Platelet mitochondrial activity and pesticide exposure in early Parkinson's disease.

BACKGROUND: Mitochondrial dysfunction has been implicated in the pathogenesis of Parkinson's disease (PD), but the cause of this dysfunction is unclear. METHODS: Platelet mitochondrial complex I and I/III (nicotinamide adenine dinucleotide cytochrome c reductase, NCCR) activities were measured in early PD patients and matched controls enrolled in a population-based case-control study. Ambient agricultural pesticide exposures were assessed with a geographic information system and California Pesticide Use Registry. RESULTS: In contrast to some previous reports, we found no differences in complex I and I/III activities in subjects with PD and controls. We did find that NCCR activity correlated with subjects' exposure to pesticides known to inhibit mitochondrial activity regardless of their diagnosis. CONCLUSIONS: Electron transport chain (ETC) activity is not altered in PD in this well-characterized cohort when compared with community-matched controls but appears to be affected by environmental toxins, such as mitochondria-inhibiting pesticides.

Dopamine depletion induces distinct compensatory gene expression changes in DARPP-32 signal transduction cascades of striatonigral and striatopallidal neurons.

Functional alterations in striatal projection neurons play a critical role in the development of motor symptoms in Parkinson's disease (PD), but their molecular adaptation to dopamine depletion remains poorly understood. In particular, type and extent of regulation in postsynaptic signal transduction pathways that determine the responsiveness of striatal projection neurons to incoming stimuli, are currently unknown. Using cell-type-specific transcriptome analyses in a rodent model of chronic dopamine depletion, we identified large-scale gene expression changes, including neurotransmitter receptors, signal transduction cascades, and target proteins of dopamine signaling in striatonigral and striatopallidal neurons. Within the dopamine- and cAMP-regulated phosphoprotein of 32 kDa (DARPP-32) cascade of enzymes that plays a central role in signal integration of dopaminoceptive neurons multiple catalytic and regulatory subunits change their mRNA expression levels. In addition to the number of genes the fact that the alterations occur at multiple levels stresses the biological relevance of transcriptional regulation for adaptations of postsynaptic signaling pathways. The overall pattern of changes in both striatonigral and striatopallidal neurons is compatible with homeostatic mechanisms. In accordance with the distinct biological effects of dopamine D(1) and D(2) receptor stimulation, the alterations of the transcriptional profiles most likely result in prodopaminergic phosphorylation patterns. Our data provide insight into the disease-related plasticity of functional genomic networks in vivo that might contribute to the protracted preclinical phase of PD. In addition, the data have potential implications for the symptomatic treatment of the disease.

Dopamine depletion induced up-regulation of HCN3 enhances rebound excitability of basal ganglia output neurons.

Motor symptoms in Parkinson's disease (PD) are associated with complex changes of firing properties in basal ganglia output neurons (BGON). The abnormalities are generally attributed to altered synaptic input and potential post-synaptic mechanisms are currently unknown. Our cell-type selective transcriptome analyses of BGON in the rat 6-hydroxydopamine (6-OHDA) model of PD identified the ion channel HCN3 as a likely contributor to altered neuronal excitability. Quantitative PCR experiments confirmed the HCN3 upregulation in the rat and mouse 6-OHDA models and also demonstrated selectivity of the effect for HCN3. In accordance with the mRNA expression data, in vitro whole cell patch-clamp recordings in BGON showed increased HCN3 current amplitudes and increased rebound excitability in BGON of 6-OHDA treated rats. These data establish HCN3 up-regulation as a novel candidate mechanism that might contribute to the in vivo changes of electrical activity in basal ganglia output neurons of the parkinsonian brain.

Neurological and neurodegenerative alterations in a transgenic mouse model expressing human alpha-synuclein under oligodendrocyte promoter: implications for multiple system atrophy.

Multiple system atrophy (MSA) is a progressive, neurodegenerative disease characterized by parkinsonism, ataxia, autonomic dysfunction, and accumulation of alpha-synuclein (alpha-syn) in oligodendrocytes. To better understand the mechanisms of neurodegeneration and the role of alpha-syn accumulation in oligodendrocytes in the pathogenesis of MSA, we generated transgenic mouse lines expressing human (h) alpha-syn under the control of the murine myelin basic protein promoter. Transgenic mice expressing high levels of halpha-syn displayed severe neurological alterations and died prematurely at 6 months of age. Furthermore, mice developed progressive accumulation of halpha-syn-immunoreactive inclusions in oligodendrocytes along the axonal tracts in the brainstem, basal ganglia, cerebellum, corpus callosum, and neocortex. The inclusions also reacted with antibodies against phospho-serine (129) halpha-syn and ubiquitin, and halpha-syn was found in the detergent-insoluble fraction. In high-expresser lines, the white matter tracts displayed intense astrogliosis, myelin pallor, and decreased neurofilament immunostaining. Accumulation of halpha-syn in oligodendrocytes also leads to prominent neurodegenerative changes in the neocortex with decreased dendritic density and to loss of dopaminergic fibers in the basal ganglia. The oligodendrocytic inclusions were composed of fibrils and accompanied by mitochondrial alterations and disruption of the myelin lamina in the axons. Together, these studies support the contention that accumulation of alpha-syn in oligodendrocytes promotes neurodegeneration and recapitulates several of the key functional and neuropathological features of MSA.

Genetic screening for a single common LRRK2 mutation in familial Parkinson's disease.

Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene cause some forms of autosomal dominant Parkinson's disease. We measured the frequency of a novel mutation (Gly2019 ser) in familial Parkinson's disease by screening genomic DNA of patients and controls. Of 767 affected individuals from 358 multiplex families, 35 (5%) individuals were either heterozygous (34) or homozygous (one) for the mutation, and had typical clinical findings of idiopathic Parkinson's disease. Thus, our results suggest that a single LRRK2 mutation causes Parkinson's disease in 5% of individuals with familial disease. Screening for this mutation should be a component of genetic testing for Parkinson's disease.

Therapeutic role of coenzyme Q(10) in Parkinson's disease.

Mitochondrial dysfunction has been well established to occur in Parkinson's disease (PD) and appears to play a role in the pathogenesis of the disorder. A key component of the mitochondrial electron transport chain (ETC) is coenzyme Q(10), which not only serves as the electron acceptor for complexes I and II of the ETC but is also an antioxidant. In addition to being crucial to the bioenergetics of the cell, mitochondria play a central role in apoptotic cell death through a number of mechanisms, and coenzyme Q(10) can affect certain of these processes. Levels of coenzyme Q(10) have been reported to be decreased in blood and platelet mitochondria from PD patients. A number of preclinical studies in in vitro and in vivo models of PD have demonstrated that coenzyme Q(10) can protect the nigrostriatal dopaminergic system. A phase II trial of coenzyme Q(10) in patients with early, untreated PD demonstrated a positive trend for coenzyme Q(10) to slow progressive disability that occurs in PD.

alpha-synuclein from platelets is not phosphorylated at serine 129 in Parkinson's disease and multiple system atrophy.

Parkinson's disease (PD) and multiple system atrophy (MSA) are characterized pathologically by inclusions in the brain containing alpha-synuclein, which is phosphorylated at serine 129. alpha-Synuclein is present not only in the brain but also in platelets; platelets have previously been used to study mitochondrial function in PD. We undertook to determine whether alpha-synuclein extracted from platelets of patients with PD and MSA is phosphorylated at serine 129 and could be used as a peripheral marker of these disorders. Immunoblots indicated that platelet alpha-synuclein is not phosphorylated at serine 129 in PD and MSA.

Mutations in DJ-1 are rare in familial Parkinson disease.

Mutations in DJ-1 (PARK7) are one cause of early-onset autosomal-recessive parkinsonism. We screened for DJ-1 mutations in 93 affected individuals from the 64 multiplex Parkinson disease (PD) families in our sample that had the highest family-specific multipoint LOD scores at the DJ-1 locus. In addition to sequencing all coding exons for alterations, we used multiplex ligation-dependent probe amplification (MLPA) to examine the genomic copy number of DJ-1 exons. A known polymorphism (R98Q) was found in five PD subjects, once as a homozygote and in the other four cases as heterozygotes. No additional missense mutations and no exon deletions or duplications were detected. Our results, in combination with those of previous studies, suggest that alterations in DJ-1 are not a common cause of familial PD.

The adult substantia nigra contains progenitor cells with neurogenic potential.

In Parkinson's disease, progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SN) leads to debilitating motor dysfunction. One current therapy aims at exogenous cellular replacement of dopaminergic function by transplanting fetal midbrain cells into the striatum, the main projection area of the SN. However, results using this approach have shown variable success. It has been proposed that cellular replacement by endogenous stem/progenitor cells may be useful for therapeutic interventions in neurodegenerative diseases, including Parkinson's disease. Although it is widely accepted that progenitor cells are present in different areas of the adult CNS, it is unclear whether such cells reside in the adult SN and whether they have the potential to replace degenerating neurons. Here, we describe a population of actively dividing progenitor cells in the adult SN, which in situ give rise to new mature glial cells but not to neurons. However, after removal from the SN, these progenitor cells immediately have the potential to differentiate into neurons. Transplantation of freshly isolated SN progenitor cells into the adult hippocampus showed that these cells also have a neuronal potential under in vivo conditions. These results suggest that progenitor cells reside in the adult SN and can give rise to new neurons when exposed to appropriate environmental signals. This developmental potential of SN progenitor cells might be useful for future endogenous cell replacement strategies in Parkinson's disease.

Natural history of multiple system atrophy in the USA: a prospective cohort study.

BACKGROUND: Multiple system atrophy is a rare, fatal neurodegenerative disorder with symptoms of autonomic failure plus parkinsonism, cerebellar ataxia, or both. We report results of the first prospective natural history study of multiple system atrophy in the USA, and the effects of phenotype and autonomic failure on prognosis. METHODS: We recruited participants with probable multiple system atrophy-of either the parkinsonism subtype (MSA-P) or the cerebellar ataxia subtype (MSA-C)-at 12 neurology centres in the USA specialising in movement or autonomic disorders. We followed up patients every 6 months for 5 years and assessed them with the Unified Multiple System Atrophy Rating Scale part I (UMSARS I; a functional score of symptoms and ability to undertake activities of daily living), UMSARS II (neurological motor evaluation), and the Composite Autonomic Symptoms Scale (COMPASS)-select (a measure of autonomic symptoms and autonomic functional status). We assessed potential predictors of outcome. We used Cox proportional hazards models to calculate univariate hazard ratios for shorter survival using age at disease onset as a continuous variable and sex, clinical phenotype, and early development of neurological and autonomic manifestations as categorical variables. FINDINGS: We recruited 175 participants. Mean age at study entry was 63·4 years (SD 8·6). Median survival from symptom onset was 9·8 years (95% CI 8·8-10·7) and median survival from enrolment was 1·8 years (0·9-2·7). Participants with severe symptomatic autonomic failure (symptomatic orthostatic hypotension, urinary incontinence, or both) at diagnosis (n=62) had a worse prognosis than those without severe disease (n=113; median survival 8·0 years, 95% CI 6·5-9·5 vs 10·3 years, 9·3-11·4; p=0·021). At baseline, patients with MSA-P (n=126) and MSA-C (n=49) had much the same symptoms and functional status: mean UMSARS I 25·2 (SD 8·08) versus 24·6 (8·34; p=0·835); mean UMSARS II 26·4 (8·8) versus 25·4 (10·5; p=0·764); COMPASS-select 43·5 (18·7) versus 42·8 (19·6; p=0·835). Progression over 5 years, assessed by change in UMSARS I, UMSARS II, and COMPASS-select, was modest. INTERPRETATION: Probable multiple system atrophy is a late-stage disease with short survival. The natural histories of MSA-P and MSA-C are similar and severe symptomatic autonomic failure at diagnosis is associated with worse prognosis. FUNDING: US National Institutes of Health, Mayo Clinic, and Kathy Shih Memorial Foundation.

Treatments of Parkinson disease: circa 2003.

Parkinson disease (PD) is a progressive degenerative neurological disorder characterized by resting tremor, bradykinesia, cogwheel rigidity, and postural instability.1 In the later stages, approximately 25% or more of patients develop cognitive compromise. The cardinal pathological features of PD are degeneration of dopaminergic neurons in the substantia nigra pars compacta and their axons, which project principally to the caudate and putamen, and the presence of eosinophilic intracytoplasmic inclusions, Lewy bodies.2-3 Although the loss of neurons is most conspicuous in the substantia nigra pars compacta, neuronal loss and/or Lewy bodies are found in other brain regions (eg, the locus coeruleus, entorhinal region, and amygdala),2 which suggests that treatments that target only the nigrostriatal dopaminergic system, though they may substantially benefit patients, are unlikely to completely resolve the deficits of PD.

Effects of coenzyme Q10 in early Parkinson disease: evidence of slowing of the functional decline.

BACKGROUND: Parkinson disease (PD) is a degenerative neurological disorder for which no treatment has been shown to slow the progression. OBJECTIVE: To determine whether a range of dosages of coenzyme Q10 is safe and well tolerated and could slow the functional decline in PD. DESIGN: Multicenter, randomized, parallel-group, placebo-controlled, double-blind, dosage-ranging trial. SETTING: Academic movement disorders clinics. PATIENTS: Eighty subjects with early PD who did not require treatment for their disability. INTERVENTIONS: Random assignment to placebo or coenzyme Q10 at dosages of 300, 600, or 1200 mg/d. MAIN OUTCOME MEASURE: The subjects underwent evaluation with the Unified Parkinson Disease Rating Scale (UPDRS) at the screening, baseline, and 1-, 4-, 8-, 12-, and 16-month visits. They were followed up for 16 months or until disability requiring treatment with levodopa had developed. The primary response variable was the change in the total score on the UPDRS from baseline to the last visit. RESULTS: The adjusted mean total UPDRS changes were +11.99 for the placebo group, +8.81 for the 300-mg/d group, +10.82 for the 600-mg/d group, and +6.69 for the 1200-mg/d group. The P value for the primary analysis, a test for a linear trend between the dosage and the mean change in the total UPDRS score, was.09, which met our prespecified criteria for a positive trend for the trial. A prespecified, secondary analysis was the comparison of each treatment group with the placebo group, and the difference between the 1200-mg/d and placebo groups was significant (P =.04). CONCLUSIONS: Coenzyme Q10 was safe and well tolerated at dosages of up to 1200 mg/d. Less disability developed in subjects assigned to coenzyme Q10 than in those assigned to placebo, and the benefit was greatest in subjects receiving the highest dosage. Coenzyme Q10 appears to slow the progressive deterioration of function in PD, but these results need to be confirmed in a larger study.

Coenzyme Q10 in neurodegenerative diseases.

Coenzyme Q(10) (ubiquinone), which serves as the electron acceptor for complexes I and II of the mitochondrial electron transport chain and also acts as an antioxidant, has the potential to be a beneficial agent in neurodegenerative diseases in which there is impaired mitochondrial function and/or excessive oxidative damage. Substantial data have accumulated to implicate these processes in the pathogenesis in certain neurodegenerative disorders, including Parkinson's disease, Huntington's disease and Friedreich's ataxia. Although no study to date has unequivocally demonstrated that coenzyme Q(10) can slow the progression of a neurodegenerative disease, recent clinical trials in these three disorders suggest that supplemental coenzyme Q(10) can slow the functional decline in these disorders, particularly Parkinson's disease.

Mitochondrial dysfunction and possible treatments in Parkinson's disease--a review.

Mitochondria are central not only to the bioenergetics of the cell but also to the process of apoptotic cell death. Substantial data indicate mitochondrial dysfunction, particularly of complex I of the electron transport chain, in some patients with Parkinson's disease (PD), and it appears likely that mitochondria contribute to the pathogenic processes that occurs in this disorder. Treatments targeted at mitochondrial function hold promise to slow the progression of PD.

Tropicamide effects on pupil size and pupillary light reflexes in Alzheimer's and Parkinson's disease.

Diagnostic tests for Alzheimer's disease (AD) involving tropicamide blockade of cholinergic oculomotor functions were examined in AD patients (n=15), Parkinson's disease (PD) patients (n=15), and non-clinical control (NC) participants (n=15). Pupillographic methods were used to measure pupil diameter and pupillary light reflexes after double-blind ocular administration of dilute tropicamide (0.01%) in one eye and saline in the other eye. Changes in pupil size were measured in bright background light and near-darkness. Tropicamide increased pupil diameter to a similar extent in all three groups in light and darkness. Tropicamide also reduced the amplitude and latency of the pupillary light reflex to a similar extent for all three groups. Tropicamide pupillary response tests, therefore, were not sensitive or specific diagnostic tests for AD. Peak constriction amplitude of the pupillary light reflex was significantly reduced in both eyes in AD and PD groups relative to non-clinical controls, but AD and PD groups did not differ significantly. The pupillary light reflex test, therefore, was sensitive to AD, but lacked adequate specificity. Finally, peak constriction amplitude correlated significantly with dementia severity and donepezil treatment may have partially normalized pupillary light reflex abnormalities in AD patients. The pupillary light reflex test, therefore, may index central cholinergic dysfunction associated with disease progression and improvement in cholinergic function associated with pharmacologic treatment response in AD.

A randomized clinical trial of high-dosage coenzyme Q10 in early Parkinson disease: no evidence of benefit.

IMPORTANCE: Coenzyme Q10 (CoQ10), an antioxidant that supports mitochondrial function, has been shown in preclinical Parkinson disease (PD) models to reduce the loss of dopamine neurons, and was safe and well tolerated in early-phase human studies. A previous phase II study suggested possible clinical benefit. OBJECTIVE: To examine whether CoQ10 could slow disease progression in early PD. DESIGN, SETTING, AND PARTICIPANTS: A phase III randomized, placebo-controlled, double-blind clinical trial at 67 North American sites consisting of participants 30 years of age or older who received a diagnosis of PD within 5 years and who had the following inclusion criteria: the presence of a rest tremor, bradykinesia, and rigidity; a modified Hoehn and Yahr stage of 2.5 or less; and no anticipated need for dopaminergic therapy within 3 months. Exclusion criteria included the use of any PD medication within 60 days, the use of any symptomatic PD medication for more than 90 days, atypical or drug-induced parkinsonism, a Unified Parkinson's Disease Rating Scale (UPDRS) rest tremor score of 3 or greater for any limb, a Mini-Mental State Examination score of 25 or less, a history of stroke, the use of certain supplements, and substantial recent exposure to CoQ10. Of 696 participants screened, 78 were found to be ineligible, and 18 declined participation. INTERVENTIONS: The remaining 600 participants were randomly assigned to receive placebo, 1200 mg/d of CoQ10, or 2400 mg/d of CoQ10; all participants received 1200 IU/d of vitamin E. MAIN OUTCOMES AND MEASURES: Participants were observed for 16 months or until a disability requiring dopaminergic treatment. The prospectively defined primary outcome measure was the change in total UPDRS score (Parts I-III) from baseline to final visit. The study was powered to detect a 3-point difference between an active treatment and placebo. RESULTS: The baseline characteristics of the participants were well balanced, the mean age was 62.5 years, 66% of participants were male, and the mean baseline total UPDRS score was 22.7. A total of 267 participants required treatment (94 received placebo, 87 received 1200 mg/d of CoQ10, and 86 received 2400 mg/d of CoQ10), and 65 participants (29 who received placebo, 19 who received 1200 mg/d of CoQ10, and 17 who received 2400 mg/d of CoQ10) withdrew prematurely. Treatments were well tolerated with no safety concerns. The study was terminated after a prespecified futility criterion was reached. At study termination, both active treatment groups showed slight adverse trends relative to placebo. Adjusted mean changes (worsening) in total UPDRS scores from baseline to final visit were 6.9 points (placebo), 7.5 points (1200 mg/d of CoQ10; P = .49 relative to placebo), and 8.0 points (2400 mg/d of CoQ10; P = .21 relative to placebo). CONCLUSIONS AND RELEVANCE: Coenzyme Q10 was safe and well tolerated in this population, but showed no evidence of clinical benefit. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00740714.