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 - Ip, Chi Wang A1 - Kroner, Antje A1 - Groh, Janos A1 - Huber, Marianne A1 - Klein, Dennis A1 - Spahn, Irene A1 - Diem, Ricarda A1 - Williams, Sarah K. A1 - Nave, Klaus-Armin A1 - Edgar, Julia M. A1 - Martini, Rudolf T1 - Neuroinflammation by Cytotoxic T-Lymphocytes Impairs Retrograde Axonal Transport in an Oligodendrocyte Mutant Mouse JF - PLoS One N2 - Mice overexpressing proteolipid protein (PLP) develop a leukodystrophy-like disease involving cytotoxic, CD8+ T-lymphocytes. Here we show that these cytotoxic T-lymphocytes perturb retrograde axonal transport. Using fluorogold stereotactically injected into the colliculus superior, we found that PLP overexpression in oligodendrocytes led to significantly reduced retrograde axonal transport in retina ganglion cell axons. We also observed an accumulation of mitochondria in the juxtaparanodal axonal swellings, indicative for a disturbed axonal transport. PLP overexpression in the absence of T-lymphocytes rescued retrograde axonal transport defects and abolished axonal swellings. Bone marrow transfer from wildtype mice, but not from perforin- or granzyme B-deficient mutants, into lymphocyte-deficient PLP mutant mice led again to impaired axonal transport and the formation of axonal swellings, which are predominantly located at the juxtaparanodal region. This demonstrates that the adaptive immune system, including cytotoxic T-lymphocytes which release perforin and granzyme B, are necessary to perturb axonal integrity in the PLP-transgenic disease model. Based on our observations, so far not attended molecular and cellular players belonging to the immune system should be considered to understand pathogenesis in inherited myelin disorders with progressive axonal damage. KW - myelin KW - experimental autoimmune encephalomyelitis KW - degeneration KW - axonopathic changes KW - neural apoptosis KW - nervous system KW - motor function KW - proteolipid protein gene KW - retinal ganglion cells KW - granzyme B KW - multiple sclerosis Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-134982 VL - 7 IS - 8 ER - TY - JOUR A1 - Badr, Mohammad A1 - McFleder, Rhonda L. A1 - Wu, Jingjing A1 - Knorr, Susanne A1 - Koprich, James B. A1 - Hünig, Thomas A1 - Brotchie, Jonathan M. A1 - Volkmann, Jens A1 - Lutz, Manfred B. A1 - Ip, Chi Wang T1 - Expansion of regulatory T cells by CD28 superagonistic antibodies attenuates neurodegeneration in A53T-α-synuclein Parkinson’s disease mice JF - Journal of Neuroinflammation N2 - Background Regulatory CD4\(^+\)CD25\(^+\)FoxP3\(^+\) T cells (Treg) are a subgroup of T lymphocytes involved in maintaining immune balance. Disturbance of Treg number and impaired suppressive function of Treg correlate with Parkinson’s disease severity. Superagonistic anti-CD28 monoclonal antibodies (CD28SA) activate Treg and cause their expansion to create an anti-inflammatory environment. Methods Using the AAV1/2-A53T-α-synuclein Parkinson’s disease mouse model that overexpresses the pathogenic human A53T-α-synuclein (hαSyn) variant in dopaminergic neurons of the substantia nigra, we assessed the neuroprotective and disease-modifying efficacy of a single intraperitoneal dose of CD28SA given at an early disease stage. Results CD28SA led to Treg expansion 3 days after delivery in hαSyn Parkinson’s disease mice. At this timepoint, an early pro-inflammation was observed in vehicle-treated hαSyn Parkinson’s disease mice with elevated percentages of CD8\(^+\)CD69\(^+\) T cells in brain and increased levels of interleukin-2 (IL-2) in the cervical lymph nodes and spleen. These immune responses were suppressed in CD28SA-treated hαSyn Parkinson’s disease mice. Early treatment with CD28SA attenuated dopaminergic neurodegeneration in the SN of hαSyn Parkinson’s disease mice accompanied with reduced brain numbers of activated CD4\(^+\), CD8\(^+\) T cells and CD11b\(^+\) microglia observed at the late disease-stage 10 weeks after AAV injection. In contrast, a later treatment 4 weeks after AAV delivery failed to reduce dopaminergic neurodegeneration. Conclusions Our data indicate that immune modulation by Treg expansion at a timepoint of overt inflammation is effective for treatment of hαSyn Parkinson’s disease mice and suggest that the concept of early immune therapy could pose a disease-modifying option for Parkinson’s disease patients. KW - Parkinson’s disease KW - neuroinflammation KW - T cells KW - regulatory T cells KW - neuroprotection Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-300580 VL - 19 ER - TY - JOUR A1 - Rauschenberger, Lisa A1 - Behnke, Jennifer A1 - Grotemeyer, Alexander A1 - Knorr, Susanne A1 - Volkmann, Jens A1 - Ip, Chi Wang T1 - Age-dependent neurodegeneration and neuroinflammation in a genetic A30P/A53T double-mutated α-synuclein mouse model of Parkinson’s disease JF - Neurobiology of Disease N2 - The pathogenesis of Parkinson's disease (PD) is closely interwoven with the process of aging. Moreover, increasing evidence from human postmortem studies and from animal models for PD point towards inflammation as an additional factor in disease development. We here assessed the impact of aging and inflammation on dopaminergic neurodegeneration in the hm\(^{2}\)α-SYN-39 mouse model of PD that carries the human, A30P/A53T double-mutated α-synuclein gene. At 2–3 months of age, no significant differences were observed comparing dopaminergic neuron numbers of the substantia nigra (SN) pars compacta of hm\(^{2}\)α-SYN-39 mice with wildtype controls. At an age of 16–17 months, however, hm\(^{2}\)α-SYN-39 mice revealed a significant loss of dopaminergic SN neurons, of dopaminergic terminals in the striatum as well as a reduction of striatal dopamine levels compared to young, 2–3 months transgenic mice and compared to 16–17 months old wildtype littermates. A significant age-related correlation of infiltrating CD4+ and CD8\(^{+}\) T cell numbers with dopaminergic terminal loss of the striatum was found in hm\(^{2}\)α-SYN-39 mice, but not in wildtype controls. In the striatum of 16–17 months old wildtype mice a slightly elevated CD8\(^{+}\) T cell count and CD11b\(^{+}\) microglia cell count was observed compared to younger aged mice. Additional analyses of neuroinflammation in the nigrostriatal tract of wildtype mice did not yield any significant age-dependent changes of CD4\(^{+}\), CD8\(^{+}\) T cell and B220\(^{+}\) B cell numbers, respectively. In contrast, a significant age-dependent increase of CD8\(^{+}\) T cells, GFAP\(^{+}\) astrocytes as well as a pronounced increase of CD11b+ microglia numbers were observed in the SN of hm\(^{2}\)α-SYN-39 mice pointing towards a neuroinflammatory processes in this genetic mouse model for PD. The findings in the hm\(^{2}\)α-SYN-39 mouse model strengthen the evidence that T cell and glial cell responses are involved in the age-related neurodegeneration in PD. The slow and age-dependent progression of neurodegeneration and neuroinflammation in the hm\(^{2}\)α-SYN-39 PD rodent model underlines its translational value and makes it suitable for studying anti-inflammatory therapies. KW - Parkinson's disease KW - neuroinflammation KW - neurodegeneration Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-300629 VL - 171 ER - TY - JOUR A1 - Grotemeyer, Alexander A1 - McFleder, Rhonda Leah A1 - Wu, Jingjing A1 - Wischhusen, Jörg A1 - Ip, Chi Wang T1 - Neuroinflammation in Parkinson’s disease – putative pathomechanisms and targets for disease-modification JF - Frontiers in Immunology N2 - Parkinson’s disease (PD) is a progressive and debilitating chronic disease that affects more than six million people worldwide, with rising prevalence. The hallmarks of PD are motor deficits, the spreading of pathological α-synuclein clusters in the central nervous system, and neuroinflammatory processes. PD is treated symptomatically, as no causally-acting drug or procedure has been successfully established for clinical use. Various pathways contributing to dopaminergic neuron loss in PD have been investigated and described to interact with the innate and adaptive immune system. We discuss the possible contribution of interconnected pathways related to the immune response, focusing on the pathophysiology and neurodegeneration of PD. In addition, we provide an overview of clinical trials targeting neuroinflammation in PD. KW - Parkinson’s disease KW - neuroinflammation KW - T cells KW - microglia KW - neurodegeneration KW - animal models KW - inflammatory cascades Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-274665 SN - 1664-3224 VL - 13 ER - TY - JOUR A1 - Andreska, Thomas A1 - Lüningschrör, Patrick A1 - Wolf, Daniel A1 - McFleder, Rhonda L. A1 - Ayon-Olivas, Maurilyn A1 - Rattka, Marta A1 - Drechsler, Christine A1 - Perschin, Veronika A1 - Blum, Robert A1 - Aufmkolk, Sarah A1 - Granado, Noelia A1 - Moratalla, Rosario A1 - Sauer, Markus A1 - Monoranu, Camelia A1 - Volkmann, Jens A1 - Ip, Chi Wang A1 - Stigloher, Christian A1 - Sendtner, Michael T1 - DRD1 signaling modulates TrkB turnover and BDNF sensitivity in direct pathway striatal medium spiny neurons JF - Cell Reports N2 - Highlights • Dopamine receptor-1 activation induces TrkB cell-surface expression in striatal neurons • Dopaminergic deficits cause TrkB accumulation and clustering in the ER • TrkB clusters colocalize with cargo receptor SORCS-2 in direct pathway striatal neurons • Intracellular TrkB clusters fail to fuse with lysosomes after dopamine depletion Summary Disturbed motor control is a hallmark of Parkinson’s disease (PD). Cortico-striatal synapses play a central role in motor learning and adaption, and brain-derived neurotrophic factor (BDNF) from cortico-striatal afferents modulates their plasticity via TrkB in striatal medium spiny projection neurons (SPNs). We studied the role of dopamine in modulating the sensitivity of direct pathway SPNs (dSPNs) to BDNF in cultures of fluorescence-activated cell sorting (FACS)-enriched D1-expressing SPNs and 6-hydroxydopamine (6-OHDA)-treated rats. DRD1 activation causes enhanced TrkB translocation to the cell surface and increased sensitivity for BDNF. In contrast, dopamine depletion in cultured dSPN neurons, 6-OHDA-treated rats, and postmortem brain of patients with PD reduces BDNF responsiveness and causes formation of intracellular TrkB clusters. These clusters associate with sortilin related VPS10 domain containing receptor 2 (SORCS-2) in multivesicular-like structures, which apparently protects them from lysosomal degradation. Thus, impaired TrkB processing might contribute to disturbed motor function in PD. KW - motor learning KW - cortico-striatal synapse KW - basal ganglia KW - direct pathway KW - DRD1 KW - dSPN KW - BDNF KW - TrkB KW - synaptic plasticity KW - GPCR Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-349932 VL - 42 IS - 6 ER - TY - JOUR A1 - Grotemeyer, Alexander A1 - Fischer, Judith F. A1 - Koprich, James B. A1 - Brotchie, Jonathan M. A1 - Blum, Robert A1 - Volkmann, Jens A1 - Ip, Chi Wang T1 - Inflammasome inhibition protects dopaminergic neurons from α-synuclein pathology in a model of progressive Parkinson’s disease JF - Journal of Neuroinflammation N2 - Neuroinflammation has been suggested as a pathogenetic mechanism contributing to Parkinson’s disease (PD). However, anti-inflammatory treatment strategies have not yet been established as a therapeutic option for PD patients. We have used a human α-synuclein mouse model of progressive PD to examine the anti-inflammatory and neuroprotective effects of inflammasome inhibition on dopaminergic (DA) neurons in the substantia nigra (SN). As the NLRP3 (NOD-, LRR- and pyrin domain-containing 3)-inflammasome is a core interface for both adaptive and innate inflammation and is also highly druggable, we investigated the implications of its inhibition. Repeat administration of MCC950, an inhibitor of NLRP3, in a PD model with ongoing pathology reduced CD4\(^+\) and CD8\(^+\) T cell infiltration into the SN. Furthermore, the anti-inflammasome treatment mitigated microglial activation and modified the aggregation of α-synuclein protein in DA neurons. MCC950-treated mice showed significantly less neurodegeneration of DA neurons and a reduction in PD-related motor behavior. In summary, early inflammasome inhibition can reduce neuroinflammation and prevent DA cell death in an α-synuclein mouse model for progressive PD. KW - neurodegeneration KW - movement disorder KW - neuroinflammation KW - Parkinson’s disease KW - inflammasome KW - dopaminergic cells KW - NLRP3 KW - MCC950 KW - microglia KW - T cells Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357652 VL - 20 ER - TY - JOUR A1 - McFleder, Rhonda L. A1 - Makhotkina, Anastasiia A1 - Groh, Janos A1 - Keber, Ursula A1 - Imdahl, Fabian A1 - Peña Mosca, Josefina A1 - Peteranderl, Alina A1 - Wu, Jingjing A1 - Tabuchi, Sawako A1 - Hoffmann, Jan A1 - Karl, Ann-Kathrin A1 - Pagenstecher, Axel A1 - Vogel, Jörg A1 - Beilhack, Andreas A1 - Koprich, James B. A1 - Brotchie, Jonathan M. A1 - Saliba, Antoine-Emmanuel A1 - Volkmann, Jens A1 - Ip, Chi Wang T1 - Brain-to-gut trafficking of alpha-synuclein by CD11c\(^+\) cells in a mouse model of Parkinson’s disease JF - Nature Communications N2 - Inflammation in the brain and gut is a critical component of several neurological diseases, such as Parkinson’s disease (PD). One trigger of the immune system in PD is aggregation of the pre-synaptic protein, α-synuclein (αSyn). Understanding the mechanism of propagation of αSyn aggregates is essential to developing disease-modifying therapeutics. Using a brain-first mouse model of PD, we demonstrate αSyn trafficking from the brain to the ileum of male mice. Immunohistochemistry revealed that the ileal αSyn aggregations are contained within CD11c+ cells. Using single-cell RNA sequencing, we demonstrate that ileal CD11c\(^+\) cells are microglia-like and the same subtype of cells is activated in the brain and ileum of PD mice. Moreover, by utilizing mice expressing the photo-convertible protein, Dendra2, we show that CD11c\(^+\) cells traffic from the brain to the ileum. Together these data provide a mechanism of αSyn trafficking between the brain and gut. KW - antigen-presenting cells KW - neuroimmunology KW - Parkinson's disease Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357696 VL - 14 ER - TY - JOUR A1 - Ip, Chi Wang A1 - Wischhusen, Jörg T1 - Versatile guardians: regenerative regulatory T cells in Parkinson’s disease rodent models JF - Signal Transduction and Targeted Therapy N2 - No abstract available. KW - diseases of the nervous system KW - neuroimmunology KW - neurological disorders Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357674 VL - 8 ER - TY - JOUR A1 - Pozzi, Nicoló Gabriele A1 - Bolzoni, Francesco A1 - Biella, Gabriele Eliseo Mario A1 - Pezzoli, Gianni A1 - Ip, Chi Wang A1 - Volkmann, Jens A1 - Cavallari, Paolo A1 - Asan, Esther A1 - Isaias, Ioannis Ugo T1 - Brain noradrenergic innervation supports the development of Parkinson’s tremor: a study in a reserpinized rat model JF - Cells N2 - The pathophysiology of tremor in Parkinson’s disease (PD) is evolving towards a complex alteration to monoaminergic innervation, and increasing evidence suggests a key role of the locus coeruleus noradrenergic system (LC-NA). However, the difficulties in imaging LC-NA in patients challenge its direct investigation. To this end, we studied the development of tremor in a reserpinized rat model of PD, with or without a selective lesioning of LC-NA innervation with the neurotoxin DSP-4. Eight male rats (Sprague Dawley) received DSP-4 (50 mg/kg) two weeks prior to reserpine injection (10 mg/kg) (DR-group), while seven male animals received only reserpine treatment (R-group). Tremor, rigidity, hypokinesia, postural flexion and postural immobility were scored before and after 20, 40, 60, 80, 120 and 180 min of reserpine injection. Tremor was assessed visually and with accelerometers. The injection of DSP-4 induced a severe reduction in LC-NA terminal axons (DR-group: 0.024 ± 0.01 vs. R-group: 0.27 ± 0.04 axons/um\(^2\), p < 0.001) and was associated with significantly less tremor, as compared to the R-group (peak tremor score, DR-group: 0.5 ± 0.8 vs. R-group: 1.6 ± 0.5; p < 0.01). Kinematic measurement confirmed the clinical data (tremor consistency (% of tremor during 180 s recording), DR-group: 37.9 ± 35.8 vs. R-group: 69.3 ± 29.6; p < 0.05). Akinetic–rigid symptoms did not differ between the DR- and R-groups. Our results provide preliminary causal evidence for a critical role of LC-NA innervation in the development of PD tremor and foster the development of targeted therapies for PD patients. KW - Parkinson’s disease KW - tremor KW - locus coeruleus KW - noradrenaline KW - reserpinized rat model Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-357721 SN - 2073-4409 VL - 12 IS - 21 ER -