Parkinson Disease: Huang Z

Halkias IA, Haq I, Huang Z, Fernandez HH. · Department of Neurology, University of Florida, Gainesville, Florida 32608, USA. · Drugs Aging. · Pubmed #17432922 No free full text.

Abstract: Levodopa is available in three forms: immediate-release, orally disintegrating and sustained-release tablets. Levodopa is metabolised in the gastrointestinal tract, kidney and liver by aromatic acid dopa decarboxylase using pyridoxine as a cofactor. Approximately 70-80% of the dose is eliminated in the urine. Central conversion of levodopa to dopamine likely occurs at surviving dopaminergic terminals and at serotonergic and adrenergic nerve terminals that contain decarboxylase. Dopamine is metabolised by catechol-O-methyltransferase and monoamine oxidase. The major metabolites of dopamine are homovanillic acid and dihydroxyphenylacetic acid.Levodopa remains the most efficacious pharmacological treatment for the symptoms of Parkinson's disease (PD). Results of current levodopa trials suggest that treatment with levodopa at the onset of disease provides superior motor and functional control compared with dopamine receptor agonists. Moreover, levodopa is generally better tolerated with a lower incidence of gastrointestinal and neuropsychiatric adverse effects. The debate over the role of levodopa in the treatment of PD is fuelled by the results of in vitro studies that show generation of free radicals by levodopa and its toxic effects on cell cultures. Levodopa has also consistently been shown to produce motor fluctuations (in particular dyskinesias) sooner than has been observed in PD patients, especially younger patients, given dopamine agonists initially. However, the cumulative body of knowledge thus far does not show definitive evidence that levodopa is neurotoxic to parkinsonian patients.In older PD patients with lesser risk of motor fluctuations, levodopa may be used initially, and perhaps solely, in demented PD patients and those at higher risk of developing neuropsychiatric adverse effects. In young parkinsonian patients with mild motor dysfunction, use of levodopa may be delayed or the dosage minimised. However, because of levodopa's superior efficacy, when a rapid and sustained symptomatic improvement is required because of significant motor disability, levodopa may be used as the first-line agent regardless of age.

Huang Z, de la Fuente-Fernández R, Stoessl AJ. · Pacific Parkinson's Research Centre, University of British Columbia, Vancouver, BC, Canada. · Can J Neurol Sci. · Pubmed #12691472 No free full text.

Abstract: There is growing recognition that Parkinson's disease (PD) is likely to arise from the combined effects of genetic predisposition as well as largely unidentified environmental factors. The relative contribution of each varies from one individual to another. Even in situations where more than one family member is affected, the predominant influence may be environmental. Although responsible for only a small minority of cases of PD, recently identified genetic mutations have provided tremendous insights into the basis for neurodegeneration and have led to growing recognition of the importance of abnormal protein handling in Parkinson's as well as other neurodegenerative disorders. Abnormal protein handling may increase susceptibility to oxidative stress; conversely, numerous other factors, including oxidative stress and impaired mitochondrial function can lead to impaired protein degradation. A limited number of environmental factors are known to be toxic to the substantia nigra; in contrast, some factors such as caffeine intake and cigarette smoking may protect against the development of PD, although the mechanisms are not established. We review the various genetic and environmental factors thought to be involved in PD, as well as the mechanisms that contribute to selective nigral cell death.

Kumar A, Huang Z, de la Fuente-Fernández R. · Pacific Parkinson's Research Centre, Vancouver Hospital and Health Centre, University of British Columbia, Vancouver, British Columbia, Canada. · Adv Neurol. · Pubmed #12442678 No free full text.

This publication has no abstract.

Bayir H, Kapralov AA, Jiang J, Huang Z, Tyurina YY, Tyurin VA, Zhao Q, Belikova NA, Vlasova II, Maeda A, Zhu J, Na HM, Mastroberardino PG, Sparvero LJ, Amoscato AA, Chu CT, Greenamyre JT, Kagan VE. · Center for Free Radical and Antioxidant Health, Pittsburgh Institute for Neurodegenerative Diseases, University of Pittsburgh, Pittsburgh, Pennsylvania 15219-3130, USA. · J Biol Chem. · Pubmed #19351880 No free full text.

Abstract: Damage of presynaptic mitochondria could result in release of proapoptotic factors that threaten the integrity of the entire neuron. We discovered that alpha-synuclein (Syn) forms a triple complex with anionic lipids (such as cardiolipin) and cytochrome c, which exerts a peroxidase activity. The latter catalyzes covalent hetero-oligomerization of Syn with cytochrome c into high molecular weight aggregates. Syn is a preferred substrate of this reaction and is oxidized more readily than cardiolipin, dopamine, and other phenolic substrates. Co-localization of Syn with cytochrome c was detected in aggregates formed upon proapoptotic stimulation of SH-SY5Y and HeLa cells and in dopaminergic substantia nigra neurons of rotenone-treated rats. Syn-cardiolipin exerted protection against cytochrome c-induced caspase-3 activation in a cell-free system, particularly in the presence of H(2)O(2). Direct delivery of Syn into mouse embryonic cells conferred resistance to proapoptotic caspase-3 activation. Conversely, small interfering RNA depletion of Syn in HeLa cells made them more sensitive to dopamine-induced apoptosis. In human Parkinson disease substantia nigra neurons, two-thirds of co-localized Syn-cytochrome c complexes occurred in Lewy neurites. Taken together, these results indicate that Syn may prevent execution of apoptosis in neurons through covalent hetero-oligomerization of cytochrome c. This immediate protective function of Syn is associated with the formation of the peroxidase complex representing a source of oxidative stress and postponed damage.

Sarkar S, Davies JE, Huang Z, Tunnacliffe A, Rubinsztein DC. · Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2XY, United Kingdom. · J Biol Chem. · Pubmed #17182613 links to  free full text

Abstract: Trehalose, a disaccharide present in many non-mammalian species, protects cells against various environmental stresses. Whereas some of the protective effects may be explained by its chemical chaperone properties, its actions are largely unknown. Here we report a novel function of trehalose as an mTOR-independent autophagy activator. Trehalose-induced autophagy enhanced the clearance of autophagy substrates like mutant huntingtin and the A30P and A53T mutants of alpha-synuclein, associated with Huntington disease (HD) and Parkinson disease (PD), respectively. Furthermore, trehalose and mTOR inhibition by rapamycin together exerted an additive effect on the clearance of these aggregate-prone proteins because of increased autophagic activity. By inducing autophagy, we showed that trehalose also protects cells against subsequent pro-apoptotic insults via the mitochondrial pathway. The dual protective properties of trehalose (as an inducer of autophagy and chemical chaperone) and the combinatorial strategy with rapamycin may be relevant to the treatment of HD and related diseases, where the mutant proteins are autophagy substrates.

Yang Y, Gehrke S, Imai Y, Huang Z, Ouyang Y, Wang JW, Yang L, Beal MF, Vogel H, Lu B. · Department of Pathology and Geriatric Research, Education and Clinical Center/Veterans Affairs Palo Alto Health Care System, Stanford University School of Medicine, Palo Alto, CA 94304, USA. · Proc Natl Acad Sci U S A. · Pubmed #16818890 links to  free full text

Abstract: Mutations in Pink1, a gene encoding a Ser/Thr kinase with a mitochondrial-targeting signal, are associated with Parkinson's disease (PD), the most common movement disorder characterized by selective loss of dopaminergic neurons. The mechanism by which loss of Pink1 leads to neurodegeneration is not understood. Here we show that inhibition of Drosophila Pink1 (dPink1) function results in energy depletion, shortened lifespan, and degeneration of select indirect flight muscles and dopaminergic neurons. The muscle pathology was preceded by mitochondrial enlargement and disintegration. These phenotypes could be rescued by the wild type but not the pathogenic C-terminal deleted form of human Pink1 (hPink1). The muscle and dopaminergic phenotypes associated with dPink1 inactivation show similarity to that seen in parkin mutant flies and could be suppressed by the overexpression of Parkin but not DJ-1. Consistent with the genetic rescue results, we find that, in dPink1 RNA interference (RNAi) animals, the level of Parkin protein is significantly reduced. Together, these results implicate Pink1 and Parkin in a common pathway that regulates mitochondrial physiology and cell survival in Drosophila.

de la Fuente-Fernández R, Sossi V, Huang Z, Furtado S, Lu JQ, Calne DB, Ruth TJ, Stoessl AJ. · Pacific Parkinson's Research Centre, University of British Columbia, Vancouver, BC, Canada. · Brain. · Pubmed #15329355 links to  free full text

Abstract: Peak-dose dyskinesias are abnormal movements that usually occur 1 h after oral administration of levodopa, and often complicate chronic treatment of Parkinson's disease. We investigated by PET with [11C]raclopride whether Parkinson's disease progression modifies the striatal changes in synaptic dopamine levels induced by levodopa administration, and whether this modification, if present, could have an impact on the emergence of dyskinesias. We found that, 1 h after oral administration of standard-release 250/25 mg of levodopa/carbidopa, levodopa-induced increases in synaptic dopamine levels (as estimated by striatal changes in [11C]raclopride binding potential) correlated positively with duration of Parkinson's disease symptoms (for the caudate nucleus, r = 0.79, P < 0.001; for the putamen, r = 0.88, P < 0.0001). Patients with peak-dose dyskinesias had larger 1-h increases in synaptic dopamine levels than stable responders, but there were no between-group differences in [11C]raclopride binding 4 h post-levodopa. The corresponding (time x group) interaction term in the repeated measures analysis of covariance was significant, even after adjusting for between-group differences in duration of Parkinson's disease symptoms (for the caudate nucleus, P = 0.030; for the putamen, P = 0.021). Our results indicate that, at the synaptic level, an identical dose of levodopa induces increasingly larger 1-h changes in dopamine levels as Parkinson's disease progresses. Large levodopa-induced increases in synaptic dopamine concentration can lead to dramatic changes in receptor occupancy, which may be responsible for the emergence of peak-dose dyskinesias in Parkinson's disease.

Huang Z, Jacewicz M, Pfeiffer RF. · Department of Neurology, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA. · Mov Disord. · Pubmed #12360548 No free full text.

Abstract: Vascular parkinsonism (VP) is characterized by predominantly lower body involvement with gait impairment and postural instability, often without tremor, and by relative levodopa unresponsiveness. Neuroimaging studies demonstrate multiple infarcts or ischemic changes in periventricular white matter. Anticardiolipin antibodies (ACLA) are associated with hypercoagulable states and increased stroke risk. Review of our Movement Disorders Clinic records identified 44 individuals with a diagnosis of VP. ACLA have been obtained in 22 of these patients (mean age, 78.3 years; mean Mini-Mental Status Exam score, 25.8). Gait disturbance was the initial clinical feature in 82% of the patients, and levodopa responsiveness was present in 18% of those treated. In 9 of the 22 (40.9%), ACLA immunoglobulin G was positive. No significant differences in clinical features or risk factors (hypertension, diabetes, coronary artery disease, and clinical stroke) were evident between ACLA+ and ACLA- groups. Since the presence of ACLA in individuals with stroke is usually treated by full-scale anticoagulation with warfarin, our findings raise the question whether such treatment should also be used in persons with VP who are ACLA positive.