502 research outputs found
Ambroxol effects in glucocerebrosidase and -synuclein transgenic mice
Objective. Gaucher disease is caused by mutations in the glucocerebrosidase 1 gene that result in deficiency of the lysosomal enzyme glucocerebrosidase. Both homozygous and heterozygous glucocerebrosidase 1 mutations confer an increased risk for developing Parkinson disease. Current estimates indicate that 10 to 25% of Parkinson patients carry glucocerebrosidase 1 mutations. Ambroxol is a small molecule chaperone that has been shown to increase glucocerebrosidase activity in vitro. This study investigated the effect of ambroxol treatment on glucocerebrosidase activity and on α-synuclein and phosphorylated α-synuclein protein levels in mice.
Methods. Mice were treated with ambroxol for 12 days. After the treatment, glucocerebrosidase activity was measured in the mouse brain lysates. The brain lysates were also analyzed for α-synuclein and phosphorylated α-synuclein protein levels.
Results. Ambroxol treatment resulted in increased brain glucocerebrosidase activity in (1) wild-type mice, (2) transgenic mice expressing the heterozygous L444P mutation in the murine glucocerebrosidase 1 gene, and (3) transgenic mice overexpressing human α-synuclein. Furthermore, in the mice overexpressing human α-synuclein, ambroxol treatment decreased both α-synuclein and phosphorylated α-synuclein protein levels.
Interpretation. Our work supports the proposition that ambroxol should be further investigated as a potential novel disease-modifying therapy for treatment of Parkinson disease and neuronopathic Gaucher disease to increase glucocerebrosidase activity and decrease α-synuclein and phosphorylated α-synuclein protein levels
Distinct Changes in cAMP and Extracellular Signal-Regulated Protein Kinase Signalling in L-DOPA-Induced Dyskinesia
Background: In rodents, the development of dyskinesia produced by L-DOPA in the dopamine-depleted striatum occurs in response to increased dopamine D1 receptor-mediated activation of the cAMP- protein kinase A and of the Rasextracellular signal-regulated kinase (ERK) signalling pathways. However, very little is known, in non-human primates, about the regulation of these signalling cascades and their association with the induction, manifestation and/or maintenance of dyskinesia. Methodology/Results: We here studied, in the gold-standard non-human primate model of Parkinson’s disease, the changes in PKA-dependent phosphorylation of DARPP-32 and GluR1 AMPA receptor, as well as in ERK and ribosomal protein S6 (S6) phosphorylation, associated to acute and chronic administration of L-DOPA. Increased phosphorylation of DARPP-32 and GluR1 was observed in both L-DOPA first-ever exposed and chronically-treated dyskinetic parkinsonian monkeys. In contrast, phosphorylation of ERK and S6 was enhanced preferentially after acute L-DOPA administration and decreased during the course of chronic treatment. Conclusion: Dysregulation of cAMP signalling is maintained during the course of chronic L-DOPA administration, while abnormal ERK signalling peaks during the initial phase of L-DOPA treatment and decreases following prolonged exposure
Detection of interstellar CH_3
Observations with the Short Wavelength Spectrometer (SWS) onboard the {\it
Infrared Space Observatory} (ISO) have led to the first detection of the methyl
radical in the interstellar medium. The branch at 16.5
m and the (0) line at 16.0 m have been unambiguously detected
toward the Galactic center SgrA. The analysis of the measured bands gives a
column density of (8.02.4) cm and an excitation
temperature of K. Gaseous at a similarly low excitation
temperature and are detected for the same line of sight. Using
constraints on the column density obtained from and
visual extinction, the inferred abundance is
. The chemically related
molecule is not detected, but the pure rotational lines of are seen
with the Long Wavelength Spectrometer (LWS). The absolute abundances and the
and ratios are inconsistent with published
pure gas-phase models of dense clouds. The data require a mix of diffuse and
translucent clouds with different densities and extinctions, and/or the
development of translucent models in which gas-grain chemistry, freeze-out and
reactions of with polycyclic aromatic hydrocarbons and solid
aliphatic material are included.Comment: 2 figures. ApJL, Accepte
The role of GRK6 in animal models of Parkinson's Disease and L-DOPA treatment
G protein-coupled Receptor Kinase 6 (GRK6) belongs to a family of kinases that phosphorylate GPCRs. GRK6 levels were found to be altered in Parkinson's Disease (PD) and D2 dopamine receptors are supersensitive in mice lacking GRK6 (GRK6-KO mice). To understand how GRK6 modulates the behavioral manifestations of dopamine deficiency and responses to L-DOPA, we used three approaches to model PD in GRK6-KO mice: 1) the cataleptic response to haloperidol; 2) introducing GRK6 mutation to an acute model of absolute dopamine deficiency, DDD mice; 3) hemiparkinsonian 6-OHDA model. Furthermore, dopamine-related striatal signaling was analyzed by assessing the phosphorylation of AKT/GSK3β and ERK1/2. GRK6 deficiency reduced cataleptic behavior, potentiated the acute effect of L-DOPA in DDD mice, reduced rotational behavior in hemi-parkinsonian mice, and reduced abnormal involuntary movements induced by chronic L-DOPA. These data indicate that approaches to regulate GRK6 activity could be useful in modulating both therapeutic and side-effects of L-DOPA
D/H Ratios on Saturn and Jupiter from Cassini CIRS
We present new measurements of the deuterium abundance on Jupiter and Saturn, showing evidence that Saturn's atmosphere contains less deuterium than Jupiter's. We analyzed far-infrared spectra from the Cassini Composite Infrared Spectrometer to measure the abundance of HD on both giant planets. Our estimate of the Jovian D/H = (2.95 ± 0.55) × 10−5 is in agreement with previous measurements by ISO/SWS: (2.25 ± 0.35) × 10−5, and the Galileo probe: (2.6 ± 0.7) × 10−5. In contrast, our estimate of the Saturn value of (2.10 ± 0.13) × 10−5 is somewhat lower than on Jupiter (by a factor of ), contrary to model predictions of a higher ratio: Saturn/Jupiter = 1.05–1.20. The Saturn D/H value is consistent with estimates for hydrogen in the protosolar nebula (2.1 ± 0.5) × 10−5, but its apparent divergence from the Jovian value suggests that our understanding of planetary formation and evolution is incomplete, which is in agreement with previous work.The US-based authors: J.E.D.P., C.A.N., G.L.B., R.K.A., B.E.H., and F.M.F. were supported by the NASA Cassini Mission during the period when this research was conducted. L.N.F. was supported by a Royal Society Research Fellowship at the University of Leicester. P.G.J.I. was supported by the United Kingdom Science and Technology Facilities Council.Peer-reviewedPublisher Versio
Basic Science in Movement Disorders: Fueling the Engine of Translation into Clinical Practice
\ua9 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. Basic Science is crucial for the advancement of clinical care for Movement Disorders. Here, we provide brief updates on how basic science is important for understanding disease mechanisms, disease prevention, disease diagnosis, development of novel therapies and to establish the basis for personalized medicine. We conclude the viewpoint by a call to action to further improve interactions between clinician and basic scientists. \ua9 2024 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society
Striatal Proteomic Analysis Suggests that First L-Dopa Dose Equates to Chronic Exposure
L-3,4-dihydroxypheylalanine (L-dopa)-induced dyskinesia represent a debilitating complication of therapy for Parkinson's disease (PD) that result from a progressive sensitization through repeated L-dopa exposures. The MPTP macaque model was used to study the proteome in dopamine-depleted striatum with and without subsequent acute and chronic L-dopa treatment using two-dimensional difference in-gel electrophoresis (2D-DIGE) and mass spectrometry. The present data suggest that the dopamine-depleted striatum is so sensitive to de novo L-dopa treatment that the first ever administration alone would be able (i) to induce rapid post-translational modification-based proteomic changes that are specific to this first exposure and (ii), possibly, lead to irreversible protein level changes that would be not further modified by chronic L-dopa treatment. The apparent equivalence between first and chronic L-dopa administration suggests that priming would be the direct consequence of dopamine loss, the first L-dopa administrations only exacerbating the sensitization process but not inducing it
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