The Experts below are selected from a list of 309 Experts worldwide ranked by ideXlab platform
Pawel Kermer - One of the best experts on this subject based on the ideXlab platform.
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BAG1 is neuroprotective in in vivo and in vitro models of parkinson s disease
Journal of Molecular Neuroscience, 2015Co-Authors: Pawel Kermer, Jan Liman, Mathias Bahr, Paul Lingor, Anja Köhn, Marlena Schnieder, Christoph P DohmAbstract:Bcl-2-associated athanogene-1 (BAG1) is a multifunctional protein comprising co-chaperone function, increasing Hsp70 foldase activity and chaperone-dependent protein degradation of misfolded substrates, with anti-apoptotic activity. It is neuroprotective in different models of neurological diseases, like cerebral ischemia and Huntington’s disease. In the context of Parkinson’s disease, it has recently been shown to restore DJ-1 function in an in vitro model of hereditary Parkinson’s disease. Here, we demonstrate that BAG1 overexpression in SH-SY5Y cells reduces toxicity after transfection of disease-related α-synuclein mutants. Furthermore, it protects from rotenone-induced cell death in vitro and ameliorates neuronal demise in an in vivo 1-methyl-4-phenyl-1,2,3,6,-tetrahydropyridine (MPTP) model for Parkinson’s disease after adeno-associated virus (AAV)-mediated BAG1 gene transfer into the substantia nigra in mice but showed no protective effects in an in vitro 6-hydroxidopamine model. In conclusion, we present BAG1 as a potential therapeutic target in Parkinson’s disease.
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BAG1 is Neuroprotective in In Vivo and In Vitro Models of Parkinson’s Disease
Journal of Molecular Neuroscience, 2015Co-Authors: Pawel Kermer, Jan Liman, Mathias Bahr, Paul Lingor, Anja Köhn, Marlena Schnieder, Christoph Peter DohmAbstract:Bcl-2-associated athanogene-1 (BAG1) is a multifunctional protein comprising co-chaperone function, increasing Hsp70 foldase activity and chaperone-dependent protein degradation of misfolded substrates, with anti-apoptotic activity. It is neuroprotective in different models of neurological diseases, like cerebral ischemia and Huntington’s disease. In the context of Parkinson’s disease, it has recently been shown to restore DJ-1 function in an in vitro model of hereditary Parkinson’s disease. Here, we demonstrate that BAG1 overexpression in SH-SY5Y cells reduces toxicity after transfection of disease-related α-synuclein mutants. Furthermore, it protects from rotenone-induced cell death in vitro and ameliorates neuronal demise in an in vivo 1-methyl-4-phenyl-1,2,3,6,-tetrahydropyridine (MPTP) model for Parkinson’s disease after adeno-associated virus (AAV)-mediated BAG1 gene transfer into the substantia nigra in mice but showed no protective effects in an in vitro 6-hydroxidopamine model. In conclusion, we present BAG1 as a potential therapeutic target in Parkinson’s disease.
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modulation of huntingtin toxicity by BAG1 is dependent on an intact bag domain
Molecules, 2010Co-Authors: Jan Liman, Christoph P Dohm, Mathias Bahr, Kamila Sroka, Sebastian Deeg, Pawel KermerAbstract:Huntington´s disease, one of the so-called poly-glutamine diseases, is a dominantly inherited movement disorder characterized by formation of cytosolic and nuclear inclusion bodies and progressive neurodegeneration. Recently, we have shown that Bcl-2-associated athanogene-1 (BAG1), a multifunctional co-chaperone, modulates toxicity, aggregation, degradation and subcellular distribution in vitro and in vivo of the disease-specific mutant huntingtin protein. Aiming at future small molecule-based therapeutical approaches, we further analysed structural demands for these effects employing the C-terminal deletion mutant BAGDC. We show that disruption of the BAG domain known to eliminate intracellular heat shock protein 70 (Hsp70) binding and activation also precludes binding of Siah-1 thereby leaving nuclear huntingtin translocation unaffected. At the same time BAGDC fails to induce increased proteasomal huntingtin turnover and does not inhibit intracellular huntingtin aggregation, a pre-requisite necessary for prevention of huntingtin toxicity.
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BAG1 modulates huntingtin toxicity aggregation degradation and subcellular distribution
Journal of Neurochemistry, 2009Co-Authors: Kamila Sroka, John C Reed, Mathias Bahr, Sebastian Deeg, Aaron Voigt, Jorg B Schulz, Pawel KermerAbstract:Bcl-2-associated athanogene-1 (BAG1) is a multifunctional protein delivering chaperone-recognized unfolded substrates to the proteasome for degradation. It has been shown to be essential for proper CNS development in vivo, playing a crucial role in neuronal survival and differentiation. With regard to Huntington’s disease, a sequestration of BAG1 into inclusion bodies and a neuroprotective effect in double transgenic mice have been reported. Here, we show that BAG1 reduces aggregation and accelerates degradation of mutant huntingtin (htt-mut). Moreover, it reduces nuclear levels of htt-mut. This effect can be overcome by over-expression of seven in absentia homolog 1, an E3 ligase negatively regulated by BAG1 and known to be involved in nuclear import of htt-mut. In vivo, BAG1 proved to be protective in a Drosophila melanogaster Huntington’s disease model, preventing photoreceptor cell loss induced by htt-mut. In summary, we present BAG1 as a therapeutic tool modulating key steps in htt toxicity in vitro and ameliorating htt toxicity in vivo.
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Neuron-specific overexpression of the co-chaperone Bcl-2-associated athanogene-1 in superoxide dismutase 1G93A–transgenic mice
Neuroscience, 2008Co-Authors: Gundula Rohde, John C Reed, Pawel Kermer, M. Bähr, Jochen H. WeishauptAbstract:Abstract Bcl-2-associated athanogene-1 (BAG1) binds heat-shock protein 70 (Hsp70)/Hsc70, increases intracellular chaperone activity in neurons and proved to be protective in several models for neurodegeneration. Mutations in the superoxide dismutase 1 (SOD1) gene account for approximately 20% of familial amyotrophic lateral sclerosis (ALS) cases. A common property shared by all mutant SOD1 (mtSOD1) species is abnormal protein folding and the propensity to form aggregates. Toxicity and aggregate formation of mutant SOD1 can be overcome by enhanced chaperone function in vitro . Moreover, expression of mtSOD1 decreases BAG1 levels in a motoneuronal cell line. Thus, several lines of evidence suggested a protective role of BAG1 in mtSOD1-mediated motoneuron degeneration. To explore the therapeutic potential of BAG1 in a model for ALS, we generated SOD1 G93A /BAG1 double transgenic mice expressing BAG1 in a neuron-specific pattern. Surprisingly, substantially increased BAG1 protein levels in spinal cord neurons did not significantly alter the phenotype of SOD1 G93A -transgenic mice. Hence, expression of BAG1 is not sufficient to protect against mtSOD1-induced motor dysfunction in vivo . Our work shows that, in contrast to the in vitro situation, modulation of multiple cellular functions in addition to enhanced expression of a single chaperone is required to protect against SOD1 toxicity, highlighting the necessity of combined treatment strategies for ALS.
John C Reed - One of the best experts on this subject based on the ideXlab platform.
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BAG1 modulates huntingtin toxicity aggregation degradation and subcellular distribution
Journal of Neurochemistry, 2009Co-Authors: Kamila Sroka, John C Reed, Mathias Bahr, Sebastian Deeg, Aaron Voigt, Jorg B Schulz, Pawel KermerAbstract:Bcl-2-associated athanogene-1 (BAG1) is a multifunctional protein delivering chaperone-recognized unfolded substrates to the proteasome for degradation. It has been shown to be essential for proper CNS development in vivo, playing a crucial role in neuronal survival and differentiation. With regard to Huntington’s disease, a sequestration of BAG1 into inclusion bodies and a neuroprotective effect in double transgenic mice have been reported. Here, we show that BAG1 reduces aggregation and accelerates degradation of mutant huntingtin (htt-mut). Moreover, it reduces nuclear levels of htt-mut. This effect can be overcome by over-expression of seven in absentia homolog 1, an E3 ligase negatively regulated by BAG1 and known to be involved in nuclear import of htt-mut. In vivo, BAG1 proved to be protective in a Drosophila melanogaster Huntington’s disease model, preventing photoreceptor cell loss induced by htt-mut. In summary, we present BAG1 as a therapeutic tool modulating key steps in htt toxicity in vitro and ameliorating htt toxicity in vivo.
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Neuron-specific overexpression of the co-chaperone Bcl-2-associated athanogene-1 in superoxide dismutase 1G93A–transgenic mice
Neuroscience, 2008Co-Authors: Gundula Rohde, John C Reed, Pawel Kermer, M. Bähr, Jochen H. WeishauptAbstract:Abstract Bcl-2-associated athanogene-1 (BAG1) binds heat-shock protein 70 (Hsp70)/Hsc70, increases intracellular chaperone activity in neurons and proved to be protective in several models for neurodegeneration. Mutations in the superoxide dismutase 1 (SOD1) gene account for approximately 20% of familial amyotrophic lateral sclerosis (ALS) cases. A common property shared by all mutant SOD1 (mtSOD1) species is abnormal protein folding and the propensity to form aggregates. Toxicity and aggregate formation of mutant SOD1 can be overcome by enhanced chaperone function in vitro . Moreover, expression of mtSOD1 decreases BAG1 levels in a motoneuronal cell line. Thus, several lines of evidence suggested a protective role of BAG1 in mtSOD1-mediated motoneuron degeneration. To explore the therapeutic potential of BAG1 in a model for ALS, we generated SOD1 G93A /BAG1 double transgenic mice expressing BAG1 in a neuron-specific pattern. Surprisingly, substantially increased BAG1 protein levels in spinal cord neurons did not significantly alter the phenotype of SOD1 G93A -transgenic mice. Hence, expression of BAG1 is not sufficient to protect against mtSOD1-induced motor dysfunction in vivo . Our work shows that, in contrast to the in vitro situation, modulation of multiple cellular functions in addition to enhanced expression of a single chaperone is required to protect against SOD1 toxicity, highlighting the necessity of combined treatment strategies for ALS.
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BAG1 promotes axonal outgrowth and regeneration in vivo via raf 1 and reduction of rock activity
Brain, 2008Co-Authors: Veronique Planchamp, John C Reed, Mathias Bahr, Pawel Kermer, Christina Bermel, Lars Tonges, Thomas Ostendorf, Sebastian Kugler, Paul LingorAbstract:Improved survival of injured neurons and the inhibition of repulsive environmental signalling are prerequisites for functional regeneration. BAG1 (Bcl-2-associated athanogene-1) is an Hsp70/Hsc70 -binding protein, which has been shown to suppress apoptosis and enhance neuronal differentiation. We investigated BAG1 as a therapeutic molecule in the lesioned visual system in vivo. Using an adeno-associated viral vector, BAG1 (AAV.BAG1) was expressed in retinal ganglion cells (RGC) and then tested in models of optic nerve axotomy and optic nerve crush. BAG1 significantly increased RGC survival as compared to adeno-associated viral vector enhanced green fluorescent protein (AAV.EGFP) treated controls and this was independently confirmed in transgenic mice overexpressing BAG1 in neurons. The numbers and lengths of regenerating axons after optic nerve crush were also significantly increased in the AAV.BAG1 group. In pRGC cultures, BAG1-over-expression resulted in a 3- fold increase in neurite length and growth cone surface. Interestingly, BAG1 induced an intracellular translocation of Raf-1 and ROCK2 and ROCK activity was decreased in a Raf-1-dependent manner by BAG1-over-expression. In summary, we show that BAG1 acts in a dual role by inhibition of lesion-induced apoptosis and interaction with the inhibitory ROCK signalling cascade. BAG1 is therefore a promising molecule to be further examined as a putative therapeutic tool in neurorestorative strategies.
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BAG1 promotes axonal outgrowth and regeneration in vivo via Raf-1 and reduction of ROCK activity.
Brain : a journal of neurology, 2008Co-Authors: Veronique Planchamp, John C Reed, Mathias Bahr, Pawel Kermer, Christina Bermel, Lars Tonges, Thomas Ostendorf, Sebastian Kugler, Paul LingorAbstract:Improved survival of injured neurons and the inhibition of repulsive environmental signalling are prerequisites for functional regeneration. BAG1 (Bcl-2-associated athanogene-1) is an Hsp70/Hsc70-binding protein, which has been shown to suppress apoptosis and enhance neuronal differentiation. We investigated BAG1 as a therapeutic molecule in the lesioned visual system in vivo. Using an adeno-associated viral vector, BAG1 (AAV.BAG1) was expressed in retinal ganglion cells (RGC) and then tested in models of optic nerve axotomy and optic nerve crush. BAG1 significantly increased RGC survival as compared to adeno-associated viral vector enhanced green fluorescent protein (AAV.EGFP) treated controls and this was independently confirmed in transgenic mice over-expressing BAG1 in neurons. The numbers and lengths of regenerating axons after optic nerve crush were also significantly increased in the AAV.BAG1 group. In pRGC cultures, BAG1-over-expression resulted in a approximately 3-fold increase in neurite length and growth cone surface. Interestingly, BAG1 induced an intracellular translocation of Raf-1 and ROCK2 and ROCK activity was decreased in a Raf-1-dependent manner by BAG1-over-expression. In summary, we show that BAG1 acts in a dual role by inhibition of lesion-induced apoptosis and interaction with the inhibitory ROCK signalling cascade. BAG1 is therefore a promising molecule to be further examined as a putative therapeutic tool in neurorestorative strategies.
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sex dependent effect of BAG1 in ameliorating motor deficits of huntington disease transgenic mice
Journal of Biological Chemistry, 2008Co-Authors: Shanshan Huang, John C Reed, Meredith Roberts, Shihua Li, Xiaojiang LiAbstract:The pathogenesis of Huntington disease (HD) is attributed to the misfolding of huntingtin (htt) caused by an expanded polyglutamine (polyQ) domain. Considerable effort has been devoted to identifying molecules that can prevent or reduce htt misfolding and the associated neuropathology. Although overexpression of chaperones is known to reduce htt cytotoxicity in cellular models, only modest protection is seen with Hsp70 overexpression in HD mouse models. Because the activity of Hsp70 is modulated by co-chaperones, an interesting issue is whether the in vivo effects of chaperones on polyQ protein toxicity are dependent on other modulators. In the present study, we focused on BAG1, a co-chaperone that interacts with Hsp70 and regulates its activity. Of htt mice expressing the N171-82Q mutant, we found that male N171-82Q mice show a greater deficit in rotarod performance than female N171-82Q mice. This sex-dependent motor deficit was improved by crossing N171-82Q mice with transgenic mice overexpressing BAG1 in neurons. Transgenic BAG1 also reduces the levels of mutant htt in synaptosomal fraction of male HD mice. Overexpression of BAG1 augmented the effects of Hsp70 by reducing aggregation of mutant htt in cultured cells and improving neurite outgrowth in htt-transfected PC12 cells. These findings suggest that the effects of chaperones on HD pathology are influenced by both their modulators and sex-dependent factors.
Mathias Bahr - One of the best experts on this subject based on the ideXlab platform.
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aav mediated expression of BAG1 and rock2 shrna promote neuronal survival and axonal sprouting in a rat model of rubrospinal tract injury
Journal of Neurochemistry, 2015Co-Authors: Malleswari Challagundla, Mathias Bahr, Thomas Ostendorf, Sebastian Kugler, Jan C Koch, Vinicius Toledo Ribas, Uwe Michel, Frank Bradke, Hans Werner Muller, Paul LingorAbstract:A lesion to the rat rubrospinal tract is a model for traumatic spinal cord lesions and results in atrophy of the red nucleus neurons, axonal dieback, and locomotor deficits. In this study, we used adeno-associated virus (AAV)-mediated over-expression of BAG1 and ROCK2-shRNA in the red nucleus to trace [by co-expression of enhanced green fluorescent protein (EGFP)] and treat the rubrospinal tract after unilateral dorsal hemisection. We investigated the effects of targeted gene therapy on neuronal survival, axonal sprouting of the rubrospinal tract, and motor recovery 12 weeks after unilateral dorsal hemisection at Th8 in rats. In addition to the evaluation of BAG1 and ROCK2 as therapeutic targets in spinal cord injury, we aimed to demonstrate the feasibility and the limits of an AAV-mediated protein over-expression versus AAV.shRNA-mediated down-regulation in this traumatic CNS lesion model. Our results demonstrate that BAG1 and ROCK2-shRNA both promote neuronal survival of red nucleus neurons and enhance axonal sprouting proximal to the lesion. Understanding the mechanisms involved in neuronal survival and axonal regeneration after spinal cord injury (SCI) is pivotal for the development of new therapies. We showed that over-expression of BAG1 (Bcl-2-associated athanogene-1) and down-regulation of ROCK2 (Rho-associated protein kinase) improve neuronal survival and axonal sprouting after SCI. Our results imply that BAG1 and ROCK2 represent interesting molecular targets that can be used in future therapeutic strategies for the treatment of SCI. AAV = adeno-associated virus.
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AAV‐mediated expression of BAG1 and ROCK2‐shRNA promote neuronal survival and axonal sprouting in a rat model of rubrospinal tract injury
Journal of Neurochemistry, 2015Co-Authors: Malleswari Challagundla, Mathias Bahr, Thomas Ostendorf, Sebastian Kugler, Jan C Koch, Vinicius Toledo Ribas, Uwe Michel, Frank Bradke, Hans Werner Muller, Paul LingorAbstract:A lesion to the rat rubrospinal tract is a model for traumatic spinal cord lesions and results in atrophy of the red nucleus neurons, axonal dieback, and locomotor deficits. In this study, we used adeno-associated virus (AAV)-mediated over-expression of BAG1 and ROCK2-shRNA in the red nucleus to trace [by co-expression of enhanced green fluorescent protein (EGFP)] and treat the rubrospinal tract after unilateral dorsal hemisection. We investigated the effects of targeted gene therapy on neuronal survival, axonal sprouting of the rubrospinal tract, and motor recovery 12 weeks after unilateral dorsal hemisection at Th8 in rats. In addition to the evaluation of BAG1 and ROCK2 as therapeutic targets in spinal cord injury, we aimed to demonstrate the feasibility and the limits of an AAV-mediated protein over-expression versus AAV.shRNA-mediated down-regulation in this traumatic CNS lesion model. Our results demonstrate that BAG1 and ROCK2-shRNA both promote neuronal survival of red nucleus neurons and enhance axonal sprouting proximal to the lesion. Understanding the mechanisms involved in neuronal survival and axonal regeneration after spinal cord injury (SCI) is pivotal for the development of new therapies. We showed that over-expression of BAG1 (Bcl-2-associated athanogene-1) and down-regulation of ROCK2 (Rho-associated protein kinase) improve neuronal survival and axonal sprouting after SCI. Our results imply that BAG1 and ROCK2 represent interesting molecular targets that can be used in future therapeutic strategies for the treatment of SCI. AAV = adeno-associated virus.
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BAG1 is Neuroprotective in In Vivo and In Vitro Models of Parkinson’s Disease
Journal of Molecular Neuroscience, 2015Co-Authors: Pawel Kermer, Jan Liman, Mathias Bahr, Paul Lingor, Anja Köhn, Marlena Schnieder, Christoph Peter DohmAbstract:Bcl-2-associated athanogene-1 (BAG1) is a multifunctional protein comprising co-chaperone function, increasing Hsp70 foldase activity and chaperone-dependent protein degradation of misfolded substrates, with anti-apoptotic activity. It is neuroprotective in different models of neurological diseases, like cerebral ischemia and Huntington’s disease. In the context of Parkinson’s disease, it has recently been shown to restore DJ-1 function in an in vitro model of hereditary Parkinson’s disease. Here, we demonstrate that BAG1 overexpression in SH-SY5Y cells reduces toxicity after transfection of disease-related α-synuclein mutants. Furthermore, it protects from rotenone-induced cell death in vitro and ameliorates neuronal demise in an in vivo 1-methyl-4-phenyl-1,2,3,6,-tetrahydropyridine (MPTP) model for Parkinson’s disease after adeno-associated virus (AAV)-mediated BAG1 gene transfer into the substantia nigra in mice but showed no protective effects in an in vitro 6-hydroxidopamine model. In conclusion, we present BAG1 as a potential therapeutic target in Parkinson’s disease.
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BAG1 is neuroprotective in in vivo and in vitro models of parkinson s disease
Journal of Molecular Neuroscience, 2015Co-Authors: Pawel Kermer, Jan Liman, Mathias Bahr, Paul Lingor, Anja Köhn, Marlena Schnieder, Christoph P DohmAbstract:Bcl-2-associated athanogene-1 (BAG1) is a multifunctional protein comprising co-chaperone function, increasing Hsp70 foldase activity and chaperone-dependent protein degradation of misfolded substrates, with anti-apoptotic activity. It is neuroprotective in different models of neurological diseases, like cerebral ischemia and Huntington’s disease. In the context of Parkinson’s disease, it has recently been shown to restore DJ-1 function in an in vitro model of hereditary Parkinson’s disease. Here, we demonstrate that BAG1 overexpression in SH-SY5Y cells reduces toxicity after transfection of disease-related α-synuclein mutants. Furthermore, it protects from rotenone-induced cell death in vitro and ameliorates neuronal demise in an in vivo 1-methyl-4-phenyl-1,2,3,6,-tetrahydropyridine (MPTP) model for Parkinson’s disease after adeno-associated virus (AAV)-mediated BAG1 gene transfer into the substantia nigra in mice but showed no protective effects in an in vitro 6-hydroxidopamine model. In conclusion, we present BAG1 as a potential therapeutic target in Parkinson’s disease.
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modulation of huntingtin toxicity by BAG1 is dependent on an intact bag domain
Molecules, 2010Co-Authors: Jan Liman, Christoph P Dohm, Mathias Bahr, Kamila Sroka, Sebastian Deeg, Pawel KermerAbstract:Huntington´s disease, one of the so-called poly-glutamine diseases, is a dominantly inherited movement disorder characterized by formation of cytosolic and nuclear inclusion bodies and progressive neurodegeneration. Recently, we have shown that Bcl-2-associated athanogene-1 (BAG1), a multifunctional co-chaperone, modulates toxicity, aggregation, degradation and subcellular distribution in vitro and in vivo of the disease-specific mutant huntingtin protein. Aiming at future small molecule-based therapeutical approaches, we further analysed structural demands for these effects employing the C-terminal deletion mutant BAGDC. We show that disruption of the BAG domain known to eliminate intracellular heat shock protein 70 (Hsp70) binding and activation also precludes binding of Siah-1 thereby leaving nuclear huntingtin translocation unaffected. At the same time BAGDC fails to induce increased proteasomal huntingtin turnover and does not inhibit intracellular huntingtin aggregation, a pre-requisite necessary for prevention of huntingtin toxicity.
Paul Lingor - One of the best experts on this subject based on the ideXlab platform.
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aav mediated expression of BAG1 and rock2 shrna promote neuronal survival and axonal sprouting in a rat model of rubrospinal tract injury
Journal of Neurochemistry, 2015Co-Authors: Malleswari Challagundla, Mathias Bahr, Thomas Ostendorf, Sebastian Kugler, Jan C Koch, Vinicius Toledo Ribas, Uwe Michel, Frank Bradke, Hans Werner Muller, Paul LingorAbstract:A lesion to the rat rubrospinal tract is a model for traumatic spinal cord lesions and results in atrophy of the red nucleus neurons, axonal dieback, and locomotor deficits. In this study, we used adeno-associated virus (AAV)-mediated over-expression of BAG1 and ROCK2-shRNA in the red nucleus to trace [by co-expression of enhanced green fluorescent protein (EGFP)] and treat the rubrospinal tract after unilateral dorsal hemisection. We investigated the effects of targeted gene therapy on neuronal survival, axonal sprouting of the rubrospinal tract, and motor recovery 12 weeks after unilateral dorsal hemisection at Th8 in rats. In addition to the evaluation of BAG1 and ROCK2 as therapeutic targets in spinal cord injury, we aimed to demonstrate the feasibility and the limits of an AAV-mediated protein over-expression versus AAV.shRNA-mediated down-regulation in this traumatic CNS lesion model. Our results demonstrate that BAG1 and ROCK2-shRNA both promote neuronal survival of red nucleus neurons and enhance axonal sprouting proximal to the lesion. Understanding the mechanisms involved in neuronal survival and axonal regeneration after spinal cord injury (SCI) is pivotal for the development of new therapies. We showed that over-expression of BAG1 (Bcl-2-associated athanogene-1) and down-regulation of ROCK2 (Rho-associated protein kinase) improve neuronal survival and axonal sprouting after SCI. Our results imply that BAG1 and ROCK2 represent interesting molecular targets that can be used in future therapeutic strategies for the treatment of SCI. AAV = adeno-associated virus.
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AAV‐mediated expression of BAG1 and ROCK2‐shRNA promote neuronal survival and axonal sprouting in a rat model of rubrospinal tract injury
Journal of Neurochemistry, 2015Co-Authors: Malleswari Challagundla, Mathias Bahr, Thomas Ostendorf, Sebastian Kugler, Jan C Koch, Vinicius Toledo Ribas, Uwe Michel, Frank Bradke, Hans Werner Muller, Paul LingorAbstract:A lesion to the rat rubrospinal tract is a model for traumatic spinal cord lesions and results in atrophy of the red nucleus neurons, axonal dieback, and locomotor deficits. In this study, we used adeno-associated virus (AAV)-mediated over-expression of BAG1 and ROCK2-shRNA in the red nucleus to trace [by co-expression of enhanced green fluorescent protein (EGFP)] and treat the rubrospinal tract after unilateral dorsal hemisection. We investigated the effects of targeted gene therapy on neuronal survival, axonal sprouting of the rubrospinal tract, and motor recovery 12 weeks after unilateral dorsal hemisection at Th8 in rats. In addition to the evaluation of BAG1 and ROCK2 as therapeutic targets in spinal cord injury, we aimed to demonstrate the feasibility and the limits of an AAV-mediated protein over-expression versus AAV.shRNA-mediated down-regulation in this traumatic CNS lesion model. Our results demonstrate that BAG1 and ROCK2-shRNA both promote neuronal survival of red nucleus neurons and enhance axonal sprouting proximal to the lesion. Understanding the mechanisms involved in neuronal survival and axonal regeneration after spinal cord injury (SCI) is pivotal for the development of new therapies. We showed that over-expression of BAG1 (Bcl-2-associated athanogene-1) and down-regulation of ROCK2 (Rho-associated protein kinase) improve neuronal survival and axonal sprouting after SCI. Our results imply that BAG1 and ROCK2 represent interesting molecular targets that can be used in future therapeutic strategies for the treatment of SCI. AAV = adeno-associated virus.
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BAG1 is Neuroprotective in In Vivo and In Vitro Models of Parkinson’s Disease
Journal of Molecular Neuroscience, 2015Co-Authors: Pawel Kermer, Jan Liman, Mathias Bahr, Paul Lingor, Anja Köhn, Marlena Schnieder, Christoph Peter DohmAbstract:Bcl-2-associated athanogene-1 (BAG1) is a multifunctional protein comprising co-chaperone function, increasing Hsp70 foldase activity and chaperone-dependent protein degradation of misfolded substrates, with anti-apoptotic activity. It is neuroprotective in different models of neurological diseases, like cerebral ischemia and Huntington’s disease. In the context of Parkinson’s disease, it has recently been shown to restore DJ-1 function in an in vitro model of hereditary Parkinson’s disease. Here, we demonstrate that BAG1 overexpression in SH-SY5Y cells reduces toxicity after transfection of disease-related α-synuclein mutants. Furthermore, it protects from rotenone-induced cell death in vitro and ameliorates neuronal demise in an in vivo 1-methyl-4-phenyl-1,2,3,6,-tetrahydropyridine (MPTP) model for Parkinson’s disease after adeno-associated virus (AAV)-mediated BAG1 gene transfer into the substantia nigra in mice but showed no protective effects in an in vitro 6-hydroxidopamine model. In conclusion, we present BAG1 as a potential therapeutic target in Parkinson’s disease.
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BAG1 is neuroprotective in in vivo and in vitro models of parkinson s disease
Journal of Molecular Neuroscience, 2015Co-Authors: Pawel Kermer, Jan Liman, Mathias Bahr, Paul Lingor, Anja Köhn, Marlena Schnieder, Christoph P DohmAbstract:Bcl-2-associated athanogene-1 (BAG1) is a multifunctional protein comprising co-chaperone function, increasing Hsp70 foldase activity and chaperone-dependent protein degradation of misfolded substrates, with anti-apoptotic activity. It is neuroprotective in different models of neurological diseases, like cerebral ischemia and Huntington’s disease. In the context of Parkinson’s disease, it has recently been shown to restore DJ-1 function in an in vitro model of hereditary Parkinson’s disease. Here, we demonstrate that BAG1 overexpression in SH-SY5Y cells reduces toxicity after transfection of disease-related α-synuclein mutants. Furthermore, it protects from rotenone-induced cell death in vitro and ameliorates neuronal demise in an in vivo 1-methyl-4-phenyl-1,2,3,6,-tetrahydropyridine (MPTP) model for Parkinson’s disease after adeno-associated virus (AAV)-mediated BAG1 gene transfer into the substantia nigra in mice but showed no protective effects in an in vitro 6-hydroxidopamine model. In conclusion, we present BAG1 as a potential therapeutic target in Parkinson’s disease.
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BAG1 promotes axonal outgrowth and regeneration in vivo via raf 1 and reduction of rock activity
Brain, 2008Co-Authors: Veronique Planchamp, John C Reed, Mathias Bahr, Pawel Kermer, Christina Bermel, Lars Tonges, Thomas Ostendorf, Sebastian Kugler, Paul LingorAbstract:Improved survival of injured neurons and the inhibition of repulsive environmental signalling are prerequisites for functional regeneration. BAG1 (Bcl-2-associated athanogene-1) is an Hsp70/Hsc70 -binding protein, which has been shown to suppress apoptosis and enhance neuronal differentiation. We investigated BAG1 as a therapeutic molecule in the lesioned visual system in vivo. Using an adeno-associated viral vector, BAG1 (AAV.BAG1) was expressed in retinal ganglion cells (RGC) and then tested in models of optic nerve axotomy and optic nerve crush. BAG1 significantly increased RGC survival as compared to adeno-associated viral vector enhanced green fluorescent protein (AAV.EGFP) treated controls and this was independently confirmed in transgenic mice overexpressing BAG1 in neurons. The numbers and lengths of regenerating axons after optic nerve crush were also significantly increased in the AAV.BAG1 group. In pRGC cultures, BAG1-over-expression resulted in a 3- fold increase in neurite length and growth cone surface. Interestingly, BAG1 induced an intracellular translocation of Raf-1 and ROCK2 and ROCK activity was decreased in a Raf-1-dependent manner by BAG1-over-expression. In summary, we show that BAG1 acts in a dual role by inhibition of lesion-induced apoptosis and interaction with the inhibitory ROCK signalling cascade. BAG1 is therefore a promising molecule to be further examined as a putative therapeutic tool in neurorestorative strategies.
Jan Liman - One of the best experts on this subject based on the ideXlab platform.
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BAG1 is Neuroprotective in In Vivo and In Vitro Models of Parkinson’s Disease
Journal of Molecular Neuroscience, 2015Co-Authors: Pawel Kermer, Jan Liman, Mathias Bahr, Paul Lingor, Anja Köhn, Marlena Schnieder, Christoph Peter DohmAbstract:Bcl-2-associated athanogene-1 (BAG1) is a multifunctional protein comprising co-chaperone function, increasing Hsp70 foldase activity and chaperone-dependent protein degradation of misfolded substrates, with anti-apoptotic activity. It is neuroprotective in different models of neurological diseases, like cerebral ischemia and Huntington’s disease. In the context of Parkinson’s disease, it has recently been shown to restore DJ-1 function in an in vitro model of hereditary Parkinson’s disease. Here, we demonstrate that BAG1 overexpression in SH-SY5Y cells reduces toxicity after transfection of disease-related α-synuclein mutants. Furthermore, it protects from rotenone-induced cell death in vitro and ameliorates neuronal demise in an in vivo 1-methyl-4-phenyl-1,2,3,6,-tetrahydropyridine (MPTP) model for Parkinson’s disease after adeno-associated virus (AAV)-mediated BAG1 gene transfer into the substantia nigra in mice but showed no protective effects in an in vitro 6-hydroxidopamine model. In conclusion, we present BAG1 as a potential therapeutic target in Parkinson’s disease.
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BAG1 is neuroprotective in in vivo and in vitro models of parkinson s disease
Journal of Molecular Neuroscience, 2015Co-Authors: Pawel Kermer, Jan Liman, Mathias Bahr, Paul Lingor, Anja Köhn, Marlena Schnieder, Christoph P DohmAbstract:Bcl-2-associated athanogene-1 (BAG1) is a multifunctional protein comprising co-chaperone function, increasing Hsp70 foldase activity and chaperone-dependent protein degradation of misfolded substrates, with anti-apoptotic activity. It is neuroprotective in different models of neurological diseases, like cerebral ischemia and Huntington’s disease. In the context of Parkinson’s disease, it has recently been shown to restore DJ-1 function in an in vitro model of hereditary Parkinson’s disease. Here, we demonstrate that BAG1 overexpression in SH-SY5Y cells reduces toxicity after transfection of disease-related α-synuclein mutants. Furthermore, it protects from rotenone-induced cell death in vitro and ameliorates neuronal demise in an in vivo 1-methyl-4-phenyl-1,2,3,6,-tetrahydropyridine (MPTP) model for Parkinson’s disease after adeno-associated virus (AAV)-mediated BAG1 gene transfer into the substantia nigra in mice but showed no protective effects in an in vitro 6-hydroxidopamine model. In conclusion, we present BAG1 as a potential therapeutic target in Parkinson’s disease.
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modulation of huntingtin toxicity by BAG1 is dependent on an intact bag domain
Molecules, 2010Co-Authors: Jan Liman, Christoph P Dohm, Mathias Bahr, Kamila Sroka, Sebastian Deeg, Pawel KermerAbstract:Huntington´s disease, one of the so-called poly-glutamine diseases, is a dominantly inherited movement disorder characterized by formation of cytosolic and nuclear inclusion bodies and progressive neurodegeneration. Recently, we have shown that Bcl-2-associated athanogene-1 (BAG1), a multifunctional co-chaperone, modulates toxicity, aggregation, degradation and subcellular distribution in vitro and in vivo of the disease-specific mutant huntingtin protein. Aiming at future small molecule-based therapeutical approaches, we further analysed structural demands for these effects employing the C-terminal deletion mutant BAGDC. We show that disruption of the BAG domain known to eliminate intracellular heat shock protein 70 (Hsp70) binding and activation also precludes binding of Siah-1 thereby leaving nuclear huntingtin translocation unaffected. At the same time BAGDC fails to induce increased proteasomal huntingtin turnover and does not inhibit intracellular huntingtin aggregation, a pre-requisite necessary for prevention of huntingtin toxicity.
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subcellular distribution affects BAG1 function
Brain Research, 2008Co-Authors: Jan Liman, John C Reed, Christoph P Dohm, Mathias Bahr, Lena Faida, Pawel KermerAbstract:BAG1 is a potent neuroprotectant as well as a marker of differentiation in neuronal cells. It is known that BAG1 mainly localizes to the nucleus during neuronal development, whereas BAG1 shifts to the cytosol upon neuronal differentiation suggesting that distinct BAG1 functions depend on its subcellular localization. Here, we show that forced BAG1 expression within the nucleus when compared to full-length BAG1 expression and to control cells completely abolishes the neuroprotective effects of BAG1 supporting the notion that cytosolic interaction with Hsp70 is mandatory for BAG1 mediated neuroprotection. At the same time, we observed that cells can no longer differentiate into post-mitotic neurons when BAG1 is only present in the nucleus. In addition, phospho-Erk levels are decreased in those cells indicating that BAG1 has to translocate to the cytosol for Raf-dependent MAPK activation.
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interaction of BAG1 and hsp70 mediates neuroprotectivity and increases chaperone activity
Molecular and Cellular Biology, 2005Co-Authors: Jan Liman, John C Reed, Sundar Ganesan, Christoph P Dohm, Stan Krajewski, Mathias Bahr, Fred S Wouters, Pawel KermerAbstract:Bcl-2-associated athanogene 1 (BAG1) is the first identified member of the BAG protein family, which consists of at least six different members identified in mammals to date. With the exception of BAG5, all BAG family members share the highly conserved BAG domain near the C terminus (37). The BAG family proteins differ in various other domains, allowing interactions with cellular binding partners and differential subcellular targeting. BAG1 binds to the ATPase domain of the 70-kDa heat shock protein (Hsp70) and its cognate protein Hsc70 (hereafter referred to as Hsp70), which are chaperones, through the BAG domain, thereby serving as a cochaperone and modulating chaperone activity (37-39). Moreover, multiple functions of BAG1 have been proposed; these include interaction and activation of the serine/threonine-specific protein kinase Raf-1 via its N-terminal domain (34, 45) as well as binding to steroid hormone and other receptors (2, 45, 50). Many studies dealing with BAG1 function revealed that it increases resistance to death stimuli when overexpressed in vitro, including in neuronal cells (19, 31, 35, 38, 43, 44). The neuroprotective effects were confirmed in vivo with transgenic mice overexpressing BAG1. Explanted primary neurons displayed increased resistance against glutamate toxicity. Moreover, BAG1 proved to be neuroprotective against stroke induced by middle cerebral artery occlusion in these mice (18). Apart from its antiapoptotic effects, BAG1 also accelerates differentiation when overexpressed in neurons (19). In fact, BAG1−/− mice die during embryogenesis due to failed neurogenesis (46; unpublished observations), indicating an important role for the BAG1 gene in neuronal differentiation, neuronal survival, or both in vivo. It has been proposed that these multifunctional properties of BAG1 depend on its interactions with cellular binding partners. For example, there is evidence for a balance between BAG1 binding to Raf-1 or Hsp70 (34). This scenario raises the possibility that BAG1 promotes cell growth by binding to and stimulating the activity of Raf-1, whereas its antiapoptotic effects are modulated by its interaction with Hsp70. Thus, BAG1 may serve as a molecular switch, encouraging cells to proliferate and differentiate under permissive conditions and allowing survival under nonpermissive conditions (34, 37, 45). Moreover, conflicting data have been reported regarding the modulation of chaperone activity by BAG1. While BAG1 was originally characterized as an inhibitor of Hsp70 activity in vitro, recent evidence suggests that BAG1 can act as a stimulatory or an inhibitory cochaperone, depending on cell type, cofactor expression, and concentration (10, 41). To resolve the question of how the interaction of BAG1 and Hsp70 influences chaperone activity in single neuronal cells, we generated a chaperone-dependent yellow fluorescent protein (YFP) folding mutant (cdYFP) and measured its refolding in rat nigral CSM14.1 and human SHSY-5Y neuroblastoma cells stably overexpressing full-length BAG1 or a truncated BAG1 construct (BAGΔC) lacking the ability to bind Hsp70. Cells overexpressing BAGΔC were also characterized and compared to those containing full-length BAG1 (19) with regard to neuronal differentiation and susceptibility to apoptosis. Here we show for the first time, using intact cells of different species, that BAG1 is a potent inducer of Hsp70 chaperone activity in neurons and that BAG1 neuroprotectivity is dependent on this cochaperone effect. In contrast, the ability of BAG1 to promote neuronal differentiation is independent of Hsp70 binding and cochaperone activity.