "platform" to develop new therapeutic interventions for PD.

Molecular mechanisms of the neuroprotective/neurorescue action of multi-target green tea polyphenols.

Mounting evidence suggests that lifestyle factors, especially nutrition are essential factor for healthy ageing. However, as a result of the increase in life expectance, neurodegenerative diseases like Alzheimer's and Parkinson's (AD and PD, respectively) are becoming an increasing burden, as aging is their main risk factor. Brain aging and neurodegenerative diseases of the elderly are characterized by oxidative damage, dysregulation of redox metals homeostasis and inflammation. Thus, it is not surprising that a large amount of drugs/agents in therapeutic use for these conditions are antioxidants/metal complexing, bioenergetic and anti-inflammatory agents. Natural plant polyphenols (flavonoids and non-flavonoids) are the most abundant antioxidants in the diet and as such, are ideal nutraceuticals for neutralizing stress-induced free radicals and inflammation. Human epidemiological and new animal data suggest that green and black flavonoids named catechins, may help protecting the aging brain and reduce the incidence of dementia, AD and PD. This review will present salient features of the beneficial multi-pharmacological actions of black and green tea polyphenols in aging and neurodegeneration, and speculate on their potential in drug combination to target distinct pathologies as a therapeutic disease modification approach.

Targeting SKP1, an ubiquitin E3 ligase component found decreased in sporadic Parkinson's disease.

Microarray-derived transcriptomic studies in human substantia nigra pars compacta (SNpc) samples from sporadic Parkinson's disease (SPD) cases have opened an avenue to concentrate on potential gene intersections or cross-talks along the dopaminergic (DAergic) neurodegenerative cascade in SPD. One emerging gene candidate identified by our group was SKP1A (p19, S-phase kinase-associated protein 1A), found significantly decreased in the SNpc. It is part of the SCF (Skp1, Cullin 1, F-box protein) complex, the largest class of sophisticated ubiquitin-proteasome/E3 ligases, and can directly interact with Fbxo7, a gene defective in PARK15-linked PD. In vitro target validation by viral-mediated RNA interference revealed that the deficiency of Skp1 in a mouse SN-derived DAergic neuronal cell line potentiated the damage caused by exogenous insults implicated in PD pathology and caused the death of neurons undergoing differentiation, which developed Lewy body-like, α-synuclein-positive inclusions preceding cell death. Furthermore, recent animal studies show that site-directed intranigral stereotaxic injections of lentiviruses targeting SKP1A induce pathological and behavioral deficits in mice, supporting a significant role of Skp1 in SN DAergic neuronal survival in SPD. Thus, strategies aimed at increasing the activity or content of Skp1 may represent a novel therapeutic approach that has the potential to treat PD.

Neuroprotective profile of the multitarget drug rasagiline in Parkinson's disease.

Monoamine oxidase (MAO) inhibitors were reported to have therapeutic value in several common neurodegenerative conditions owed to their diverse pharmacological functions in neuron survival. Rasagiline (N-propargyl-1-(R)-aminoindan) is a novel, highly potent irreversible MAO-B inhibitor in the treatment of Parkinson's disease (PD). It has been demonstrated to be neuroprotective in PD model systems by preventing the formation of reactive oxygen species derived from prevention of derived from oxidation of dopamine by MAO-B and via an antiapoptotic action, which appears to be independent of MAO-B inhibition and related to its embedded N-propargyl moiety. This review reflects on earlier and present evidence supporting a role for rasagiline as a neuroprotective molecule in the treatment of PD.

Understanding the broad-spectrum neuroprotective action profile of green tea polyphenols in aging and neurodegenerative diseases.

During the last century, the world population has shown a staggering increase in its proportion of elderly members and thus, neurodegenerative diseases like Alzheimer's and Parkinson's diseases (AD and PD, respectively) are becoming an increasing burden. Brain aging and neurodegenerative diseases of the elderly are characterized by oxidative damage, dysregulation of redox metals homeostasis and inflammation, supporting a therapeutic use of antioxidants. Natural plant polyphenols (flavonoids and non-flavonoids) are the most abundant antioxidants in the diet and as such, are ideal nutraceuticals for neutralizing stress-induced free radicals and inflammation. Human epidemiological and new animal data suggest that green and black tea drinking (enriched in a class of flavonoids named catechins) may help protecting the aging brain and reduce the incidence of dementia, AD, and PD. Mechanistic studies on the neuroprotective/neuroregenerative effects of green tea catechins revealed that they act not only as antioxidants metal chelators, but also as modulators of intracellular neuronal signaling and metabolism, cell survival/death genes, and mitochondrial function. Thus, these dietary compounds are receiving significant attention as therapeutic multifunctional cytoprotective agents that simultaneously manipulate various brain targets. The scope of this review is to assess and put into perspective salient features of the beneficial brain action of natural, non-toxic green tea catechins in aging-impaired cognition and neurodegenerative diseases and to discuss a scenario concerning their potential, in drug combination, to target distinct pathologies, in the quest for a disease modifying therapy.

PGC-1α, a potential therapeutic target for early intervention in Parkinson's disease.

Parkinson's disease affects 5 million people worldwide, but the molecular mechanisms underlying its pathogenesis are still unclear. Here, we report a genome-wide meta-analysis of gene sets (groups of genes that encode the same biological pathway or process) in 410 samples from patients with symptomatic Parkinson's and subclinical disease and healthy controls. We analyzed 6.8 million raw data points from nine genome-wide expression studies, and 185 laser-captured human dopaminergic neuron and substantia nigra transcriptomes, followed by two-stage replication on three platforms. We found 10 gene sets with previously unknown associations with Parkinson's disease. These gene sets pinpoint defects in mitochondrial electron transport, glucose utilization, and glucose sensing and reveal that they occur early in disease pathogenesis. Genes controlling cellular bioenergetics that are expressed in response to peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) are underexpressed in Parkinson's disease patients. Activation of PGC-1α results in increased expression of nuclear-encoded subunits of the mitochondrial respiratory chain and blocks the dopaminergic neuron loss induced by mutant α-synuclein or the pesticide rotenone in cellular disease models. Our systems biology analysis of Parkinson's disease identifies PGC-1α as a potential therapeutic target for early intervention.

The novel multifunctional, iron-chelating drugs M30 and HLA20 protect pancreatic beta-cell lines from oxidative stress damage.

Increasing evidence suggests that oxidative stress (OS)-induced pancreatic beta-cell impairments is involved in diabetes and diabetic complications. Our group has recently synthesized two multifunctional nontoxic, lipophilic, iron-chelating drugs, 5-{N-methyl-N-propargylaminomethyl}-8-hydroxyquinoline (M30) and 5-{4-propargylpiperazin-1-ylmethyl}-8-hydroxyquinoline (HLA20), for the treatment of various OS-mediated pathogeneses. These compounds contain the N-propargylamine cytoprotective moiety of the antiparkinsonian drug rasagiline (Azilect) and the iron-complexing component 8-hydroxyquinoline. The aim of this research was to evaluate the protective effect of the multifunctional iron-chelating drugs on rat insulin-producing pancreatic beta-cells (INS-1E and RINm) against OS-induced cytotoxicity. We found that M30 and HLA20 markedly and dose-dependently inhibited H(2)O(2)-induced cytotoxicity, associated with decreased intracellular reactive oxygen species formation and increased catalase activity. In accordance, the catalase inhibitor 3-amino-1,2,4-triazol blocked the protective action of M30 against H(2)O(2)-induced damage. Both compounds significantly increased the levels of the iron-responsive protein transferrin receptor indicating their iron-chelating effect. Further mechanistic studies showed that M30 and HLA20 attenuated H(2)O(2)-induced mitochondrial membrane potential loss, decreased the release of cytochrome c into the cytoplasm, and inhibited the activation of caspase-3, suggesting that these drugs may produce cytoprotective effects via the preservation of mitochondrial function. These results indicate that the novel drugs, M30 and HLA20 display significant cytoprotective activity against OS-induced cytotoxicity in insulin producing beta-cells, which might be of therapeutic use in the treatment of diabetes mellitus.

Low dosage of rasagiline and epigallocatechin gallate synergistically restored the nigrostriatal axis in MPTP-induced parkinsonism.

BACKGROUND: The anti-Parkinson monoamine oxidase B inhibitor rasagiline appears to be the first neuroprotective disease-modifying therapy in early-stage Parkinson's disease (PD). OBJECTIVE: Using a polypharmacy paradigm, we tested whether the distinct neuroprotective pharmacological profile of rasagiline would complement that of (-)-epigallocatechin-3-gallate (EGCG), the main antioxidant/iron chelator polyphenol constituent of green tea, and restore the neuronal loss and molecular targets damaged in animal parkinsonism. METHODS/RESULTS: We show by high-performance liquid chromatography, immunohistochemistry and Western blot analyses that the combination of rasagiline and EGCG, at subliminal doses which have no profound protective effect, acts synergistically to restore the nigrostriatal axis in N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice. A detailed analysis revealed a complementary action of these drugs, differentially acting at MPTP-injured molecules/targets in the substantia nigra (SN): induction of brain-derived neurotrophic factor by rasagiline, increased membranal levels of the protein kinase C alpha-isoform by EGCG and a synergistic replenishment of their downstream effector, the serine/threonine kinase Akt/protein kinase B, suggesting that this kinase might represent one point of convergence of the distinct mechanisms of action of the drug cocktail. CONCLUSION: These results provide molecular evidence that activation of multiple brain targets by the combination of rasagiline and EGCG may synergistically contribute to the rescue of the dopamine neurons in the SN and replenishment of striatal dopamine. This may have important implications for rasagiline-treated PD patients who could further benefit from an adjunct administration of EGCG.

Silencing/overexpressing selected genes as a model of sporadic Parkinson's disease.

BACKGROUND: High-throughput gene-based platform studies in human postmortem substantia nigra (SN) from sporadic Parkinson's disease (PD) cases have revealed significant dysregulation of genes involved in biological processes linked to previously established neurodegenerative mechanisms in both sporadic and hereditary PD. OBJECTIVE: Our study aimed to develop a new genetic model of PD by modulating the expression of single genes that were found to be most significantly affected in SN of sporadic PD. METHODS: SN-derived cell line (SN4741 cells) was infected with short hairpin RNA lentiviruses carrying different gene-specific sequences. RESULTS: Silencing of the E3 ligase ubiquitin SKP1A resulted in a decline in the expression of dopaminergic phenotypic markers together with progression into an aberrant cell cycle and death. Furthermore, added knockout of the dopamine-metabolizing enzyme aldehyde dehydrogenase, found almost absent in sporadic PD SN pars compacta, exacerbated the vulnerability of SKP1A-silenced neurons to MPP(+) and neurotrophin deprivation. CONCLUSION: Future studies should focus on a careful consideration of crucial dopaminergic gene network interactions as emerged from human sporadic PD, which will serve as a basis for the development of a slowly progressive genetic animal model of sporadic PD, with the potential of evaluating drugs with 'disease-modifying activity'.

Biomarkers for prediction and targeted prevention of Alzheimer's and Parkinson's diseases: evaluation of drug clinical efficacy.

Neurodegenerative diseases like Parkinson's disease (PD) and Alzheimer's disease (AD) are considered disorders of multifactorial origin, inevitably progressive and having a long preclinical period. Therefore, the availability of biological markers or biomarkers (BMs) for early disease diagnosis will impact the management of AD and PD in several dimensions; it will 1) help to capture high-risk individuals before symptoms develop, a stage where prevention efforts might be expected to have their greatest impact; 2) provide a measure of disease progression that can be evaluated objectively, while clinical measures are much less accurate; 3) help to discriminate between true AD or PD and other causes of a similar clinical syndrome; 4) delineate pathophysiological processes responsible for the disease; 5) determine the clinical efficacy of novel, disease-modifying (neuroprotective) strategies. In the long run the availability of reliable BMs will significantly advance the research and therapeutics of AD and PD.

A sporadic Parkinson disease model via silencing of the ubiquitin-proteasome/E3 ligase component SKP1A.

The aim of this study was to develop a new model of sporadic Parkinson disease (PD) based on silencing of the SKP1A gene, a component of the ubiquitin-proteasome/E3 ligase complex, Skp1, Cullin 1, F-box protein, which was found to be highly decreased in the substantia nigra of sporadic PD patients. Initially, an embryonic mouse substantia nigra-derived cell line (SN4741 cells) was infected with short hairpin RNA lentiviruses encoding the murine transcript of the SKP1A gene or with scrambled vector. SKP1A silencing resulted in increased susceptibility to neuronal damages induced by the parkinsonism-inducing neurotoxin 1-methyl-4-phenylpyridinium ion and serum starvation, in parallel with a decline in the expression of the dopaminergic markers, dopamine transporter and vesicular monoamine transporter-2. SKP1A-deficient cells presented a delay in completion of the cell cycle and the inability to arrest at the G(0)/G(1) phase when induced to differentiate. Instead, the cells progressed through S phase, developing rounded aggregates with characteristics of aggresomes including immunoreactivity for gamma-tubulin, alpha-synuclein, ubiquitin, tyrosine hydroxylase, Hsc-70 (70-kDa heat shock cognate protein), and proteasome subunit, and culminating in a lethal phenotype. Conversely, stably enforced expression of wild type SKP1A duplicated the survival index of naïve SN4741 cells under proteasomal inhibition injury, suggesting a new structural role of SKP1 in dopaminergic neuronal function, besides its E3 ligase activity. These results link, for the first time, SKP1 to dopamine neuronal function and survival, suggesting an essential role in sporadic PD. In summary, this new model has reproduced to a significant extent the molecular alterations described in sporadic PD at the cellular level, implicating Skp1 as a potential modifier in sporadic PD neurodegeneration.

Biomarkers for evaluation of clinical efficacy of multipotential neuroprotective drugs for Alzheimer's and Parkinson's diseases.

During the last century, the world population has shown a staggering increase in its proportion of elderly members and thus neurodegenerative diseases like Alzheimer's disease (AD) and Parkinson's disease (PD), respectively, are becoming an increasing burden on society. Among the diverse, significant challenges facing clinicians, is the improvement of diagnostic measures to detect early and subtle symptoms, a phase in which prevention efforts might be expected to have their greatest impact and provide a measure of disease progression that can be evaluated during the course of drug treatment. At present, clinical diagnosis of AD and PD is based on a constellation of symptoms and manifestations, although the disease originated several years earlier. Given the multiple etiological nature of AD and PD, it is reasonable to assume that the initial causative pathobiological processes may differ between the affected individuals. Therefore, the availability of biological markers or biomarkers will help not only early disease diagnosis, but also delineate the pathological mechanisms more definitively and reliably than the traditional cognitive and neurological phenotypes. In the current article, we review the literature on biochemical, genetic, and neuroimaging biomarkers and discuss their predictive value as indicative for disease vulnerability to detect individuals at risk for PD and AD, and to determine the clinical efficacy of novel, disease-modifying (neuroprotective) strategies.

Modeling sporadic Parkinson's disease by silencing the ubiquitin E3 ligase component, SKP1A.

Large-scale transcriptomics analysis of gene expression profile of sporadic Parkinson's disease (PD) substantia nigra (SN) has identified a number of differentially expressed genes participating in the neurotoxic cascade of DA neurons death, in particular those related to handling of proteins, dopaminergic transmission and iron metabolism. One of them, SKP1A (p19, S-phase kinase-associated protein 1A), an essential component of the ubiquitin-E3 ligase Skp1, Cullin 1, F-box protein (SCF) complex, has been found to be significantly decreased in the SN pars compacta of post-mortem parkinsonian brains. Recently, a new genetic cell model of sporadic PD was developed by knocking-down SKP1A in SN-derived cell-line infected with short hairpin RNA lentiviruses. SKP1A deficiency resulted in increased susceptibility to cell death and a decline in the expression of dopaminergic phenotypic markers. SKP1A-silenced cells were unable to arrest at G(0)/G(1,) when induced to differentiate, entering into an aberrant cell cycle and progressive death. During this process the cells developed rounded aggregates with characteristics of LB-like inclusions (aggresomes) including immunoreactivity for gamma-tubulin, alpha-synuclein, ubiquitin, tyrosine hydroxylase, Hsc-70 and proteasome subunit. In conclusion, future studies should focus on a careful consideration of crucial dopaminergic interacting genes, as emerged from human sporadic PD, which will serve as a basis for the development of a slowly progressive genetic animal model of sporadic PD, with the potential of evaluating drugs with "disease modifying activity".

Simultaneous manipulation of multiple brain targets by green tea catechins: a potential neuroprotective strategy for Alzheimer and Parkinson diseases.

Current therapeutic approaches for Alzheimer and Parkinson disease (AD and PD, respectively) are merely symptomatic, intended for the treatment of symptoms, but offer only partial benefit, without any disease-modifying activity. Novel promising strategies suggest the use of antiinflammatory drugs, antioxidants, iron-complexing molecules, neurotrophic factor delivery, inhibitors of the amyloid precursor protein (APP)-processing secretases, gamma and beta (that generate the amyloid-beta peptides, Abeta), anti-Abeta aggregation molecules, the interference with lipid cholesterol metabolism and naturally occurring plant flavonoids to potentially reverse the course of the diseases. Human epidemiological and new animal data suggest that tea drinking may decrease the incidence of dementia, AD, and PD. In particular, its main catechin polyphenol constituent (-)-epigallocatechin-3-gallate (EGCG) has been shown to exert neuroprotective/neurorescue activities in a wide array of cellular and animal models of neurological disorders. In the current article, we review the literature on the impact of the multimodal activities of green tea polyphenols and their neuroprotective effect on AD and PD.