PTPA variants and impaired PP2A activity in early-onset parkinsonism with intellectual disability

The protein phosphatase 2A complex (PP2A), the major Ser/Thr phosphatase in the brain, is involved in a number of signalling pathways and functions, including the regulation of crucial proteins for neurodegeneration, such as alpha-synuclein, tau and LRRK2. Here, we report the identification of variants in the PTPA/PPP2R4 gene, encoding a major PP2A activator, in two families with early-onset parkinsonism and intellectual disability. We carried out clinical studies and genetic analyses, including genome-wide linkage analysis, whole-exome sequencing, and Sanger sequencing of candidate variants. We next performed functional studies on the disease-associated variants in cultured cells and knock-down of ptpa in Drosophila melanogaster. We first identified a homozygous PTPA variant, c.893T&gt;G (p.Met298Arg), in patients from a South African family with early-onset parkinsonism and intellectual disability. Screening of a large series of additional families yielded a second homozygous variant, c.512C&gt;A (p.Ala171Asp), in a Libyan family with a similar phenotype. Both variants co-segregate with disease in the respective families. The affected subjects display juvenile-onset parkinsonism and intellectual disability. The motor symptoms were responsive to treatment with levodopa and deep brain stimulation of the subthalamic nucleus. In overexpression studies, both the PTPA p.Ala171Asp and p.Met298Arg variants were associated with decreased PTPA RNA stability and decreased PTPA protein levels; the p.Ala171Asp variant additionally displayed decreased PTPA protein stability. Crucially, expression of both variants was associated with decreased PP2A complex levels and impaired PP2A phosphatase activation. PTPA orthologue knock-down in Drosophila neurons induced a significant impairment of locomotion in the climbing test. This defect was age-dependent and fully reversed by L-DOPA treatment. We conclude that bi-allelic missense PTPA variants associated with impaired activation of the PP2A phosphatase cause autosomal recessive early-onset parkinsonism with intellectual disability. Our findings might also provide new insights for understanding the role of the PP2A complex in the pathogenesis of more common forms of neurodegeneration.</p

A new MRI rating scale for progressive supranuclear palsy and multiple system atrophy: validity and reliability

AIM To evaluate a standardised MRI acquisition protocol and a new image rating scale for disease severity in patients with progressive supranuclear palsy (PSP) and multiple systems atrophy (MSA) in a large multicentre study. METHODS The MRI protocol consisted of two-dimensional sagittal and axial T1, axial PD, and axial and coronal T2 weighted acquisitions. The 32 item ordinal scale evaluated abnormalities within the basal ganglia and posterior fossa, blind to diagnosis. Among 760 patients in the study population (PSP = 362, MSA = 398), 627 had per protocol images (PSP = 297, MSA = 330). Intra-rater (n = 60) and inter-rater (n = 555) reliability were assessed through Cohen's statistic, and scale structure through principal component analysis (PCA) (n = 441). Internal consistency and reliability were checked. Discriminant and predictive validity of extracted factors and total scores were tested for disease severity as per clinical diagnosis. RESULTS Intra-rater and inter-rater reliability were acceptable for 25 (78%) of the items scored (≥ 0.41). PCA revealed four meaningful clusters of covarying parameters (factor (F) F1: brainstem and cerebellum; F2: midbrain; F3: putamen; F4: other basal ganglia) with good to excellent internal consistency (Cronbach α 0.75-0.93) and moderate to excellent reliability (intraclass coefficient: F1: 0.92; F2: 0.79; F3: 0.71; F4: 0.49). The total score significantly discriminated for disease severity or diagnosis; factorial scores differentially discriminated for disease severity according to diagnosis (PSP: F1-F2; MSA: F2-F3). The total score was significantly related to survival in PSP (p<0.0007) or MSA (p<0.0005), indicating good predictive validity. CONCLUSIONS The scale is suitable for use in the context of multicentre studies and can reliably and consistently measure MRI abnormalities in PSP and MSA. Clinical Trial Registration Number The study protocol was filed in the open clinical trial registry (http://www.clinicaltrials.gov) with ID No NCT00211224

Stimulation subthalamique et maladie de parkinson (effet sur l'expérience émotionnelle musicale)

La stimulation cérébrale profonde (SCP) du noyau subthalamique (NST), proposé aux patients parkinsoniens pour améliorer les symptômes moteurs, a d'autres effets, notamment sur l'expérience émotionnelle subjective. La musique permet de susciter un spectre large d'émotions plus nuancées que les émotions basiques, dédiées à la fonction de survie de l'individu. La Geneva Emotional Music Scale semble être l'échelle la plus adaptée aux émotions musicales pour auto évaluer le ressenti émotionnel. 16 patients parkinsoniens pré-opératoire, 16 patients parkinsoniens post-opératoire de la SCP du NST, et 16 sujets témoins ont été soumis à une procédure d'induction émotionnelle par la musique. Il a été observé des modifications subtiles du ressenti émotionnel du groupe post-opératoire par rapport au groupe pré-opératoire, suggérant un effet de la modulation de l'activité du NST par la SCP. Ces résultats confirment l'implication du NST dans l'émergence de l'expérience émotionnelle subjective.RENNES1-BU Santé (352382103) / SudocSudocFranceF

From Shadow to Spotlight: The (Re)discovery of Trepanned Skulls in France During the 19th Century

International audienceObjective: To understand the French interest in trepanation that emerged following Broca’s paper (1867) in various scientific disciplines, including neurology. To describe the trepanned skulls found on French soil during the 19th century.Background: The study of trepanation is one of Paul Broca’s many contributions to the medical field. His interest in brains and skulls led Ephraim Georges Squier, an American diplomat and archaeologist, to travel to Paris to show him an old Peruvian skull presenting a seemingly man-made rectangular opening. Following this encounter, Broca published a first analysis on Squier’s skull in 1867, suggesting that the cranial opening was the result of surgery. This landmark paper initiated a scientific fascination with ancient skulls found on French soil.Design/Methods: A literature search for French articles related to trepanned skulls discovery and/or analysis between 1800 and 1900 was undertaken, using various databases such as Calames, BnF Gallica Archives, JStor, Internet Archive and Google Scholar.Results: The discovery of trepanned skulls, particularly from the Neolithic period, was not rare on French soil. If some of these skulls were found prior to 1867, and even before the birth of the 19th century, the majority of them were retrieved and analyzed following the excitement initiated by Broca’s papers. Along with Paul Broca, Barthélémy Prunières, Ernest Chantre, Paul du Chatellier and Armand de Quatrefages are the most prominent figures in the study of trepanation in France during the 19th century. Together, they described dozens of trepanned skulls found in different areas (eg: Lozère, Bretagne or Paris Bassin) and discussed several theories on trepanation.Conclusions: The study of French ancient skulls, initiated by a brilliant neurologist, brought together experts from several disciplines (archeology, neurology and anthropology), highlighting the close relationship that has always existed between medicine and humanities

La perfusion sous-cutanée continue d'apomorphine dans le traitement de la maladie de Parkinson (l'expérience bretonne)

RENNES1-BU Santé (352382103) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

L'IRM cérébrale préopératoire est-elle prédictive du bénéfice de la stimulation sous-thalamique dans la maladie de Parkinson ? Etude pilote sur 20 patients

RENNES1-BU Santé (352382103) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Etude prospective de la prise de poids et de l'apport énergétique après stimulation sous-thalamique, pallidale et thalamique dans la maladie de Parkinson

RENNES1-BU Santé (352382103) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

La dopathérapie en perfusion continue intraduodénale dans la maladie de Parkinson (intérêt de DUODOPA®)

RENNES1-BU Santé (352382103) / SudocLYON1-BU Santé (693882101) / SudocSudocFranceF

Effet de la stimulation sous-thalamique sur la dysarthrie parkinsonnienne (étude clinique et acoustique)

RENNES1-BU Santé (352382103) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Effets de la stimulation chronique à haute fréquence du noyau sous-thalamique sur l'expérience émotionnelle ches les patients atteints de la maladie de Parkinson

RENNES1-BU Santé (352382103) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF