TY  - JOUR
A1  - Rauschenberger, Lisa
A1  - Knorr, Susanne
A1  - Pisani, Antonio
A1  - Hallett, Mark
A1  - Volkmann, Jens
A1  - Ip, Chi Wang
T1  - Second hit hypothesis in dystonia: Dysfunctional cross talk between neuroplasticity and environment?
JF  - Neurobiology of Disease
N2  - One of the great mysteries in dystonia pathophysiology is the role of environmental factors in disease onset and development. Progress has been made in defining the genetic components of dystonic syndromes, still the mechanisms behind the discrepant relationship between dystonic genotype and phenotype remain largely unclear. Within this review, the preclinical and clinical evidence for environmental stressors as disease modifiers in dystonia pathogenesis are summarized and critically evaluated. The potential role of extragenetic factors is discussed in monogenic as well as adult-onset isolated dystonia. The available clinical evidence for a "second hit" is analyzed in light of the reduced penetrance of monogenic dystonic syndromes and put into context with evidence from animal and cellular models. The contradictory studies on adult-onset dystonia are discussed in detail and backed up by evidence from animal models. Taken together, there is clear evidence of a gene-environment interaction in dystonia, which should be considered in the continued quest to unravel dystonia pathophysiology.
KW  - dystonia
KW  - second hit
KW  - pathophysiology
KW  - gene-environment interaction
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-265028
VL  - 159
ER  - 
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  -