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1.  Phenotype in parkinsonian and nonparkinsonian LRRK2 G2019S mutation carriers 
Neurology  2011;77(4):325-333.
Using a family study design, we describe the motor and nonmotor phenotype in probands with LRRK2 G2019S mutations and family members and compare these individuals to patients with idiopathic Parkinson disease (iPD) and unrelated controls.
Probands with G2019S mutations and their first-degree relatives, subjects with iPD, and unrelated control subjects were identified from 4 movement disorders centers. All underwent neurologic examinations and tests of olfaction, color vision, anxiety, and depression inventories.
Tremor was more often a presenting feature among 25 individuals with LRRK2-associated PD than among 84 individuals with iPD. Subjects with LRRK2-PD had better olfactory identification compared with subjects with iPD, higher Beck Depression Inventory scores, and higher error scores on Farnsworth-Munsell 100-Hue test of color discrimination. Postural or action tremor was more common among 29 nonmanifesting mutation carriers compared with 53 noncarriers within the families. Nonparkinsonian family members had higher Unified Parkinson's Disease Rating Scale motor scores, more constipation, and worse color discrimination than controls, regardless of mutation status.
Although tremor is a more common presenting feature of LRRK2-PD than iPD and some nonmotor features differed in degree, the phenotype is largely overlapping. Postural or action tremor may represent an early sign. Longitudinal evaluation of a large sample of nonmanifesting carriers will be required to describe any premotor phenotype that may allow early diagnosis.
PMCID: PMC3140802  PMID: 21753163
2.  Drug-induced deactivation of inhibitory networks predicts pathological gambling in PD (e–Pub ahead of print)  
Neurology  2010;75(19):1711-1716.
Some patients with Parkinson disease (PD) develop pathological gambling when treated with dopamine agonists (DAs). However, little is known about DA-induced changes in neuronal networks that may underpin this drug-induced change in behavior in vulnerable individuals. In this case-control study, we aimed to investigate DA-induced changes in brain activity that may differentiate patients with PD with DA-induced pathological gambling (gamblers) from patients with PD without such a history (controls).
Following overnight withdrawal of antiparkinsonian medication, patients were studied with H2 15O PET before and after administration of DA (3 mg apomorphine) to measure changes in regional cerebral blood flow as an index of regional brain activity during a card selection game with probabilistic feedback.
We observed that the direction of DA-related activity change in brain areas that are implicated in impulse control and response inhibition (lateral orbitofrontal cortex, rostral cingulate zone, amygdala, external pallidum) distinguished gamblers from controls. DA significantly increased activity in these areas in controls, while gamblers showed a significant DA-induced reduction of activity.
We propose that in vulnerable patients with PD, DAs produce an abnormal neuronal pattern that resembles those found in nonparkinsonian pathological gambling and drug addiction. DA-induced disruption of inhibitory key functions—outcome monitoring (rostral cingulate zone), acquisition and retention of negative action-outcome associations (amygdala and lateral orbitofrontal cortex)—together with restricted access of those areas to executive control (external pallidum)—may well explain loss of impulse control and response inhibition in vulnerable patients with PD, thereby fostering the development of pathological gambling.
= analysis of variance;
= dopamine agonist;
= Gambling Symptom Assessment Scale;
= external pallidum;
= Montréal Neurological Institute;
= orbitofrontal cortex;
= Parkinson disease;
= regional cerebral blood flow;
= rostral cingulated zone;
= Unified Parkinson's Disease Rating Scale.
PMCID: PMC3033606  PMID: 20926784
3.  Thalamic Neuronal and EMG Activity in Psychogenic Dystonia compared with Organic Dystonia 
This study is a retrospective analysis of thalamic neuronal and electromyogram activities between subjects with organic dystonia and a subject with psychogenic dystonia, in whom a thalamotomy was carried out before a diagnosis psychogenic dystonia was made.
The electromyogram signal to noise ratio in the lowest frequency band (<0.76Hz, dystonia frequency – DF) in the electromyogram was not significantly different by diagnosis or muscle (Table 1). The coherence at dystonia frequency for wrist flexors X biceps electromyograms was significantly higher in organic dystonia, while the phase was not apparently different from zero for either diagnosis.
In a thalamic pallidal relay nucleus (ventral oral posterior), neuronal firing rates were not apparently different between psychogenic and organic dystonia. The neuronal signal to noise ratio in ventral oral posterior was significantly higher in organic dystonia than in psychogenic dystonia, while both were greater than in controls with chronic pain. Spike X electromyogram coherence was not apparently different between psychogenic and organic dystonia. The proportion of thalamic cells responding to joint movements was higher in the cerebellar relay nucleus (ventral intermediate) of psychogenic dystonia than organic dystonia.
These results suggest that some features, such as firing rates and thalamic reorganization, are similar in psychogenic and organic dystonia. Other features differ, such as the coherence between the electromyograms from different muscles, and the thalamic neuronal signal to noise ratio, which may reflect pathophysiological factors in organic dystonia.
PMCID: PMC3690304  PMID: 21500279
Psychogenic Dystonia; Organic Dystonia; Human thalamus; Neuronal activity; Plasticity; Dystonia related activity
4.  Hemichorea-hemiballism associated with hyperglycemia and a developmental venous anomaly 
Neurology  2012;78(11):838.
PMCID: PMC3304947  PMID: 22411959
5.  IRF4 and BATF are critical for CD8+ T-cell function following infection with LCMV 
Cell Death and Differentiation  2014;21(7):1050-1060.
CD8+ T-cell functions are critical for preventing chronic viral infections by eliminating infected cells. For healthy immune responses, beneficial destruction of infected cells must be balanced against immunopathology resulting from collateral damage to tissues. These processes are regulated by factors controlling CD8+ T-cell function, which are still incompletely understood. Here, we show that the interferon regulatory factor 4 (IRF4) and its cooperating binding partner B-cell-activating transcription factor (BATF) are necessary for sustained CD8+ T-cell effector function. Although Irf4–/– CD8+ T cells were initially capable of proliferation, IRF4 deficiency resulted in limited CD8+ T-cell responses after infection with the lymphocytic choriomeningitis virus. Consequently, Irf4–/– mice established chronic infections, but were protected from fatal immunopathology. Absence of BATF also resulted in reduced CD8+ T-cell function, limited immunopathology, and promotion of viral persistence. These data identify the transcription factors IRF4 and BATF as major regulators of antiviral cytotoxic T-cell immunity.
PMCID: PMC4207473  PMID: 24531538
IRF4; BATF; CD8+ T cells; LCMV; immunopathology; hepatitis
6.  Reactive oxygen species delay control of lymphocytic choriomeningitis virus 
Cell Death and Differentiation  2013;20(4):649-658.
Cluster of differentiation (CD)8+ T cells are like a double edged sword during chronic viral infections because they not only promote virus elimination but also induce virus-mediated immunopathology. Elevated levels of reactive oxygen species (ROS) have been reported during virus infections. However, the role of ROS in T-cell-mediated immunopathology remains unclear. Here we used the murine lymphocytic choriomeningitis virus to explore the role of ROS during the processes of virus elimination and induction of immunopathology. We found that virus infection led to elevated levels of ROS producing granulocytes and macrophages in virus-infected liver and spleen tissues that were triggered by the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. Lack of the regulatory subunit p47phox of the NADPH oxidase diminished ROS production in these cells. While CD8+ T cells exhibited ROS production that was independent of NADPH oxidase expression, survival and T-cell function was elevated in p47phox-deficient (Ncf1−/−) mice. In the absence of p47phox, enhanced T-cell immunity promoted virus elimination and blunted corresponding immunopathology. In conclusion, we find that NADPH-mediated production of ROS critically impairs the immune response, impacting elimination of virus and outcome of liver cell damage.
PMCID: PMC3595491  PMID: 23328631
hepatitis; virus; ROS; liver cell damage
7.  Novel Antiplatelet Agent Use for Acute Coronary Syndrome in the Emergency Department: A Review 
Background. Acute Coronary Syndrome (ACS) is a clinical condition encompassing ST Segment Elevation Myocardial Infarction (STEMI), Non-ST Segment Elevation Myocardial Infarction (NSTEMI), and Unstable Angina (UA) and is characterized by ruptured coronary plaque, ischemic stress, and/or myocardial injury. Emergency department (ED) physicians are on the front lines of ACS management. The role of new antiplatelet agents ticagrelor and prasugrel in acute ED management of ACS has not yet been defined. Objective. To critically review clinical trials using ticagrelor and prasugrel in the treatment of ACS and inform practitioners of their potential utility in treating ACS in the ED. Results. Trials on the efficacy of ticagrelor and prasugrel achieve statistical significance in decreasing composite endpoints in select patient populations. Conclusion. The use of ticagrelor and prasugrel as first line ED treatment of ACS is not well established. Current evidence supports the use of several agents with the final decision based on treatment protocols conjointly developed between cardiology and emergency medicine (EM). Further clinical trials involving head-to-head trials or comparisons of drug-based strategies are required to show superiority in reducing cardiac endpoints with regard to ED initiation of treatment.
PMCID: PMC3594944  PMID: 23509665
9.  Increased striatal dopamine release in Parkinsonian patients with pathological gambling: a [11C] raclopride PET study 
Brain : a journal of neurology  2009;132(Pt 5):1376-1385.
Pathological gambling is an impulse control disorder reported in association with dopamine agonists used to treat Parkinson’s disease. Although impulse control disorders are conceptualized as lying within the spectrum of addictions, little neurobiological evidence exists to support this belief. Functional imaging studies have consistently demonstrated abnormalities of dopaminergic function in patients with drug addictions, but to date no study has specifically evaluated dopaminergic function in Parkinson’s disease patients with impulse control disorders. We describe results of a [11C] raclopride positron emission tomography (PET) study comparing dopaminergic function during gambling in Parkinson’s disease patients, with and without pathological gambling, following dopamine agonists. Patients with pathological gambling demonstrated greater decreases in binding potential in the ventral striatum during gambling (13.9%) than control patients (8.1%), likely reflecting greater dopaminergic release. Ventral striatal bindings at baseline during control task were also lower in patients with pathological gambling. Although prior imaging studies suggest that abnormality in dopaminergic binding and dopamine release may be markers of vulnerability to addiction, this study presents the first evidence of these phenomena in pathological gambling. The emergence of pathological gambling in a number of Parkinson’s disease patients may provide a model into the pathophysiology of this disorder.
PMCID: PMC3479148  PMID: 19346328 CAMSID: cams2369
Parkinson’s disease; dopamine; impulse control disorders; pathological gambling; PET; functional imaging
10.  Brain Connectivity Analysis: A Short Survey 
This short survey the reviews recent literature on brain connectivity studies. It encompasses all forms of static and dynamic connectivity whether anatomical, functional, or effective. The last decade has seen an ever increasing number of studies devoted to deduce functional or effective connectivity, mostly from functional neuroimaging experiments. Resting state conditions have become a dominant experimental paradigm, and a number of resting state networks, among them the prominent default mode network, have been identified. Graphical models represent a convenient vehicle to formalize experimental findings and to closely and quantitatively characterize the various networks identified. Underlying these abstract concepts are anatomical networks, the so-called connectome, which can be investigated by functional imaging techniques as well. Future studies have to bridge the gap between anatomical neuronal connections and related functional or effective connectivities.
PMCID: PMC3477528  PMID: 23097663
11.  Development of Brainstem-Evoked Responses in Congenital Auditory Deprivation 
Neural Plasticity  2012;2012:182767.
To compare the development of the auditory system in hearing and completely acoustically deprived animals, naive congenitally deaf white cats (CDCs) and hearing controls (HCs) were investigated at different developmental stages from birth till adulthood. The CDCs had no hearing experience before the acute experiment. In both groups of animals, responses to cochlear implant stimulation were acutely assessed. Electrically evoked auditory brainstem responses (E-ABRs) were recorded with monopolar stimulation at different current levels. CDCs demonstrated extensive development of E-ABRs, from first signs of responses at postnatal (p.n.) day 3 through appearance of all waves of brainstem response at day 8 p.n. to mature responses around day 90 p.n.. Wave I of E-ABRs could not be distinguished from the artifact in majority of CDCs, whereas in HCs, it was clearly separated from the stimulus artifact. Waves II, III, and IV demonstrated higher thresholds in CDCs, whereas this difference was not found for wave V. Amplitudes of wave III were significantly higher in HCs, whereas wave V amplitudes were significantly higher in CDCs. No differences in latencies were observed between the animal groups. These data demonstrate significant postnatal subcortical development in absence of hearing, and also divergent effects of deafness on early waves II–IV and wave V of the E-ABR.
PMCID: PMC3389724  PMID: 22792488
12.  Tauopathies with parkinsonism: clinical spectrum, neuropathologic basis, biological markers, and treatment options 
Tauopathies with parkinsonism represent a spectrum of disease entities unified by the pathologic accumulation of hyperphosphorylated tau protein fragments within the central nervous system. These pathologic characteristics suggest shared pathogenetic pathways and possible molecular targets for disease-modifying therapeutic interventions. Natural history studies, for instance, in progressive supranuclear palsy, frontotemporal dementia with parkinsonism linked to chromosome 17, corticobasal degeneration, and Niemann-Pick disease type C as well as in amyotrophic lateral sclerosis/Parkinson–dementia complex permit clinical characterization of the disease phenotypes and are crucial to the development and validation of biological markers for differential diagnostics and disease monitoring, for example, by use of neuroimaging or proteomic approaches. The wide pathologic and clinical spectrum of the tauopathies with parkinsonism is reviewed in this article, and perspectives on future advances in the understanding of the pathogenesis are given, together with potential therapeutic strategies.
PMCID: PMC2847416  PMID: 19364361
corticobasal degeneration; frontotemporal dementia with parkinsonism linked to chromosome 17; microtubule-associated protein tau, multiple system atrophy; Parkinson disease; parkinsonism; progressive supranuclear palsy; tauopathies
13.  Mirror movements in Parkinson's disease: effect of dopaminergic drugs 
PMCID: PMC2077552  PMID: 16980659
14.  A case of a psychogenic “jumpy stump” 
PMCID: PMC2077761  PMID: 16914768
15.  Neurovascular relationship at the trigeminal root entry zone in persistent idiopathic facial pain: findings from MRI 3D visualisation 
Background: Patients with atypical neuralgia or atypical facial pain have been surgically treated with microvascular decompression (MVD) of the trigeminal root entry zone (TREZ). There are no data regarding the sensitivity and specificity of a vessel–TREZ relationship as a cause of pain in patients with persistent idiopathic facial pain (PIFP) according to the definition given by the International Headache Society (IHS).
Methods: The TREZ was visualised by 3D CISS MRI in 12 patients with unilateral PIFP according to the IHS criteria.
Results: The frequency of artery–TREZ, vein–TREZ, or vessel (artery/vein)–TREZ contacts on the symptomatic and asymptomatic sides did not differ significantly. On the symptomatic side, vessel–TREZ contact was found in 58% of patients (sensitivity). On the asymptomatic side, vessel–TREZ contact was absent in 33% of patients (specificity).
Conclusions: On the basis of the low sensitivity and specificity found in the present study, PIFP cannot be attributed to a vessel–TREZ contact, and therefore, pain relief after MVD cannot be expected.
PMCID: PMC1739384  PMID: 16227540
16.  Knowledge-based gene expression classification via matrix factorization 
Bioinformatics  2008;24(15):1688-1697.
Motivation: Modern machine learning methods based on matrix decomposition techniques, like independent component analysis (ICA) or non-negative matrix factorization (NMF), provide new and efficient analysis tools which are currently explored to analyze gene expression profiles. These exploratory feature extraction techniques yield expression modes (ICA) or metagenes (NMF). These extracted features are considered indicative of underlying regulatory processes. They can as well be applied to the classification of gene expression datasets by grouping samples into different categories for diagnostic purposes or group genes into functional categories for further investigation of related metabolic pathways and regulatory networks.
Results: In this study we focus on unsupervised matrix factorization techniques and apply ICA and sparse NMF to microarray datasets. The latter monitor the gene expression levels of human peripheral blood cells during differentiation from monocytes to macrophages. We show that these tools are able to identify relevant signatures in the deduced component matrices and extract informative sets of marker genes from these gene expression profiles. The methods rely on the joint discriminative power of a set of marker genes rather than on single marker genes. With these sets of marker genes, corroborated by leave-one-out or random forest cross-validation, the datasets could easily be classified into related diagnostic categories. The latter correspond to either monocytes versus macrophages or healthy vs Niemann Pick C disease patients.
Supplementary information: Supplementary data are available at Bioinformatics online.
PMCID: PMC2638868  PMID: 18535085
17.  Cerebral vasomotor reactivity testing in head injury: the link between pressure and flow 
Background: It has been suggested that a moving correlation index between mean arterial blood pressure and intracranial pressure, called PRx, can be used to monitor and quantify cerebral vasomotor reactivity in patients with head injury.
Objectives: To validate this index and study its relation with cerebral blood flow velocity and cerebral autoregulation; and to identify variables associated with impairment or preservation of cerebral vasomotor reactivity.
Methods: The PRx was validated in a prospective study of 40 head injured patients. A PRx value of less than 0.3 indicates intact cerebral vasomotor reactivity, and a value of more than 0.3, impaired reactivity. Arterial blood pressure, intracranial pressure, mean cerebral perfusion pressure, and cerebral blood flow velocity, measured bilaterally with transcranial Doppler ultrasound, were recorded. Dynamic cerebrovascular autoregulation was measured using a moving correlation coefficient between arterial blood pressure and cerebral blood flow velocity, the Mx, for each cerebral hemisphere. All variables were compared in patients with intact and impaired cerebral vasomotor reactivity.
Results: No correlation between arterial blood pressure or cerebral perfusion pressure and cerebral blood flow velocity was seen in 19 patients with intact cerebral vasomotor reactivity. In contrast, the correlation between these variables was significant in 21 patients with impaired cerebral vasomotor reactivity, whose cerebral autoregulation was reduced. There was no correlation with intracranial pressure, arterial blood pressure, cerebral perfusion pressure, or interhemispheric cerebral autoregulation differences, but the values for these indices were largely within normal limits.
Conclusions: The PRx is valid for monitoring and quantifying cerebral vasomotor reactivity in patients with head injury. This intracranial pressure based index reflects changes in cerebral blood flow and cerebral autoregulatory capacity, suggesting a close link between blood flow and intracranial pressure in head injured patients. This explains why increases in arterial blood pressure and cerebral perfusion pressure may be useful for reducing intracranial pressure in selected head injured patients (those with intact cerebral vasomotor reactivity).
PMCID: PMC1738604  PMID: 12876233
18.  Continuous monitoring of cerebrovascular autoregulation: a validation study 
Background: Continuous monitoring of dynamic cerebral autoregulation, using a moving correlation index of cerebral perfusion pressure and mean middle cerebral artery flow velocity, may be useful in patients with severe traumatic brain injury to guide treatment, and has been shown to be of prognostic value.
Objective: To compare an index of dynamic cerebral autoregulation (Mx) with an index of static cerebral autoregulation (sRoR).
Methods: Mx was validated in a prospective comparative study against sRoR, using 83 testing sessions in 17 patients with traumatic brain injury. sRoR and Mx were calculated simultaneously during pharmacologically induced blood pressure variations.
Results: Mx was significantly correlated with sRoR (R = -0.78, p < 0.05). Nine patients were found to have failure of cerebral autoregulation, with an sRoR value < 50%. If an Mx value of 0.3 was used as the cut off point for failure of cerebral autoregulation, this index had 100% sensitivity and 90% specificity for demonstrating failure of autoregulation compared with the sRoR. An increase in cerebral blood flow velocity correlated significantly with Mx (R = 0.73, p < 0.05) but not with cerebral perfusion pressure (R = 0.41).
Conclusions: Dynamic and static cerebral autoregulation are significantly correlated in traumatic brain injury. Cerebral autoregulation can be monitored continuously, graded, and reliably assessed using a moving correlation analysis of cerebral perfusion pressure and cerebral blood flow velocity (Mx). The Mx index can be used to monitor cerebral blood flow regulation. It is useful in traumatic brain injury because it does not require any external stimulus.
PMCID: PMC1737892  PMID: 11971041
19.  Study of clinical features of amyloid angiopathy hemorrhage and hypertensive intracerebral hemorrhage 
Objective: The purpose of this study was to differentiate between cerebral amyloid angiopathy (CAA) and hypertension (HTN) based on hemorrhage pattern interpretation. Methods: From June 1994 to Oct., 2000, 83 patients admitted to our service with acute intracerebral hemorrhage (ICH) were investigated retrospectively; 41 patients with histologically proven diagnosis of cerebral amyloid angiography and 42 patients with clear history of hypertension were investigated. Results: Patients with a CAA-related ICH were significantly older than patients with a HTN-related ICH (74.0 years vs 66.5 years, P<0.05). There was a significantly higher number of hematomas≥30 ml in CAA (85.3%) when compared with HTN (59.5%). No basal ganglional hemorrhage was seen in CAA, but in 40.5% in HTN. In CAA-related ICH, subarachnoid hemorrhage (SAH) was seen in 26 patients (63.4%) compared to only 11 patients (26.2%) in HTN-related ICH. Intraventricular hemorrhage was seen in 24.4% in CAA, and in 26.2% in HTN. Typical features of CAA-related ICH included lobar distribution affecting mainly the lobar superficial areas, lobulated appearance, rupture into the subarachnoid space, and secondary IVH from the lobar hemorrhage. More specifically, multiplicity of hemorrhage, bilaterality, and repeated episodes also strongly suggest the diagnosis of CAA. Multiple hemorrhages, defined as 2 or more separate hematomas in multiple lobes, accounted for 17.1% in CAA-related ICH. Conclusion: There are certain features in CAA on CT and MRI and in clinical settings. To some extent, these features may contribute to distinguishing CAA from HTN related ICH.
PMCID: PMC1388732  PMID: 15362199
Intracerebral hemorrhage; Cerebral amyloid angiopathy; Hypertension; Diagnosis; Computed tomography; Magnetic resonance imaging
20.  Dystonia in progressive supranuclear palsy. 
OBJECTIVES: To document the nature, distribution, and frequency of dystonic symptoms in progressive supranuclear palsy (PSP). METHODS: Charts and videotapes of all clinically diagnosed patients with PSP seen between 1983 and 1993 were reviewed and the occurrence, nature, and distribution of all dystonic symptoms were recorded. RESULTS: Of 83 identified cases 38 had some dystonic features. Twenty (24%) had blepharospasm (one was induced by levodopa), 22 (27%) had limb dystonia (one was induced by electroconvulsive therapy and another by levodopa), 14 (17%) had axial dystonia in extension, one had oromandibular dystonia induced by levodopa, and two had other cranial dystonias. Six patients had limb dystonia as an early or presenting feature, sometimes leading to misdiagnosis of cortical-basal ganglionic degeneration. All three patients who had postmortem confirmation of the diagnosis had other concurrent disease. One patient with bilateral limb dystonia and blepharospasm had evidence of previous hydrocephalus and severe arteriosclerotic changes. One with arm dystonia also had cerebrovascular disease and one with hemidystonia also had rare swollen chromatolytic neurons in the frontotemporal cortex. CONCLUSIONS: Dystonia is a common manifestation of PSP. Limb dystonia is particularly common and may indicate the presence of concurrent disease. When dystonia occurs in PSP, dopaminergic medication should be cautiously reduced or discontinued to rule out the possibility of treatment induced symptoms.
PMCID: PMC1074090  PMID: 9120447
21.  Atypical dopa responsive parkinsonism in a patient with megalencephaly, midbrain Lewy body disease, and some pathological features of Hallervorden-Spatz disease. 
A 38 year old patient with megalencephaly, mental retardation, and lifelong tremor developed levodopa responsive parkinsonism in his mid-30s followed by the appearance of dyskinesiae, motor fluctuations, hallucinations, and dementia. Brain MRI showed, as well as other changes, iron deposition in the globus pallidus, substantia nigra, and the pulvinar of the thalamus. Postmortem examination disclosed depigmentation of the substantia nigra pars compacta with neuronal loss, gliosis, and Lewy body formation. Axonal dystrophic spheroids, neuronal loss, calcification, and iron deposition were found in the substantia nigra pars reticulata. Less severe changes without neuronal loss were seen in the globus pallidus. This combination of megalencephaly with neuroaxonal changes predominantly in the pars reticulata and Lewy body degeneration isolated to the substantia nigra pars compacta has not been previously reported.
PMCID: PMC1074055  PMID: 8937352
22.  Rhodobacter capsulatus CycH: a bipartite gene product with pleiotropic effects on the biogenesis of structurally different c-type cytochromes. 
Journal of Bacteriology  1996;178(17):5279-5290.
While searching for components of the soluble electron carrier (cytochrome c2)-independent photosynthetic (Ps) growth pathway in Rhodobacter capsulatus, a Ps- mutant (FJM13) was isolated from a Ps+ cytochrome c2-strain. This mutant could be complemented to Ps+ growth by cycA encoding the soluble cytochrome c2 but was unable to produce several c-type cytochromes. Only cytochrome c1 of the cytochrome bc1 complex was present in FJM13 cells grown on enriched medium, while cells grown on minimal medium contained at various levels all c-type cytochromes, including the membrane-bound electron carrier cytochrome cy. Complementation of FJM13 by a chromosomal library lacking cycA yielded a DNA fragment which also complemented a previously described Ps- mutant, MT113, known to lack all c-type cytochromes. Deletion and DNA sequence analyses revealed an open reading frame homologous to cycH, involved in cytochrome c biogenesis. The cycH gene product (CycH) is predicted to be a bipartite protein with membrane-associated amino-terminal (CycH1) and periplasmic carboxyl-terminal (CycH2) subdomains. Mutations eliminating CyCH drastically decrease the production or all known c-type cytochromes. However, mutations truncating only its CycH2 subdomain always produce cytochrome c1 and affect the presence of other cytochromes to different degrees in a growth medium-dependent manner. Thus, the subdomain CycH1 is sufficient for the proper maturation of cytochrome c1 which is the only known c-type cytochrome anchored to the cytoplasmic membrane by its carboxyl terminus, while CycH2 is required for efficient biogenesis of other c-type cytochromes. These findings demonstrate that the two subdomains of CycH play different roles in the biogenesis of topologically distinct c-type cytochromes and reconcile the apparently conflicting data previously obtained for other species.
PMCID: PMC178328  PMID: 8752349
24.  Membrane-associated cytochrome cy of Rhodobacter capsulatus is an electron carrier from the cytochrome bc1 complex to the cytochrome c oxidase during respiration. 
Journal of Bacteriology  1995;177(3):608-613.
We have recently established that the facultative phototrophic bacterium Rhodobacter capsulatus has two different pathways for reduction of the photooxidized reaction center during photosynthesis (F.E. Jenney and F. Daldal, EMBO J. 12:1283-1292, 1993; F.E. Jenney, R.C. Prince, and F. Daldal, Biochemistry 33:2496-2502, 1994). One pathway is via the well-characterized, water-soluble cytochrome c2 (cyt c2), and the other is via a novel membrane-associated c-type cytochrome named cyt cy. In this work, we probed the role of cyt cy in respiratory electron transport by isolating a set of R. capsulatus mutants lacking either cyt c2 or cyt cy, in the presence or in the absence of a functional quinol oxidase-dependent alternate respiratory pathway. The growth and inhibitor sensitivity patterns of these mutants, their respiratory rates in the presence of specific inhibitors, and the oxidation-reduction kinetics of c-type cytochromes monitored under appropriate conditions demonstrated that cyt cy, like cyt c2, connects the bc1 complex and the cyt c oxidase during respiratory electron transport. Whether cyt c2 and cyt cy are the only electron carriers between these two energy-transducing membrane complexes of R. capsulatus is unknown.
PMCID: PMC176634  PMID: 7836293

Results 1-25 (37)