Combined therapy with cyclodextrin/allopregnanolone and miglustat improves motor but not cognitiv... more Combined therapy with cyclodextrin/allopregnanolone and miglustat improves motor but not cognitive functions in Niemann–Pick Type C1 mice
b ¨¨ Abstract Mutations in two genes, a-synuclein and parkin, have been identified as some rare c... more b ¨¨ Abstract Mutations in two genes, a-synuclein and parkin, have been identified as some rare causes for familial Parkinson's disease (PD). a-Synuclein and parkin protein have subsequently been identified in Lewy bodies (LB). To gain further insight into the pathogenesis of PD we investigated the role of neurofilament light (NF-L), another component of LB aggregation. A detailed mutation search of the NF-L gene in 328 sporadic and familial PD patients of German ancestry revealed three silent DNA changes (G163A, C224T, C487T) in three unrelated patients. Analysis of the promoter region of the NF-L gene identified a total of three base pair substitutions defining five haplotypes. Association studies based on these haplotypes revealed no significant differences between PD patients and 344 control individuals. Therefore, NF-L is unlikely to play a major role in the pathogenesis of PD. 2002 Elsevier Science B.V. All rights reserved. Theme: Disorders of the nervous system Topic: D...
The predominant characteristic of Parkinson's disease is the loss of dopaminergic neurons in ... more The predominant characteristic of Parkinson's disease is the loss of dopaminergic neurons in the substantia nigra pars compacta and axonal degeneration of dopaminergic fibers in the striatum. Subsequently, a disinhibition of tonically active striatal cholinergic interneurons results in local hypercholinism, changing the basal ganglia circuitry and causing motor symptoms. To circumvent the numerous severe side effects of a systematic anticholinergic pharmacotherapy, an anticholinergic therapy locally restricted to the striatum is achieved by local botulinum neurotoxin-A application. Botulinum neurotoxin-A prevents the release of acetylcholine from presynaptic boutons; this has been used in medicine for the controlled paralysis of smooth and striated muscles. Intrastriatal injections of botulinum neurotoxin-A in 6-hydroxydopamine-induced hemiparkinsonian rats have been investigated with respect to morphological and behavioral outcomes. In naive rats, a mild effect of botulinum neu...
Rare diseases are a heterogeneous group of very different clinical syndromes. Their most common c... more Rare diseases are a heterogeneous group of very different clinical syndromes. Their most common causes are defects in the hereditary material, and they can therefore be passed on to descendants. Rare diseases become manifest in almost all organs and often have a systemic expressivity, i.e., they affect several organs simultaneously. An effective causal therapy is often not available and can only be developed when the underlying causes of the disease are understood. In this review, we focus on Niemann–Pick disease type C1 (NPC1), which is a rare lipid-storage disorder. Lipids, in particular phospholipids, are a major component of the cell membrane and play important roles in cellular functions, such as extracellular receptor signaling, intracellular second messengers and cellular pressure regulation. An excessive storage of fats, as seen in NPC1, can cause permanent damage to cells and tissues in the brain and peripheral nervous system, but also in other parts of the body. Here, we s...
Synphilin-1 is linked to the pathogenesis of Parkinson's disease (PD) based on its identifica... more Synphilin-1 is linked to the pathogenesis of Parkinson's disease (PD) based on its identification as an alpha-synuclein (PARK1) and parkin (PARK2) interacting protein. Moreover, synphilin-1 is a component of Lewy bodies (LB) in brains of sporadic PD patients. Therefore, we performed a detailed mutation analysis of the synphilin-1 gene in 328 German familial and sporadic PD patients. In two apparently sporadic PD patients we deciphered a novel C to T transition in position 1861 of the coding sequence leading to an amino acid substitution from arginine to cysteine in position 621 (R621C). This mutation was absent in a total of 702 chromosomes of healthy German controls. To define a possible role of mutant synphilin-1 in the pathogenesis of PD we performed functional analyses in SH-SY5Y cells. We found synphilin-1 capable of producing cytoplasmic inclusions in transfected cells. Moreover we observed a significantly reduced number of inclusions in cells expressing C621 synphilin-1 c...
Background. For neurodegenerative diseases such as Huntington’s disease (HD), early diagnosis is ... more Background. For neurodegenerative diseases such as Huntington’s disease (HD), early diagnosis is essential to treat patients and delay symptoms. Impaired olfaction, as observed as an early symptom in Parkinson´s disease, may also constitute a key symptom in HD. However, there are few reports on olfactory deficits in HD. Therefore, we aimed to investigate, in a transgenic rat model of HD: (1) whether general olfactory impairment exists and (2) whether there are disease-specific dynamics of olfactory dysfunction when the vomeronasal (VNE) and main olfactory epithelium (MOE) are compared. Methods. We used male rats of transgenic line 22 (TG22) of the bacterial artificial chromosome Huntington disease model (BACHD), aged 3 days or 6 months. Cell proliferation, apoptosis and macrophage activity were examined with immunohistochemistry in the VNE and MOE. Results. No differences were observed in cellular parameters in the VNE between the groups. However, the MOE of the 6-month-old HD anima...
Forelimb stepping is a widely used test for the assessment of forelimb akinesia in hemiparkinsoni... more Forelimb stepping is a widely used test for the assessment of forelimb akinesia in hemiparkinsonian (hemi-PD) rats. The initiation time (IT) is considered the most sensitive parameter in the stepping test procedure. Here we propose a novel, reliable, and simple method for the measurement of IT of both forelimbs in both forehand and backhand directions in rats. Evaluating the same videos taken for quantifying adjusting steps, IT measurements were done without additional experiments. This is in contrast to the classical approach introduced by Olsson et al. (1995), in which separate experiments are necessary. We successfully applied our approach to hemi-PD rats intrastriatally treated with botulinum neurotoxin-A (BoNT-A). In naïve rats, an IT of about 0.62 s was found, and in right-sided hemi-PD rats the IT of the left forepaw increased to about 3.62 s. These hemi-PD rats showed, however, reduced ITs of the impaired left forepaws 1 month and the second time 7 months after induction of ...
Background Periductal stromal tumors of the breast are exceedingly rare biphasic breast tumors wi... more Background Periductal stromal tumors of the breast are exceedingly rare biphasic breast tumors with close morphological relationship to phyllodes tumors. So far, results of genetic analyses on these tumors have not been reported. Case presentation A 50 year old female patient was admitted to the hospital because of a palpable lump in her right breast with a diameter of approximately 5–6 cm which was surgically removed by lumpectomy. Histologic examination revealed a biphasic breast tumor classified as periductal stromal tumor. Array analysis showed a pseudotetraploid tumor with a copy number of 4 for most of the chromosomes. In addition, further changes of chromosomes 1, 5, and 6 were noted but there were no mutations of MED12 as those frequently seen in fibroadenomas or phyllodes tumors. Conclusions The genetic alterations observed indicate karyotypic evolution leading to marked heterogeneity which fits with the tumor´s histologic and cytologic appearance as well as with its malign...
Thyroid Adenoma Associated (THADA) is a protein-coding gene that maps to chromosomal band 2p21 an... more Thyroid Adenoma Associated (THADA) is a protein-coding gene that maps to chromosomal band 2p21 and first has been described as a target of recurrent translocation partner in thyroid tumors. Many genome-wide association studies have revealed an association between THADA and two frequent human diseases, i.e. type 2 diabetes and polycystic ovary syndrome. Nevertheless, the function of its protein is not been completely understood. However, recent evidence suggests that in a Drosophila model THADA can act as a sarco/endoplasmic reticulum Ca2+-ATPase (SERCA)-interacting protein which uncouples SERCA from this function. Once being uncoupled, SERCA produces an increased amount of heat without transporting calcium thus triggering nonshivering thermogenesis. This data prompted us to compare human THADA with that of 65 other eutherian mammals. This includes a comparison of THADA of a variety of eutherian mammals with that of the naked-mole rat (Heterocephalus glaber) which is known to display...
Experimental autoimmune encephalomyelitis (EAE) is the most commonly used multiple sclerosis anim... more Experimental autoimmune encephalomyelitis (EAE) is the most commonly used multiple sclerosis animal model. EAE mice typically develop motor deficits in a caudal-to-rostral pattern when inflammatory lesions have already developed. However, to monitor more subtle behavioral deficits during lesion development (i.e., pre-clinical phase), more sophisticated methods are needed. Here, we investigated whether high speed ventral plane videography can be applied to monitor early motor deficits during ‘pre-clinical’ EAE. For this purpose, EAE was induced in C57BL/6 mice and gait abnormalities were quantified using the DigiGait™ apparatus. Gait deficits were related to histopathological changes. 10 out of 10 control (100%), and 14 out of 18 (77.8%) pre-clinical EAE mice could be evaluated using DigiGait™. EAE severity was not influenced by DigiGait™-related mice handlings. Most gait parameters recorded from day 6 post-immunization until the end of the experiment were found to be stable in contr...
International journal of molecular sciences, Jan 6, 2017
Niemann-Pick disease type C1 (NPC1) is a fatal neurovisceral lysosomal lipid storage disorder. Th... more Niemann-Pick disease type C1 (NPC1) is a fatal neurovisceral lysosomal lipid storage disorder. The mutation of the NPC1 protein affects the homeostasis and transport of cholesterol and glycosphingolipids from late endosomes/lysosomes to the endoplasmic reticulum resulting in progressive neurodegeneration. Since olfactory impairment is one of the earliest symptoms in many neurodegenerative disorders, we focused on alterations of the olfactory epithelium in an NPC1 mouse model. Previous findings revealed severe morphological and immunohistochemical alterations in the olfactory system of NPC1(-/-) mutant mice compared with healthy controls (NPC1(+/+)). Based on immunohistochemical evaluation of the olfactory epithelium, we analyzed the impact of neurodegeneration in the olfactory epithelium of NPC1(-/-) mice and observed considerable loss of mature olfactory receptor neurons as well as an increased number of proliferating and apoptotic cells. Additionally, after administration of two d...
Olfactory deficits occur as early non-motor symptoms of idiopathic Parkinson’s disease (PD) in hu... more Olfactory deficits occur as early non-motor symptoms of idiopathic Parkinson’s disease (PD) in humans. The first central relay of the olfactory pathway, the olfactory bulb (OB), depends, among other things, on an intact, functional crosstalk between dopaminergic interneurons and dopamine receptors (D2/D3R). In rats, hemiparkinsonism (hemi-PD) can be induced by unilateral injection of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle (MFB), disrupting dopaminergic neurons of the substantia nigra pars compacta (SNpc). In a previous study, we showed that subsequent injection of botulinum neurotoxin-A (BoNT-A) into the striatum can reverse most of the pathological motor symptoms and normalize the D2/D3R availability. To determine whether this rat model is suitable to explain olfactory deficits that occur in humans with PD, we examined the availability of D2/D3R by longitudinal [18F]fallypride-PET/CT, the density of tyrosine hydroxylase immunoreactivity in the OB, olfactory per...
Combined therapy with cyclodextrin/allopregnanolone and miglustat improves motor but not cognitiv... more Combined therapy with cyclodextrin/allopregnanolone and miglustat improves motor but not cognitive functions in Niemann–Pick Type C1 mice
b ¨¨ Abstract Mutations in two genes, a-synuclein and parkin, have been identified as some rare c... more b ¨¨ Abstract Mutations in two genes, a-synuclein and parkin, have been identified as some rare causes for familial Parkinson's disease (PD). a-Synuclein and parkin protein have subsequently been identified in Lewy bodies (LB). To gain further insight into the pathogenesis of PD we investigated the role of neurofilament light (NF-L), another component of LB aggregation. A detailed mutation search of the NF-L gene in 328 sporadic and familial PD patients of German ancestry revealed three silent DNA changes (G163A, C224T, C487T) in three unrelated patients. Analysis of the promoter region of the NF-L gene identified a total of three base pair substitutions defining five haplotypes. Association studies based on these haplotypes revealed no significant differences between PD patients and 344 control individuals. Therefore, NF-L is unlikely to play a major role in the pathogenesis of PD. 2002 Elsevier Science B.V. All rights reserved. Theme: Disorders of the nervous system Topic: D...
The predominant characteristic of Parkinson's disease is the loss of dopaminergic neurons in ... more The predominant characteristic of Parkinson's disease is the loss of dopaminergic neurons in the substantia nigra pars compacta and axonal degeneration of dopaminergic fibers in the striatum. Subsequently, a disinhibition of tonically active striatal cholinergic interneurons results in local hypercholinism, changing the basal ganglia circuitry and causing motor symptoms. To circumvent the numerous severe side effects of a systematic anticholinergic pharmacotherapy, an anticholinergic therapy locally restricted to the striatum is achieved by local botulinum neurotoxin-A application. Botulinum neurotoxin-A prevents the release of acetylcholine from presynaptic boutons; this has been used in medicine for the controlled paralysis of smooth and striated muscles. Intrastriatal injections of botulinum neurotoxin-A in 6-hydroxydopamine-induced hemiparkinsonian rats have been investigated with respect to morphological and behavioral outcomes. In naive rats, a mild effect of botulinum neu...
Rare diseases are a heterogeneous group of very different clinical syndromes. Their most common c... more Rare diseases are a heterogeneous group of very different clinical syndromes. Their most common causes are defects in the hereditary material, and they can therefore be passed on to descendants. Rare diseases become manifest in almost all organs and often have a systemic expressivity, i.e., they affect several organs simultaneously. An effective causal therapy is often not available and can only be developed when the underlying causes of the disease are understood. In this review, we focus on Niemann–Pick disease type C1 (NPC1), which is a rare lipid-storage disorder. Lipids, in particular phospholipids, are a major component of the cell membrane and play important roles in cellular functions, such as extracellular receptor signaling, intracellular second messengers and cellular pressure regulation. An excessive storage of fats, as seen in NPC1, can cause permanent damage to cells and tissues in the brain and peripheral nervous system, but also in other parts of the body. Here, we s...
Synphilin-1 is linked to the pathogenesis of Parkinson's disease (PD) based on its identifica... more Synphilin-1 is linked to the pathogenesis of Parkinson's disease (PD) based on its identification as an alpha-synuclein (PARK1) and parkin (PARK2) interacting protein. Moreover, synphilin-1 is a component of Lewy bodies (LB) in brains of sporadic PD patients. Therefore, we performed a detailed mutation analysis of the synphilin-1 gene in 328 German familial and sporadic PD patients. In two apparently sporadic PD patients we deciphered a novel C to T transition in position 1861 of the coding sequence leading to an amino acid substitution from arginine to cysteine in position 621 (R621C). This mutation was absent in a total of 702 chromosomes of healthy German controls. To define a possible role of mutant synphilin-1 in the pathogenesis of PD we performed functional analyses in SH-SY5Y cells. We found synphilin-1 capable of producing cytoplasmic inclusions in transfected cells. Moreover we observed a significantly reduced number of inclusions in cells expressing C621 synphilin-1 c...
Background. For neurodegenerative diseases such as Huntington’s disease (HD), early diagnosis is ... more Background. For neurodegenerative diseases such as Huntington’s disease (HD), early diagnosis is essential to treat patients and delay symptoms. Impaired olfaction, as observed as an early symptom in Parkinson´s disease, may also constitute a key symptom in HD. However, there are few reports on olfactory deficits in HD. Therefore, we aimed to investigate, in a transgenic rat model of HD: (1) whether general olfactory impairment exists and (2) whether there are disease-specific dynamics of olfactory dysfunction when the vomeronasal (VNE) and main olfactory epithelium (MOE) are compared. Methods. We used male rats of transgenic line 22 (TG22) of the bacterial artificial chromosome Huntington disease model (BACHD), aged 3 days or 6 months. Cell proliferation, apoptosis and macrophage activity were examined with immunohistochemistry in the VNE and MOE. Results. No differences were observed in cellular parameters in the VNE between the groups. However, the MOE of the 6-month-old HD anima...
Forelimb stepping is a widely used test for the assessment of forelimb akinesia in hemiparkinsoni... more Forelimb stepping is a widely used test for the assessment of forelimb akinesia in hemiparkinsonian (hemi-PD) rats. The initiation time (IT) is considered the most sensitive parameter in the stepping test procedure. Here we propose a novel, reliable, and simple method for the measurement of IT of both forelimbs in both forehand and backhand directions in rats. Evaluating the same videos taken for quantifying adjusting steps, IT measurements were done without additional experiments. This is in contrast to the classical approach introduced by Olsson et al. (1995), in which separate experiments are necessary. We successfully applied our approach to hemi-PD rats intrastriatally treated with botulinum neurotoxin-A (BoNT-A). In naïve rats, an IT of about 0.62 s was found, and in right-sided hemi-PD rats the IT of the left forepaw increased to about 3.62 s. These hemi-PD rats showed, however, reduced ITs of the impaired left forepaws 1 month and the second time 7 months after induction of ...
Background Periductal stromal tumors of the breast are exceedingly rare biphasic breast tumors wi... more Background Periductal stromal tumors of the breast are exceedingly rare biphasic breast tumors with close morphological relationship to phyllodes tumors. So far, results of genetic analyses on these tumors have not been reported. Case presentation A 50 year old female patient was admitted to the hospital because of a palpable lump in her right breast with a diameter of approximately 5–6 cm which was surgically removed by lumpectomy. Histologic examination revealed a biphasic breast tumor classified as periductal stromal tumor. Array analysis showed a pseudotetraploid tumor with a copy number of 4 for most of the chromosomes. In addition, further changes of chromosomes 1, 5, and 6 were noted but there were no mutations of MED12 as those frequently seen in fibroadenomas or phyllodes tumors. Conclusions The genetic alterations observed indicate karyotypic evolution leading to marked heterogeneity which fits with the tumor´s histologic and cytologic appearance as well as with its malign...
Thyroid Adenoma Associated (THADA) is a protein-coding gene that maps to chromosomal band 2p21 an... more Thyroid Adenoma Associated (THADA) is a protein-coding gene that maps to chromosomal band 2p21 and first has been described as a target of recurrent translocation partner in thyroid tumors. Many genome-wide association studies have revealed an association between THADA and two frequent human diseases, i.e. type 2 diabetes and polycystic ovary syndrome. Nevertheless, the function of its protein is not been completely understood. However, recent evidence suggests that in a Drosophila model THADA can act as a sarco/endoplasmic reticulum Ca2+-ATPase (SERCA)-interacting protein which uncouples SERCA from this function. Once being uncoupled, SERCA produces an increased amount of heat without transporting calcium thus triggering nonshivering thermogenesis. This data prompted us to compare human THADA with that of 65 other eutherian mammals. This includes a comparison of THADA of a variety of eutherian mammals with that of the naked-mole rat (Heterocephalus glaber) which is known to display...
Experimental autoimmune encephalomyelitis (EAE) is the most commonly used multiple sclerosis anim... more Experimental autoimmune encephalomyelitis (EAE) is the most commonly used multiple sclerosis animal model. EAE mice typically develop motor deficits in a caudal-to-rostral pattern when inflammatory lesions have already developed. However, to monitor more subtle behavioral deficits during lesion development (i.e., pre-clinical phase), more sophisticated methods are needed. Here, we investigated whether high speed ventral plane videography can be applied to monitor early motor deficits during ‘pre-clinical’ EAE. For this purpose, EAE was induced in C57BL/6 mice and gait abnormalities were quantified using the DigiGait™ apparatus. Gait deficits were related to histopathological changes. 10 out of 10 control (100%), and 14 out of 18 (77.8%) pre-clinical EAE mice could be evaluated using DigiGait™. EAE severity was not influenced by DigiGait™-related mice handlings. Most gait parameters recorded from day 6 post-immunization until the end of the experiment were found to be stable in contr...
International journal of molecular sciences, Jan 6, 2017
Niemann-Pick disease type C1 (NPC1) is a fatal neurovisceral lysosomal lipid storage disorder. Th... more Niemann-Pick disease type C1 (NPC1) is a fatal neurovisceral lysosomal lipid storage disorder. The mutation of the NPC1 protein affects the homeostasis and transport of cholesterol and glycosphingolipids from late endosomes/lysosomes to the endoplasmic reticulum resulting in progressive neurodegeneration. Since olfactory impairment is one of the earliest symptoms in many neurodegenerative disorders, we focused on alterations of the olfactory epithelium in an NPC1 mouse model. Previous findings revealed severe morphological and immunohistochemical alterations in the olfactory system of NPC1(-/-) mutant mice compared with healthy controls (NPC1(+/+)). Based on immunohistochemical evaluation of the olfactory epithelium, we analyzed the impact of neurodegeneration in the olfactory epithelium of NPC1(-/-) mice and observed considerable loss of mature olfactory receptor neurons as well as an increased number of proliferating and apoptotic cells. Additionally, after administration of two d...
Olfactory deficits occur as early non-motor symptoms of idiopathic Parkinson’s disease (PD) in hu... more Olfactory deficits occur as early non-motor symptoms of idiopathic Parkinson’s disease (PD) in humans. The first central relay of the olfactory pathway, the olfactory bulb (OB), depends, among other things, on an intact, functional crosstalk between dopaminergic interneurons and dopamine receptors (D2/D3R). In rats, hemiparkinsonism (hemi-PD) can be induced by unilateral injection of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle (MFB), disrupting dopaminergic neurons of the substantia nigra pars compacta (SNpc). In a previous study, we showed that subsequent injection of botulinum neurotoxin-A (BoNT-A) into the striatum can reverse most of the pathological motor symptoms and normalize the D2/D3R availability. To determine whether this rat model is suitable to explain olfactory deficits that occur in humans with PD, we examined the availability of D2/D3R by longitudinal [18F]fallypride-PET/CT, the density of tyrosine hydroxylase immunoreactivity in the OB, olfactory per...
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