Emmanuel Roze

Role of the ERK/MSK1 signalling pathway in chromatin remodelling and brain responses to drugs of abuse.

Drugs of abuse induce neuroadaptations through regulation of gene expression. Although much attention has focused on transcription factor activities, new concepts have recently emerged on the role of chromatin remodelling as a prerequisite for regulation of gene expression in neurons. Thus, for transcription to occur, chromatin must be decondensed, a dynamic process that depends on post‐translational modifications of histones. We review here these modifications with a particular emphasis on the role of histone H3 phosphorylation at the promoter of specific genes, including c‐fos and c‐jun. We trace the signalling pathways involved in H3 phosphorylation and provide evidence for a role of mitogen and stress‐activated protein kinase‐1 (MSK1) downstream from the MAPK/extracellular‐signal regulated kinase (ERK) cascade. In response to cocaine, MSK1 controls an early phase of histone H3 phosphorylation at the c‐fos promoter in striatal neurons. MSK1 action may be potentiated by the concomitant inhibition of protein phosphatase 1 by nuclear translocation of dopamine‐ and cAMP‐regulated phosphoprotein Mr = 32 000. H3 phosphorylation by MSK1 is critically involved in c‐fos transcription, and cocaine‐induced locomotor sensitization. Thus, ERK plays a dual role in gene regulation and drug addiction by direct activation of transcription factors and by chromatin remodelling.

Cerebellar Processing of Sensory Inputs Primes Motor Cortex Plasticity

Plasticity of the human primary motor cortex (M1) has a critical role in motor control and learning. The cerebellum facilitates these functions using sensory feedback. We investigated whether cerebellar processing of sensory afferent information influences the plasticity of the primary motor cortex (M1). Theta-burst stimulation protocols (TBS), both excitatory and inhibitory, were used to modulate the excitability of the posterior cerebellar cortex and to condition an ongoing M1 plasticity. M1 plasticity was subsequently induced in 2 different ways: by paired associative stimulation (PAS) involving sensory processing and TBS that exclusively involves intracortical circuits of M1. Cerebellar excitation attenuated the PAS-induced M1 plasticity, whereas cerebellar inhibition enhanced and prolonged it. Furthermore, cerebellar inhibition abolished the topography-specific response of PAS-induced M1 plasticity, with the effects spreading to adjacent motor maps. Conversely, cerebellar excitation had no effect on the TBS-induced M1 plasticity. This demonstrates the key role of the cerebellum in priming M1 plasticity, and we propose that it is likely to occur at the thalamic or olivo-dentate nuclear level by influencing the sensory processing. We suggest that such a cerebellar priming of M1 plasticity could shape the impending motor command by favoring or inhibiting the recruitment of several muscle representations.

Myoclonus or tremor in orthostatism: an under-recognized cause of unsteadiness in Parkinson's disease.

Patients with Parkinsons disease (PD) often complain of unsteadiness. This can occur as the result of various neurological dysfunctions, including changes in postural adjustments, loss of postural reflexes, axial akinesia and rigidity, freezing and/or postural hypotension. In some cases these symptoms remain unexplained, and rare cases of unsteadiness have been attributed to tremor on standing. To delineate this condition, we investigated 11 consecutive PD patients with unexplained unsteadiness because of tremor on standing, seen in our department over a 6‐year period. All the patients had detailed clinical and electrophysiological investigations based on surface polygraphic electromyographic recordings. Four patients had fast orthostatic tremor (13–18 Hz), one had intermediate orthostatic tremor (8–9 Hz), and three had slow orthostatic tremor (4–6 Hz). The remaining 3 patients had orthostatic myoclonus, a condition that has not previously been reported in PD. Patients with fast tremor improved on clonazepam. Patients with slow tremor and myoclonus improved on levodopa and sometimes benefited further when clonazepam was added. These observations show the usefulness of neurophysiological investigations for diagnosing and treating unexplained unsteadiness in Parkinsons disease.

Benign hereditary chorea: phenotype, prognosis, therapeutic outcome and long term follow-up in a large series with new mutations in the TITF1/NKX2-1 gene

Background Benign hereditary chorea (BHC) is a rare autosomal dominant disorder characterised by childhood onset that tends to improve in adulthood. The associated gene, NKX2-1 (previously called TITF1), is essential for organogenesis of the basal ganglia, thyroid and lungs. The aim of the study was to refine the movement disorders phenotype. We also studied disease course and response to therapy in a large series of genetically proven patients. Methods We analysed clinical, genetic findings and follow-up data in 28 NKX2-1 mutated BHC patients from 13 families. Results All patients had private mutations, including seven new mutations, three previously reported mutations and three sporadic deletions encompassing the NKX2-1 gene. Hypotonia and chorea were present in early infancy, with delayed walking ability (25/28); dystonia, myoclonus and tics were often associated. Attention deficit hyperactivity disorder (ADHD) was present in seven. Among the 14 patients followed-up until adulthood, nine had persistent mild chorea, two had near total resolution of chorea but persistent disabling prominent myoclonus and three recovered completely. Learning difficulties were observed in 20/28 patients, and three had mental retardation. Various combinations of BHC, thyroid (67%) and lung (46%) features were noted. We found no genotype–phenotype correlation. A rapid and sustained beneficial effect on chorea was obtained in 5/8 patients treated with tetrabenazine. Conclusion Early onset chorea preceded by hypotonia is suggestive of BHC. Associated thyroid or respiratory disorders further support the diagnosis and call for genetic studies. Tetrabenazine may be an interesting option to treat disabling chorea.

Mitogen- and stress-activated protein kinase-1 deficiency is involved in expanded-huntingtin-induced transcriptional dysregulation and striatal death

Huntingtons disease (HD) is a neurodegenerative disorder due to an abnormal polyglutamine expansion in the N‐terminal region of huntingtin protein (Exp‐Htt). This expansion causes protein aggregation and neuronal dysfunction and death. Transcriptional dysregulation due to Exp‐Htt participates in neuronal death in HD. Here, using the R6/2 transgenic mouse model of HD, we identified a new molecular alteration that could account for gene dysregulation in these mice. Despite a nuclear activation of the mitogen‐activated protein kinase/extracellular regulated kinase (ERK) along with Elk‐1 and cAMP responsive element binding, two transcription factors involved in c‐Fos transcription, we failed to detect any histone H3 phosphorylation, which is expected after nuclear ERK activation. Accordingly, we found in the striatum of these mice a deficiency of mitogen‐ and stress‐activated kinase‐1 (MSK‐1), a kinase downstream ERK, critically involved in H3 phosphorylation and c‐Fos induction. We extended this observation to Exp‐Htt‐expressing striatal neurons and postmortem brains of HD patients. In vitro, knocking out MSK‐1 expression potentiated Exp‐Htt‐induced striatal death. Its overexpression induced H3 phosphorylation and c‐Fos expression and totally protected against striatal neurodegeneration induced by Exp‐Htt. We propose that MSK‐1 deficiency is involved in transcriptional dysregulation and striatal degeneration. Restoration of its expression and activity may be a new therapeutic target in HD. Roze E., Betuing, S., Deyts, C., Marcon, E., Brami‐Cherrier, K., Pages, C., Humbert, S., Mérienne, K., Caboche J. Mitogen‐ and stress‐activated protein kinase‐1 deficiency is involved in expanded‐hunting‐tin‐induced transcriptional dysregulation and striatal death. FASEB J. 22, 1083–1093 (2008)

Dystonia and parkinsonism in GM1 type 3 gangliosidosis.

GM1 gangliosidosis is due to β‐galactosidase deficiency. Only patients with type 3 disease survive into adulthood and develop movement disorders. Clinical descriptions of this form are rare, particularly in non‐Japanese patients. We describe four new patients and systematically analyze all previous reports found by a literature search and contacts with the authors for additional information. Generalized dystonia remained the predominant feature throughout the disease course and was often associated with akinetic–rigid parkinsonism. GM1 gangliosidosis must be considered as a cause of early‐onset generalized dystonia, particularly in patients with short stature and skeletal dysplasia.

PRRT2 mutations and paroxysmal disorders.

In the past year, mutations in the PRRT2 gene have been identified in patients with paroxysmal kinesigenic dyskinesia and other paroxysmal disorders. We conducted a review of the literature on PRRT2 mutation‐associated disorders. Our objectives were to describe the wide clinical spectrum associated with PRRT2 mutations, and to present the current hypotheses on the underlying pathophysiology. PRRT2 mutations are associated with a wide range of clinical syndromes: the various paroxysmal dyskinesias, infantile seizures, paroxysmal torticollis, migraine, hemiplegic migraine, episodic ataxia and even intellectual disability in the homozygous state. The PRRT2 protein, through its interaction with SNAP‐25, could play a role in synaptic regulation in the cortex and the basal ganglia. The pathogenesis may be caused by PRRT2 loss of function, which may induce synaptic deregulation and neuronal hyperexcitability. However, this does not explain the phenotypic variability, which is likely modulated by environmental factors, modifier genes or age‐dependent expression. The clinical spectrum of PRRT2 mutations has expanded among paroxysmal disorders and beyond. Unraveling the molecular pathways linking the genetic defect to its clinical expression will be crucial for the diagnosis and treatment of these disorders.

Haloperidol protects striatal neurons from dysfunction induced by mutated huntingtin in vivo.

Huntingtons disease (HD) results from an abnormal polyglutamine extension in the N-terminal region of the huntingtin protein. This mutation causes preferential degeneration of striatal projection neurons. We previously demonstrated, in vitro, that dopaminergic D2 receptor stimulation acted synergistically with mutated huntingtin (expHtt) to increase aggregate formation and striatal death. In the present work, we extend these observations to an in vivo system based on lentiviral-mediated expression of expHtt in the rat striatum. The early and chronic treatment with the D2 antagonist haloperidol decanoate protects striatal neurons from expHtt-induced dysfunction, as analyzed by DARPP-32 and NeuN stainings. Haloperidol treatment also reduces aggregates formation, an effect that is maintained over time. These findings indicate that D2 receptors activation contributes to the deleterious effects of expHtt on striatal function and may represent an interesting early target to alter the subsequent course of neuropathology in HD.

Case-control study of writer's cramp

Task-specific focal dystonias are thought to be due to a combination of individual vulnerability and environmental factors. There are no case-control studies of risk factors for writers cramp. We undertook a case-control study of 104 consecutive patients and matched controls to identify risk factors for the condition. We collected detailed data on medical history and writing history as part of hobbies or occupation. Cases had a college or university degree more frequently than controls [OR = 4.6 (1.3-20.5), P = 0.01]. The risk of writers cramp increased with the time spent writing each day (P-trend = 0.001) and was also associated with an abrupt increase in the writing time during the year before onset (OR = 5.7, 95% CI = 1.3-33.9, P = 0.02). Head trauma with loss of consciousness [OR = 3.5 (1.0-15.7), P = 0.05] and myopia [OR = 4.1 (1.7-12.0), P = 0.0009] were both associated with the condition but it was not significantly associated with peripheral trauma, left-handedness, constrained writing, writing in stressful situations or the choice of writing tool. The dose-effect relationship between writers cramp and the time spent handwriting each day, and the additional burden of acute triggers such as an abrupt increase in the writing time in the year before onset, point to a disruptive phenomenon in predisposed subjects. Homeostatic regulation of cortical plasticity may be overwhelmed, resulting in dystonia.

The improvement of movement and speech during rapid eye movement sleep behaviour disorder in multiple system atrophy

Multiple system atrophy is an atypical parkinsonism characterized by severe motor disabilities that are poorly levodopa responsive. Most patients develop rapid eye movement sleep behaviour disorder. Because parkinsonism is absent during rapid eye movement sleep behaviour disorder in patients with Parkinsons disease, we studied the movements of patients with multiple system atrophy during rapid eye movement sleep. Forty-nine non-demented patients with multiple system atrophy and 49 patients with idiopathic Parkinsons disease were interviewed along with their 98 bed partners using a structured questionnaire. They rated the quality of movements, vocal and facial expressions during rapid eye movement sleep behaviour disorder as better than, equal to or worse than the same activities in an awake state. Sleep and movements were monitored using video-polysomnography in 22/49 patients with multiple system atrophy and in 19/49 patients with Parkinsons disease. These recordings were analysed for the presence of parkinsonism and cerebellar syndrome during rapid eye movement sleep movements. Clinical rapid eye movement sleep behaviour disorder was observed in 43/49 (88%) patients with multiple system atrophy. Reports from the 31/43 bed partners who were able to evaluate movements during sleep indicate that 81% of the patients showed some form of improvement during rapid eye movement sleep behaviour disorder. These included improved movement (73% of patients: faster, 67%; stronger, 52%; and smoother, 26%), improved speech (59% of patients: louder, 55%; more intelligible, 17%; and better articulated, 36%) and normalized facial expression (50% of patients). The rate of improvement was higher in Parkinsons disease than in multiple system atrophy, but no further difference was observed between the two forms of multiple system atrophy (predominant parkinsonism versus cerebellar syndrome). Video-monitored movements during rapid eye movement sleep in patients with multiple system atrophy revealed more expressive faces, and movements that were faster and more ample in comparison with facial expression and movements during wakefulness. These movements were still somewhat jerky but lacked any visible parkinsonism. Cerebellar signs were not assessable. We conclude that parkinsonism also disappears during rapid eye movement sleep behaviour disorder in patients with multiple system atrophy, but this improvement is not due to enhanced dopamine transmission because these patients are not levodopa-sensitive. These data suggest that these movements are not influenced by extrapyramidal regions; however, the influence of abnormal cerebellar control remains unclear. The transient disappearance of parkinsonism here is all the more surprising since no treatment (even dopaminergic) provides a real benefit in this disabling disease.