TY  - JOUR
A1  - Ip, Chi Wang
A1  - Isaias, Ioannis U.
A1  - Kusche-Tekin, Burak B.
A1  - Klein, Dennis
A1  - Groh, Janos
A1  - O´Leary, Aet
A1  - Knorr, Susanne
A1  - Higuchi, Takahiro
A1  - Koprich, James B.
A1  - Brotchie, Jonathan M.
A1  - Toyka, Klaus V.
A1  - Reif, Andreas
A1  - Volkmann, Jens
T1  - Tor1a+/- mice develop dystonia-like movements via a striatal dopaminergic dysregulation triggered by peripheral nerve injury
JF  - Acta Neuropathologica Communications
N2  - Isolated generalized dystonia is a central motor network disorder characterized by twisted movements or postures. The most frequent genetic cause is a GAG deletion in the Tor1a (DYT1) gene encoding torsinA with a reduced penetrance of 30-40 % suggesting additional genetic or environmental modifiers. Development of dystonia-like movements after a standardized peripheral nerve crush lesion in wild type (wt) and Tor1a+/- mice, that express 50 % torsinA only, was assessed by scoring of hindlimb movements during tail suspension, by rotarod testing and by computer-assisted gait analysis. Western blot analysis was performed for dopamine transporter (DAT), D1 and D2 receptors from striatal and quantitative RT-PCR analysis for DAT from midbrain dissections. Autoradiography was used to assess the functional DAT binding in striatum. Striatal dopamine and its metabolites were analyzed by high performance liquid chromatography. After nerve crush injury, we found abnormal posturing in the lesioned hindlimb of both mutant and wt mice indicating the profound influence of the nerve lesion (15x vs. 12x relative to control) resembling human peripheral pseudodystonia. In mutant mice the phenotypic abnormalities were increased by about 40 % (p < 0.05). This was accompanied by complex alterations of striatal dopamine homeostasis. Pharmacological blockade of dopamine synthesis reduced severity of dystonia-like movements, whereas treatment with L-Dopa aggravated these but only in mutant mice suggesting a DYT1 related central component relevant to the development of abnormal involuntary movements. Our findings suggest that upon peripheral nerve injury reduced torsinA concentration and environmental stressors may act in concert in causing the central motor network dysfunction of DYT1 dystonia.
KW  - Dystonia
KW  - DYT1
KW  - dopamine
KW  - peripheral injury
KW  - second hit
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-147839
VL  - 4
IS  - 108
ER  - 
TY  - JOUR
A1  - Isaias, Ioannis Ugo
A1  - Spiegel, Jörg
A1  - Brumberg, Joachim
A1  - Cosgrove, Kelly P.
A1  - Marotta, Giorgio
A1  - Oishi, Naoya
A1  - Higuchi, Takahiro
A1  - Küsters, Sebastian
A1  - Schiller, Markus
A1  - Dillmann, Ulrich
A1  - van Dyck, Christopher H.
A1  - Buck, Andreas
A1  - Herrmann, Ken
A1  - Schloegl, Susanne
A1  - Volkmann, Jens
A1  - Lassmann, Michael
A1  - Fassbender, Klaus
A1  - Lorenz, Reinhard
A1  - Samnick, Samuel
T1  - Nicotinic acetylcholine receptor density in cognitively intact subjects at an early stage of Parkinson's disease
JF  - Frontiers in Aging Neuroscience
N2  - We investigated in vivo brain nicotinic acetylcholine receptor (nAChR) distribution in cognitively intact subjects with Parkinson's disease (PD) at an early stage of the disease. Fourteen patients and 13 healthy subjects were imaged with single photon emission computed tomography and the radiotracer 5-[(123)I]iodo-3-[2(S)-2-azetidinylmethoxy]pyridine ([(123)I]5IA). Patients were selected according to several criteria, including short duration of motor signs (<7 years) and normal scores at an extensive neuropsychological evaluation. In PD patients, nAChR density was significantly higher in the putamen, the insular cortex and the supplementary motor area and lower in the caudate nucleus, the orbitofrontal cortex, and the middle temporal gyrus. Disease duration positively correlated with nAChR density in the putamen ipsilateral (ρ = 0.56, p < 0.05) but not contralateral (ρ = 0.49, p = 0.07) to the clinically most affected hemibody. We observed, for the first time in vivo, higher nAChR density in brain regions of the motor and limbic basal ganglia circuits of subjects with PD. Our findings support the notion of an up-regulated cholinergic activity at the striatal and possibly cortical level in cognitively intact PD patients at an early stage of disease.
KW  - nicotinic receptors
KW  - Parkinson disease
KW  - 5IA-SPECT
KW  - dopamine acetylcholine
KW  - cognitive decline
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-119351
VL  - 6
ER  -