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2.  The Differential Effects of Wild-Type and Mutated K-Ras on MST2 Signaling Are Determined by K-Ras Activation Kinetics 
Molecular and Cellular Biology  2013;33(9):1859-1868.
K-Ras is frequently mutated in human cancers. Mutant (mt) K-Ras can stimulate both oncogenic transformation and apoptosis through activation of extracellular signal-regulated kinase (ERK) and AKT pathways and the MST2 pathway, respectively. The biological outcome is determined by the balance and cross talk between these pathways. In colorectal cancer (CRC), a K-Ras mutation is negatively correlated with MST2 expression, as mt K-Ras can induce apoptosis by activating the MST2 pathway. However, wild-type (wt) K-Ras can prevent the activation of the MST2 pathway upon growth factor stimulation and enable transformation by mt K-Ras in CRC cells that express MST2. Here we have investigated the mechanism by which wt and mt K-Ras differentially regulate the MST2 pathway and MST2-dependent apoptosis. The ability of K-Ras to activate MST2 and MST2-dependent apoptosis is determined by the differential activation kinetics of mt K-Ras and wt K-Ras. Chronic activation of K-Ras by mutation or overexpression of Ras exchange factors results in the activation of MST2 and LATS1, increased MST2-LATS1 complex formation, and apoptosis. In contrast, transient K-Ras activation upon epidermal growth factor (EGF) stimulation prevents the formation of the MST2-LATS1 complex in an AKT-dependent manner. Our data suggest that the close relationship between Ras prosurvival and proapoptotic signaling is coordinated via the differential regulation of the MST2-LATS1 interaction by transient and chronic stimuli.
PMCID: PMC3624182  PMID: 23459937
3.  The natural history of multiple system atrophy: a prospective European cohort study 
Lancet Neurology  2013;12(3):264-274.
Multiple system atrophy (MSA) is a fatal and still poorly understood degenerative movement disorder that is characterised by autonomic failure, cerebellar ataxia, and parkinsonism in various combinations. Here we present the final analysis of a prospective multicentre study by the European MSA Study Group to investigate the natural history of MSA.
Patients with a clinical diagnosis of MSA were recruited and followed up clinically for 2 years. Vital status was ascertained 2 years after study completion. Disease progression was assessed using the unified MSA rating scale (UMSARS), a disease-specific questionnaire that enables the semiquantitative rating of autonomic and motor impairment in patients with MSA. Additional rating methods were applied to grade global disease severity, autonomic symptoms, and quality of life. Survival was calculated using a Kaplan-Meier analysis and predictors were identified in a Cox regression model. Group differences were analysed by parametric tests and non-parametric tests as appropriate. Sample size estimates were calculated using a paired two-group t test.
141 patients with moderately severe disease fulfilled the consensus criteria for MSA. Mean age at symptom onset was 56·2 (SD 8·4) years. Median survival from symptom onset as determined by Kaplan-Meier analysis was 9·8 years (95% CI 8·1–11·4). The parkinsonian variant of MSA (hazard ratio [HR] 2·08, 95% CI 1·09–3·97; p=0·026) and incomplete bladder emptying (HR 2·10, 1·02–4·30; p=0·044) predicted shorter survival. 24-month progression rates of UMSARS activities of daily living, motor examination, and total scores were 49% (9·4 [SD 5·9]), 74% (12·9 [8·5]), and 57% (21·9 [11·9]), respectively, relative to baseline scores. Autonomic symptom scores progressed throughout the follow-up. Shorter symptom duration at baseline (OR 0·68, 0·5–0·9; p=0·006) and absent levodopa response (OR 3·4, 1·1–10·2; p=0·03) predicted rapid UMSARS progression. Sample size estimation showed that an interventional trial with 258 patients (129 per group) would be able to detect a 30% effect size in 1-year UMSARS motor examination decline rates at 80% power.
Our prospective dataset provides new insights into the evolution of MSA based on a follow-up period that exceeds that of previous studies. It also represents a useful resource for patient counselling and planning of multicentre trials.
Fifth Framework Programme of the European Union, the Oesterreichische Nationalbank, and the Austrian Science Fund.
PMCID: PMC3581815  PMID: 23391524
4.  α-Synucleinopathy associated with G51D SNCA mutation: a link between Parkinson’s disease and multiple system atrophy? 
Acta Neuropathologica  2013;125(5):753-769.
We report a British family with young-onset Parkinson’s disease (PD) and a G51D SNCA mutation that segregates with the disease. Family history was consistent with autosomal dominant inheritance as both the father and sister of the proband developed levodopa-responsive parkinsonism with onset in their late thirties. Clinical features show similarity to those seen in families with SNCA triplication and to cases of A53T SNCA mutation. Post-mortem brain examination of the proband revealed atrophy affecting frontal and temporal lobes in addition to the caudate, putamen, globus pallidus and amygdala. There was severe loss of pigmentation in the substantia nigra and pallor of the locus coeruleus. Neuronal loss was most marked in frontal and temporal cortices, hippocampal CA2/3 subregions, substantia nigra, locus coeruleus and dorsal motor nucleus of the vagus. The cellular pathology included widespread and frequent neuronal α-synuclein immunoreactive inclusions of variable morphology and oligodendroglial inclusions similar to the glial cytoplasmic inclusions of multiple system atrophy (MSA). Both inclusion types were ubiquitin and p62 positive and were labelled with phosphorylation-dependent anti-α-synuclein antibodies In addition, TDP-43 immunoreactive inclusions were observed in limbic regions and in the striatum. Together the data show clinical and neuropathological similarities to both the A53T SNCA mutation and multiplication cases. The cellular neuropathological features of this case share some characteristics of both PD and MSA with additional unique striatal and neocortical pathology. Greater understanding of the disease mechanism underlying the G51D mutation could aid in understanding of α-synuclein biology and its impact on disease phenotype.
Electronic supplementary material
The online version of this article (doi:10.1007/s00401-013-1096-7) contains supplementary material, which is available to authorized users.
PMCID: PMC3681325  PMID: 23404372
Parkinson’s disease; Multiple system atrophy; α-Synuclein; SNCA
5.  A comparative clinical, pathological, biochemical and genetic study of fused in sarcoma proteinopathies 
Brain  2011;134(9):2548-2564.
Neuronal intermediate filament inclusion disease and atypical frontotemporal lobar degeneration are rare diseases characterized by ubiquitin-positive inclusions lacking transactive response DNA-binding protein-43 and tau. Recently, mutations in the fused in sarcoma gene have been shown to cause familial amyotrophic lateral sclerosis and fused in sarcoma-positive neuronal inclusions have subsequently been demonstrated in neuronal intermediate filament inclusion disease and atypical frontotemporal lobar degeneration with ubiquitinated inclusions. Here we provide clinical, imaging, morphological findings, as well as genetic and biochemical data in 14 fused in sarcoma proteinopathy cases. In this cohort, the age of onset was variable but included cases of young-onset disease. Patients with atypical frontotemporal lobar degeneration with ubiquitinated inclusions all presented with behavioural variant frontotemporal dementia, while the clinical presentation in neuronal intermediate filament inclusion disease was more heterogeneous, including cases with motor neuron disease and extrapyramidal syndromes. Neuroimaging revealed atrophy of the frontal and anterior temporal lobes as well as the caudate in the cases with atypical frontotemporal lobar degeneration with ubiquitinated inclusions, but was more heterogeneous in the cases with neuronal intermediate filament inclusion disease, often being normal to visual inspection early on in the disease. The distribution and severity of fused in sarcoma-positive neuronal cytoplasmic inclusions, neuronal intranuclear inclusions and neurites were recorded and fused in sarcoma was biochemically analysed in both subgroups. Fused in sarcoma-positive neuronal cytoplasmic and intranuclear inclusions were found in the hippocampal granule cell layer in variable numbers. Cortical fused in sarcoma-positive neuronal cytoplasmic inclusions were often ‘Pick body-like’ in neuronal intermediate filament inclusion disease, and annular and crescent-shaped inclusions were seen in both conditions. Motor neurons contained variable numbers of compact, granular or skein-like cytoplasmic inclusions in all fused in sarcoma-positive cases in which brainstem and spinal cord motor neurons were available for study (five and four cases, respectively). No fused in sarcoma mutations were found in any cases. Biochemically, two major fused in sarcoma species were found and shown to be more insoluble in the atypical frontotemporal lobar degeneration with ubiquitinated inclusions subgroup compared with neuronal intermediate filament inclusion disease. There is considerable overlap and also significant differences in fused in sarcoma-positive pathology between the two subgroups, suggesting they may represent a spectrum of the same disease. The co-existence of fused in sarcoma-positive inclusions in both motor neurons and extramotor cerebral structures is a characteristic finding in sporadic fused in sarcoma proteinopathies, indicating a multisystem disorder.
PMCID: PMC3170529  PMID: 21752791
frontotemporal lobar degeneration; FUS; clinical presentation; neuropathology; biochemistry
6.  Deep Brain Stimulation effects in Dystonia: Time course of electrophysiological changes in early treatment 
Deep brain stimulation (DBS) to the internal globus pallidus is an effective treatment for primary dystonia. The optimal clinical effect often occurs only weeks to months after starting stimulation. To better understand the underlying electrophysiological changes in this period we assessed longitudinally two pathophysiological markers of dystonia in patients prior to and in the early treatment period (1,3,6 months) after DBS-surgery.
Transcranial magnetic stimulation was used to track changes in short latency intracortical inhibition (SICI), a measure of excitability of GABAA-ergic corticocortical connections and long-term potentiation-like synaptic plasticity (as a response to paired associative stimulation, PAS). DBS remained ON for the duration of the study.
Prior to surgery, inhibition was reduced and plasticity increased in patients compared to healthy controls. Following surgery and commencement of DBS, SICI increased towards normal levels over the following months with the same monotonic time course as the patients' clinical benefit. In contrast, synaptic plasticity changed rapidly following a non-monotonic time course: it was absent early (1 month) after surgery, and then over the following months increased towards levels observed in healthy individuals.
We postulate that before surgery pre-existing high levels of plasticity form strong memories of dystonic movement patterns. When DBS is turned ON, it disrupts abnormal basal ganglia signals resulting in the absent response to PAS at one month. Clinical benefit is delayed because engrams of abnormal movement persist and take time to normalise. Our observations suggest that plasticity may be a driver of long term therapeutic effects of DBS in dystonia.
PMCID: PMC3174341  PMID: 21547950
dystonia; deep brain stimulation; plasticity; longitudinal; human; excitability; mechanism
7.  Adult onset asymmetric upper limb tremor misdiagnosed as Parkinson’s disease: A clinical and electrophysiological study 
Approximately 10% of subjects thought clinically to have early Parkinson’s disease (PD) have normal dopaminergic functional imaging (SWEDDs – Scans Without Evidence of Dopaminergic Deficit). SWEDDs are a heterogeneous group. Here we aimed to delineate clinical and electrophysiological characteristics of a distinct subgroup of SWEDDs patients from PD and to clarify the underlying pathophysiology of this subgroup as a form of parkinsonism or dystonia. Therefore we compared clinical details of 25 patients referred with a diagnosis of tremor-dominant PD but with normal DaT SPECT scans (SWEDDs) with 12 tremor-dominant PD patients with abnormal DaT SPECT scans. We performed tremor analysis using accelerometry in the following patients with 1) SWEDDs, 2) PD, 3) primary segmental dystonia with dystonic limb tremor and 4) essential tremor (ET). We used transcranial magnetic stimulation with a facilitatory paired associative stimulation (PAS) paradigm to test if sensorimotor plasticity in SWEDDs resembled the pattern seen in PD, dystonia or ET. Although PD and SWEDDs patients shared several clinical features, the lack of true bradykinesia, occurrence of dystonia, and position- and task-specificity of tremor favoured a diagnosis of SWEDDs, whereas re-emergent tremor, true fatiguing or decrement, good response to dopaminergic drugs as well as presence of nonmotor symptoms made PD more likely. Basic tremor parameters overlapped between SWEDDs, PD, segmental dystonia and ET. However, a combination of re-emergent tremor and highest tremor amplitude in the resting condition was characteristic of PD tremor, while SWEDDs, dystonia and ET subjects had the highest tremor amplitude during action. Both SWEDDs and segmental dystonia patients exhibited an exaggerated pattern of sensorimotor plasticity in response to the PAS paradigm, with spread of excitation to an adjacent hand muscle. In contrast, PD patients showed no response to PAS, and the response of ET patients was no different from controls. Taken together, these results may help differentiate these SWEDDs patients from PD and support our hypothesis that adult-onset dystonia is the underlying diagnosis in this sub-group of patients with SWEDDs.
PMCID: PMC2996567  PMID: 20131394
SWEDDs; benign tremulous Parkinson’s disease; dystonic tremor; accelerometry; paired associative stimulation
9.  Deep brain stimulation plus best medical therapy versus best medical therapy alone for advanced Parkinson's disease (PD SURG trial): a randomised, open-label trial 
Lancet Neurology  2010;9(6):581-591.
Surgical intervention for advanced Parkinson's disease is an option if medical therapy fails to control symptoms adequately. We aimed to assess whether surgery and best medical therapy improved self-reported quality of life more than best medical therapy alone in patients with advanced Parkinson's disease.
The PD SURG trial is an ongoing randomised, open-label trial. At 13 neurosurgical centres in the UK, between November, 2000, and December, 2006, patients with Parkinson's disease that was not adequately controlled by medical therapy were randomly assigned by use of a computerised minimisation procedure to immediate surgery (lesioning or deep brain stimulation at the discretion of the local clinician) and best medical therapy or to best medical therapy alone. Patients were analysed in the treatment group to which they were randomised, irrespective of whether they received their allocated treatment. The primary endpoint was patient self-reported quality of life on the 39-item Parkinson's disease questionnaire (PDQ-39). Changes between baseline and 1 year were compared by use of t tests. This trial is registered with Current Controlled Trials, number ISRCTN34111222.
366 patients were randomly assigned to receive immediate surgery and best medical therapy (183) or best medical therapy alone (183). All patients who had surgery had deep brain stimulation. At 1 year, the mean improvement in PDQ-39 summary index score compared with baseline was 5·0 points in the surgery group and 0·3 points in the medical therapy group (difference −4·7, 95% CI −7·6 to −1·8; p=0·001); the difference in mean change in PDQ-39 score in the mobility domain between the surgery group and the best medical therapy group was −8·9 (95% CI −13·8 to −4·0; p=0·0004), in the activities of daily living domain was −12·4 (−17·3 to −7·5; p<0·0001), and in the bodily discomfort domain was −7·5 (−12·6 to −2·4; p=0·004). Differences between groups in all other domains of the PDQ-39 were not significant. 36 (19%) patients had serious surgery-related adverse events; there were no suicides but there was one procedure-related death. 20 patients in the surgery group and 13 in the best medical therapy group had serious adverse events related to Parkinson's disease and drug treatment.
At 1 year, surgery and best medical therapy improved patient self-reported quality of life more than best medical therapy alone in patients with advanced Parkinson's disease. These differences are clinically meaningful, but surgery is not without risk and targeting of patients most likely to benefit might be warranted.
UK Medical Research Council, Parkinson's UK, and UK Department of Health.
PMCID: PMC2874872  PMID: 20434403
13.  Functional neurosurgery for Parkinson’s disease 
BMJ : British Medical Journal  1998;316(7140):1259-1260.
PMCID: PMC1113027  PMID: 9554893

Results 1-19 (19)