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  - Stengel, Felix
A1  - Vulinovic, Franca
A1  - Meier, Britta
A1  - Grütz, Karen
A1  - Klein, Christine
A1  - Capetian, Philipp
T1  - Impaired differentiation of human induced neural stem cells by TOR1A overexpression
JF  - Molecular Biology Reports
N2  - DYT-TOR1A is the most common inherited dystonia caused by a three nucleotide (GAG) deletion (dE) in the TOR1A gene. Death early after birth and cortical anomalies of the full knockout in rodents underscore its developmental importance. We therefore explored the timed effects of TOR1A-wt and TOR1A-dE during differentiation in a human neural in vitro model. We used lentiviral tet-ON expression of TOR1A-wt and -dE in induced neural stem cells derived from healthy donors. Overexpression was induced during proliferation of neural precursors, during differentiation and after differentiation into mature neurons. Overexpression of both wildtype and mutated protein had no effect on the viability and cell number of neural precursors as well as mature neurons when initiated before or after differentiation. However, if induced during differentiation, overexpression of TOR1A-wt and -dE led to a pronounced reduction of mature neurons in a dose dependent manner. Our data underscores the importance of physiological expression levels of TOR1A as crucial for proper neuronal differentiation. We did not find evidence for a specific impact of the mutated TOR1A on neuronal maturation.
KW  - dystonia
KW  - DYT1
KW  - torsinA
KW  - TOR1A
KW  - neuronal stem cells
KW  - neuronal differentiation
KW  - inducible expression
Y1  - 2020
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-241177
UR  - https://doi.org/10.1007/s11033-020-05390-x
VL  - 47
ER  -