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Papers by Sankar Surendran

Journal of child neurology, 2003

Canavan's disease is an autosomal recessive disorder caused by aspartoacylase deficiency, whi... more Canavan's disease is an autosomal recessive disorder caused by aspartoacylase deficiency, which leads to accumulation of N-acetylaspartic acid in the brain and blood and an elevated level of N-acetylaspartic acid in the urine. The brain of patients with Canavan's disease shows spongy degeneration. How the enzyme deficiency and elevated N-acetylaspartic acid cause the pathophysiology observed in Canavan's disease is not obvious. The creation of a knockout mouse for Canavan's disease is being used as a tool to investigate metabolic pathways in the mouse and correlate them with the patients with Canavan's disease. The level of glutamate is lower in the knockout mouse brain than in the wild-type mouse brain, similar to what we have found in children with Canavan's disease, and so are the levels of gamma-aminobutyric acid (GABA). The level of aspartate is higher in the Canavan's disease mouse brain. The activity of aspartate aminotransferase, an enzyme involve...

Journal of child neurology, 2003

Canavan's disease is an autosomal recessive disorder caused by aspartoacylase deficiency. The... more Canavan's disease is an autosomal recessive disorder caused by aspartoacylase deficiency. The deficiency of aspartoacylase leads to increased concentration of N-acetylaspartic acid in brain and body fluids. The failure to hydrolyze N-acetylaspartic acid causes disruption of myelin, resulting in spongy degeneration of the white matter of the brain. The clinical features of the disease are hypotonia in early life, which changes to spasticity, macrocephaly, head lag, and progressive severe mental retardation. Although Canavan's disease is panethnic, it is most prevalent in the Ashkenazi Jewish population. Research at the molecular level led to the cloning of the gene for aspartoacylase and development of a knockout mouse for Canavan's disease. These developments have afforded new tools for research in the attempts to understand the pathophysiology of Canavan's disease, design new therapies, and explore methods for gene transfer to the central nervous system.

Neurochemical research, 2003

Phenylketonuria (PKU) is a metabolic disorder caused by phenylalanine hydroxylase deficiency lead... more Phenylketonuria (PKU) is a metabolic disorder caused by phenylalanine hydroxylase deficiency leading to increased levels of phenylalanine in the brain. Hyperactivity is reportedly induced by a high level of orexin A, and therefore orexin A content was studied in the PKU mice. Hypothalamus and brain stem had higher levels of orexin A compared to cerebrum and cerebellum both in wild type and PKU mice brains as observed by radioimmunoassay method. Interestingly, all these regions of the brain in PKU mouse showed a higher level of orexin A compared to the wild type. Heart and plasma also had higher levels of orexin A in PKU compared to the wild type. Immunohistochemical analysis revealed an increased number of orexin A-stained cells in the brain and heart of PKU mouse compared to the wild type. This is the first report of increased level of orexin in the PKU mouse brain. Hyperactivity is commonly observed in children with PKU; thus these findings suggest that orexin A is a contributing ...

Bioscience Hypotheses, 2008

Canavan disease is caused by aspartoacylase gene mutations. We propose that the disease occurs be... more Canavan disease is caused by aspartoacylase gene mutations. We propose that the disease occurs because accumulating N-acetyl aspartate induces nitric oxide synthase to result elevated levels of nitric oxide and consequent peroxynitrite to lead mitochondrial damage mediated cell death. a v a i l a b l e a t w w w . s c i e n c e d i r e c t . c o m j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / b i h y Bioscience Hypotheses (2008) 1, 228e229

Pathology Research International, 2011

Aspartoacylase/aminoacylase II (ASPA/ACY II) is mainly synthesized in oligodendrocytes to contrib... more Aspartoacylase/aminoacylase II (ASPA/ACY II) is mainly synthesized in oligodendrocytes to contribute in myelin synthesis. Although axonal damage is seen in the brain with human immunodeficiency virus encephalitis (HIVE), ASPA contribution in the pathology is not known. Immunostaining study showed that ASPA protein is reduced in the white matter of patients with HIVE compared to the control. Western blot study further confirmed ASPA deficiency in the HIVE brain compared to the control. This paper suggests that HIVE condition affects ASPA to contribute in myelin loss/axonal damage seen in the disease.

Proceedings of the National Academy of Sciences, 2004

Site-Directed Mutagenesis, Purification. The mutations F39L, I65T, R68S, H170D, E178G, V190A, R26... more Site-Directed Mutagenesis, Purification. The mutations F39L, I65T, R68S, H170D, E178G, V190A, R261Q, A300S, L308F, A313T, A373T, V388M, E390G, P407S, and Y414C were introduced into the pMAL-c2 plasmid containing the full-length WT PAH (wt-PAH) sequence by using the QuikChange site-directed mutagenesis kit (Stratagene). Measurement of mutant and wt-PAH activity by

Neuroscience Letters, 2009

Parkinson's disease (PD) is a neurodegenerative disorder that leads to impairment of balance and ... more Parkinson's disease (PD) is a neurodegenerative disorder that leads to impairment of balance and coordination. Therapy for the disease is still under investigation. Withania somnifera (A-Extract), a herbal medicine, has been known for a spectrum of health-promoting effects including activation of immune, muscle and neuronal systems. Therefore effect of A-Extract in the mouse model of PD was examined. The midbrain and corpus striatum of PD mouse showed increased levels of superoxide dismutase, catalase and malondialdehyde; and reduced levels of glutathione and glutathione peroxidase compared to the control. Treatment with A-Extract 100 mg/kg for 7 days significantly improved all these enzyme levels compared to A-Extract untreated PD mouse brain. In the PD mouse grooming, stride length, movement, rearing were found to be decreased compared to the control. In addition, narrow beam walk and foot slippery errors were increased. Treatment with A-Extract improved all these physiological abnormalities. These data suggests that A-Extract is a potential drug in treating oxidative damage and physiological abnormalities seen in the PD mouse, if documented also in patients with PD.

Neurological Sciences, 2010

Parkinson's disease (PD) is a neurodegenerative disorder, caused by reduced levels of catecholami... more Parkinson's disease (PD) is a neurodegenerative disorder, caused by reduced levels of catecholamines and oxidative stress. Symptoms seen in the disease include tremor, rigidity, bradykinesia and postural disability. Oxidative stress plays a key role in neurodegeneration and motor abnormalities seen in PD. Altered levels of the protein caused by these changes lead to defective ubiquitin-proteasome pathway. Neurodegeneration seen in PD and Canavan disease has a common mechanism. Recent studies suggest that herbal medicines can improve molecular changes and motor functions seen in PD.

Neurochemistry International, 2005

Phenylketonuria (PKU) is an inborn error of amino acid metabolism. Phenylalanine hydroxylase (PAH... more Phenylketonuria (PKU) is an inborn error of amino acid metabolism. Phenylalanine hydroxylase (PAH) deficiency results in accumulation of phenylalanine (Phe) in the brain and leads to pathophysiological abnormalities including cognitive defect, if Phe diet is not restricted. Neuronatin and 4-nitrophenylphosphatase domain and non-neuronal SNAP25-like protein homolog 1 (NIPSNAP1) reportedly have role in memory. Therefore, gene expression was examined in the brain of mouse model for PKU. Microarray expression analysis revealed reduced expression of calpastatin, NIPSNAP 1, rabaptin-5 and minopontin genes and overexpression of neuronatin gene in the PKU mouse brain. Altered expression of these genes was further confirmed by one-step real time RT-PCR analysis. Western blot analysis of the mouse brain showed reduced levels of calpastatin and rabaptin-5 and higher amount of neuronatin in PKU compared to the wild type. These observations in the PKU mouse brain suggest that altered expression of these genes resulting in abnormal proteome. These changes in the PKU mouse brain are likely to contribute cognitive impairment seen in the PKU mouse, if documented also in patients with PKU.

Neurobiology of Disease, 2005

Canavan disease (CD) is a neurodegenerative disorder characterized by the spongy degeneration of ... more Canavan disease (CD) is a neurodegenerative disorder characterized by the spongy degeneration of the white matter of the brain. Aspartoacylase (ASPA) gene mutation resulting enzyme deficiency is the basic cause of CD. Whether the ASPA defect in CD affects the spinal cord has been investigated using the ASPA gene knockout mouse. Luxol fast blue-hematoxylin and eosin staining in the spinal cord of the knockout mouse showed vacuolation in both white matter and gray matter areas of cervical, thoracic, lumbar, and sacral segments of the spinal cord. However, more vacuoles were seen in the gray matter than the white matter of the spinal cord. ASPA activity in the cervical, thoracic, lumbar, and sacrococcygeal regions of the spinal cord was significantly lower in the knockout mouse compared to the wild type. The enzyme defect in the knockout mouse was also confirmed using the Western blot method. These observations suggest that the ASPA gene defect in the mouse leads to spinal cord pathology, and that these changes may be partly involved in the cause of the physiological/behavioral abnormalities seen in the knockout mouse, if documented also in patients with CD.

Molecular Therapy, 2004

Phenylketonuria (PKU) is an inborn error of amino acid metabolism caused by phenylalanine hydroxy... more Phenylketonuria (PKU) is an inborn error of amino acid metabolism caused by phenylalanine hydroxylase (PAH) deficiency. Dietary treatment has been the cornerstone for controlling systemic phenylalanine (Phe) levels in PKU for the past 4 decades. Over the years, it has become clear that blood Phe concentration needs to be controlled for the life of the patient, a difficult task taking into consideration that the diet becomes very difficult to maintain. Therefore alternative models of therapy are being pursued. This review describes the progress made in enzyme replacement therapy for PKU. Two modalities are discussed, PAH and phenylalanine ammonia-lyase PAH. Developing stable and functional forms of both enzymes has proven difficult, but recent success in producing polyethylene glycol-modified forms of active and stable PAH shows promise.

Molecular Genetics and Metabolism, 2003

Canavan disease (CD) is an inherited leukodystrophy, caused by aspartoacylase (ASPA) deficiency, ... more Canavan disease (CD) is an inherited leukodystrophy, caused by aspartoacylase (ASPA) deficiency, and accumulation of N-acetylaspartic acid (NAA) in the brain. The gene for ASPA has been cloned and more than 40 mutations have been described, with two founder mutations among Ashkenazi Jewish patients. Screening of Ashkenazi Jews for these two common mutations revealed a high carrier frequency, approximately 1/40, so that programs for carrier testing are currently in practice. The enzyme deficiency in CD interferes with the normal hydrolysis of NAA, which results in disruption of myelin and spongy degeneration of the white matter of the brain. The clinical features of the disease are macrocephaly, head lag, progressive severe mental retardation, and hypotonia in early life, which later changes to spasticity. A knockout mouse for CD has been generated, and used to study the pathophysiological basis for CD. Findings from the knockout mouse indicate that this monogenic trait leads to a series of genomic interaction in the brain. Changes include low levels of glutamate and GABA. Microarray expression analysis showed low level of expression of GABA-A receptor (GABRA6) and glutamate transporter (EAAT4). The gene Spi2, a gene involved in apoptosis and cell death, showed high level of expression. Such complexity of gene interaction results in the phenotype, the proteome, with spongy degeneration of the brain and neurological impairment of the mouse, similar to the human counterpart. Aspartoacylase gene transfer trial in the mouse brain using adenoassociated virus (AAV) as a vector are encouraging showing improved myelination and decrease in spongy degeneration in the area of the injection and also beyond that site.

Journal of Ethnopharmacology, 2009

Withania somnifera root extract (Ws)/Ashwagandha/Indian ginseng is a traditional herbal medicine,... more Withania somnifera root extract (Ws)/Ashwagandha/Indian ginseng is a traditional herbal medicine, used over 4000 years in India, shown to have effect on neural growth and locomotor function. Although catecholamines and oxidative stress resulting in neurodegeneration and locomotor disorder are the main events in Parkinson's disease (PD), efficacy of the drug on these molecules and physiological abnormality are not clear. The objective of the study was to examine effect of Ws on catecholamines and physiological abnormalities seen in PD using PD model mouse. Mouse were treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) for 4 days to show biochemical and physiological abnormalities similar to patients with PD. PD mice were treated with Ws 100mg/kg body weight for 7 or 28 days. Catecholamines: dopamine (DA), 3,4-dihydroxy-phenylacetic acid (DOPAC) and homovanillic acid (HVA); antioxidants: glutathione (GSH) and glutathione peroxidase (GPx); and lipid peroxidation marker (TBARS) were analyzed in the Ws treated and untreated PD mouse striatum. Mouse treated with MPTP showed reduced levels of DA, DOPAC, HVA, GSH and GPx and induced thiobarbituric acid reactive substance (TBARS) level compared to the control. Physiological abnormalities were seen in the mouse as determined by hang test and rotarod test. Oral treatment of PD mouse Ws root extract (100mg/kg body weight) for 7 days or 28 days increased DA, DOPAC and HVA levels and normalized TBARS levels in the corpus striatum of the PD mouse. The 7 days Ws treated mice showed improved motor function as determined by hang test and rotarod test. Treatment with Ws for 28 days increased GSH and GPx levels in the striatum compared to the Ws untreated PD mouse striatum. These data suggest that Ws is a potential drug in treating catecholamines, oxidative damage and physiological abnormalities seen in the PD mouse.

Journal of Child Neurology, 2003

Patients with slightly increased excretion of N-acetylaspartic acid in urine, together with macro... more Patients with slightly increased excretion of N-acetylaspartic acid in urine, together with macrocephaly, present a dignostic dilemma for Canavan's disease. We describe a 13-year-old male patient with macrocephaly, mild developmental delay, increased signal intensity in the basal ganglia bilaterally, partial cortical blindness, and retinitis pigmentosa. Although the clinical course and magnetic resonance imaging findings did not resemble typical Canavan's disease, N-acetylaspartic acid excretion in the patient's urine was slightly elevated, 99.90 +/- 4.00 microg/mg creatinine, whereas the normal control range was < 83 microg/mg creatinine. Cultured skin fibroblasts from the patient showed no aspartoacylase activity. Cloning of genomic DNA isolated from the patient's fibroblasts showed an intronic mutation, specifically deletion of -2A and -3C at the acceptor site of exon 3 and disrupting the normal splicing of the gene. A second mutation was found in exon 6, 863 A-->G in aspartoacylase complementary DNA, causing a tyrosine-to-cysteine (Y288C) amino acid substitution. Expression of the mutation on exon 6 showed normal aspartoacylase activity. These data suggest that expression of the mutation may help to understand the enzyme defect in a patient with slightly increased N-acetylaspartic acid excretion.

Current Pharmacogenomics, 2004

... Sankar Surendran, Stephen K. Tyring, Kimberlee Michals-Matalon and Reuben Matalon ... Berger,... more ... Sankar Surendran, Stephen K. Tyring, Kimberlee Michals-Matalon and Reuben Matalon ... Berger, UV; Luthi-Carter, R.; Passani, L.; Elkabes, S.; Black, I.; Konradi, C. and Coyle, JT (1999) Glutamate carboxypeptidase II is expressed by astrocytes in the adult rat nervous system. ...

Brain Research Bulletin, 2003

Canavan disease (CD) is an autosomal recessive leukodystrophy characterized by spongy degeneratio... more Canavan disease (CD) is an autosomal recessive leukodystrophy characterized by spongy degeneration of the brain. The clinical features of CD are hypotonia, megalencephaly, and mental retardation leading to early death. While aspartoacylase (ASPA) activity increases with age in the wild type mouse brain, there is no ASPA activity in the CD mouse brain. So far ASPA deficiency and elevated NAA have been ascribed with the CD. Other factors affecting the brain that result from ASPA deficiency may lead pathophysiology of CD. The NMR spectra and amino acid analysis showed lower levels of glutamate and ␥-aminobutyric acid in the CD mouse brain compared to the wild type. Microarray gene expression on CD mouse brain showed glutamate transporter-EAAT4 and ␥-aminobutyric acid-A receptor, subunit ␣6 (GABRA6) were lower 9.7-and 119.1-fold, respectively. Serine proteinase inhibitor 2 (Spi2) was 29.9-fold higher in the CD mouse brain compared to the wild type. The decrease of GABRA6 and high expression of Spi2 in CD mouse brain were also confirmed by real-time RT-PCR. This first report showing abnormal expression of EAAT4, GABRA6, Spi2 combined with lower levels of glutamate and GABA are likely to be associated with the pathophysiology of CD.

Brain Research, 2004

Aspartoacylase (ASPA)-deficient patients [Canavan disease (CD)] reportedly have increased urinary... more Aspartoacylase (ASPA)-deficient patients [Canavan disease (CD)] reportedly have increased urinary excretion of N-acetylaspartylglutamate (NAAG), a neuropeptide abundant in the brain. Whether elevated excretion of urinary NAAG is due to ASPA deficiency, resulting in an abnormal level of brain NAAG, is examined using ASPA-deficient mouse brain. The level of NAAG in the knockout mouse brain was similar to that in the wild type. The NAAG hydrolyzing enzyme, glutamate carboxypeptidase II (GCP II), activity was normal in the knockout mouse brain. These data suggest that ASPA deficiency does not affect the NAAG or GCP II level in the knockout mouse brain, if documented also in patients with CD. D

Biochemical and Biophysical Research Communications, 2004

Orexins/hypocretins are recently discovered neuropeptides, synthesized mainly in the lateral hypo... more Orexins/hypocretins are recently discovered neuropeptides, synthesized mainly in the lateral hypothalamus of the brain. Orexins regulate various functions including sleep and apetite. We recently reported increased amount of orexin A in the phenylketonuria (PKU) mouse brain. Whether this is caused by overexpression of the precursor for orexins, prepro-orexin was studied in the PKU mouse brain. Microarray expression analysis revealed overexpression of orexin gene in the brain of PKU mouse. Quantitative realtime RT-PCR showed increased level of prepro-orexin mRNA in the PKU mouse brain. In addition, expression of genes associated with cell signal and growth regulation was also affected in the PKU mouse brain, as observed by microarray analysis. These data suggest that up-regulation of orexin mRNA expression is the possible factor for inducing high orexin A in the brain of PKU mouse. The metabolic environment in the brain of PKU mouse affects normal expression of other genes possibly to result in pathophysiology seen in the PKU mouse, if documented also in patients with PKU.

American Journal of Medical Genetics, 2002

Four patients from three families with the clinical features of DOOR syndrome (onychoosteodystrop... more Four patients from three families with the clinical features of DOOR syndrome (onychoosteodystrophy, dystrophic thumbs, sensorineural deafness, and increased urinary levels of 2-oxoglutarate) are the subjects of this report. Our report deals with the autosomal recessive form of the disease, wherein the activity of 2-oxoglutarate decarboxylase (E1 0 ) in fibroblasts and white blood cells of the patients is decreased. The activity of E1 0 in all patients' fibroblasts and white blood cells was significantly lower compared to the controls. This study demonstrates for the first time that E1 0 deficiency is an important biochemical marker for the autosomal recessive form of DOOR syndrome.

Brain Research Developmental Brain Research, Oct 15, 2004

Journal of child neurology, 2003

Canavan's disease is an autosomal recessive disorder caused by aspartoacylase deficiency, whi... more Canavan's disease is an autosomal recessive disorder caused by aspartoacylase deficiency, which leads to accumulation of N-acetylaspartic acid in the brain and blood and an elevated level of N-acetylaspartic acid in the urine. The brain of patients with Canavan's disease shows spongy degeneration. How the enzyme deficiency and elevated N-acetylaspartic acid cause the pathophysiology observed in Canavan's disease is not obvious. The creation of a knockout mouse for Canavan's disease is being used as a tool to investigate metabolic pathways in the mouse and correlate them with the patients with Canavan's disease. The level of glutamate is lower in the knockout mouse brain than in the wild-type mouse brain, similar to what we have found in children with Canavan's disease, and so are the levels of gamma-aminobutyric acid (GABA). The level of aspartate is higher in the Canavan's disease mouse brain. The activity of aspartate aminotransferase, an enzyme involve...

Journal of child neurology, 2003

Canavan's disease is an autosomal recessive disorder caused by aspartoacylase deficiency. The... more Canavan's disease is an autosomal recessive disorder caused by aspartoacylase deficiency. The deficiency of aspartoacylase leads to increased concentration of N-acetylaspartic acid in brain and body fluids. The failure to hydrolyze N-acetylaspartic acid causes disruption of myelin, resulting in spongy degeneration of the white matter of the brain. The clinical features of the disease are hypotonia in early life, which changes to spasticity, macrocephaly, head lag, and progressive severe mental retardation. Although Canavan's disease is panethnic, it is most prevalent in the Ashkenazi Jewish population. Research at the molecular level led to the cloning of the gene for aspartoacylase and development of a knockout mouse for Canavan's disease. These developments have afforded new tools for research in the attempts to understand the pathophysiology of Canavan's disease, design new therapies, and explore methods for gene transfer to the central nervous system.

Neurochemical research, 2003

Phenylketonuria (PKU) is a metabolic disorder caused by phenylalanine hydroxylase deficiency lead... more Phenylketonuria (PKU) is a metabolic disorder caused by phenylalanine hydroxylase deficiency leading to increased levels of phenylalanine in the brain. Hyperactivity is reportedly induced by a high level of orexin A, and therefore orexin A content was studied in the PKU mice. Hypothalamus and brain stem had higher levels of orexin A compared to cerebrum and cerebellum both in wild type and PKU mice brains as observed by radioimmunoassay method. Interestingly, all these regions of the brain in PKU mouse showed a higher level of orexin A compared to the wild type. Heart and plasma also had higher levels of orexin A in PKU compared to the wild type. Immunohistochemical analysis revealed an increased number of orexin A-stained cells in the brain and heart of PKU mouse compared to the wild type. This is the first report of increased level of orexin in the PKU mouse brain. Hyperactivity is commonly observed in children with PKU; thus these findings suggest that orexin A is a contributing ...

Bioscience Hypotheses, 2008

Canavan disease is caused by aspartoacylase gene mutations. We propose that the disease occurs be... more Canavan disease is caused by aspartoacylase gene mutations. We propose that the disease occurs because accumulating N-acetyl aspartate induces nitric oxide synthase to result elevated levels of nitric oxide and consequent peroxynitrite to lead mitochondrial damage mediated cell death. a v a i l a b l e a t w w w . s c i e n c e d i r e c t . c o m j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / b i h y Bioscience Hypotheses (2008) 1, 228e229

Pathology Research International, 2011

Aspartoacylase/aminoacylase II (ASPA/ACY II) is mainly synthesized in oligodendrocytes to contrib... more Aspartoacylase/aminoacylase II (ASPA/ACY II) is mainly synthesized in oligodendrocytes to contribute in myelin synthesis. Although axonal damage is seen in the brain with human immunodeficiency virus encephalitis (HIVE), ASPA contribution in the pathology is not known. Immunostaining study showed that ASPA protein is reduced in the white matter of patients with HIVE compared to the control. Western blot study further confirmed ASPA deficiency in the HIVE brain compared to the control. This paper suggests that HIVE condition affects ASPA to contribute in myelin loss/axonal damage seen in the disease.

Proceedings of the National Academy of Sciences, 2004

Site-Directed Mutagenesis, Purification. The mutations F39L, I65T, R68S, H170D, E178G, V190A, R26... more Site-Directed Mutagenesis, Purification. The mutations F39L, I65T, R68S, H170D, E178G, V190A, R261Q, A300S, L308F, A313T, A373T, V388M, E390G, P407S, and Y414C were introduced into the pMAL-c2 plasmid containing the full-length WT PAH (wt-PAH) sequence by using the QuikChange site-directed mutagenesis kit (Stratagene). Measurement of mutant and wt-PAH activity by

Neuroscience Letters, 2009

Parkinson's disease (PD) is a neurodegenerative disorder that leads to impairment of balance and ... more Parkinson's disease (PD) is a neurodegenerative disorder that leads to impairment of balance and coordination. Therapy for the disease is still under investigation. Withania somnifera (A-Extract), a herbal medicine, has been known for a spectrum of health-promoting effects including activation of immune, muscle and neuronal systems. Therefore effect of A-Extract in the mouse model of PD was examined. The midbrain and corpus striatum of PD mouse showed increased levels of superoxide dismutase, catalase and malondialdehyde; and reduced levels of glutathione and glutathione peroxidase compared to the control. Treatment with A-Extract 100 mg/kg for 7 days significantly improved all these enzyme levels compared to A-Extract untreated PD mouse brain. In the PD mouse grooming, stride length, movement, rearing were found to be decreased compared to the control. In addition, narrow beam walk and foot slippery errors were increased. Treatment with A-Extract improved all these physiological abnormalities. These data suggests that A-Extract is a potential drug in treating oxidative damage and physiological abnormalities seen in the PD mouse, if documented also in patients with PD.

Neurological Sciences, 2010

Parkinson's disease (PD) is a neurodegenerative disorder, caused by reduced levels of catecholami... more Parkinson's disease (PD) is a neurodegenerative disorder, caused by reduced levels of catecholamines and oxidative stress. Symptoms seen in the disease include tremor, rigidity, bradykinesia and postural disability. Oxidative stress plays a key role in neurodegeneration and motor abnormalities seen in PD. Altered levels of the protein caused by these changes lead to defective ubiquitin-proteasome pathway. Neurodegeneration seen in PD and Canavan disease has a common mechanism. Recent studies suggest that herbal medicines can improve molecular changes and motor functions seen in PD.

Neurochemistry International, 2005

Phenylketonuria (PKU) is an inborn error of amino acid metabolism. Phenylalanine hydroxylase (PAH... more Phenylketonuria (PKU) is an inborn error of amino acid metabolism. Phenylalanine hydroxylase (PAH) deficiency results in accumulation of phenylalanine (Phe) in the brain and leads to pathophysiological abnormalities including cognitive defect, if Phe diet is not restricted. Neuronatin and 4-nitrophenylphosphatase domain and non-neuronal SNAP25-like protein homolog 1 (NIPSNAP1) reportedly have role in memory. Therefore, gene expression was examined in the brain of mouse model for PKU. Microarray expression analysis revealed reduced expression of calpastatin, NIPSNAP 1, rabaptin-5 and minopontin genes and overexpression of neuronatin gene in the PKU mouse brain. Altered expression of these genes was further confirmed by one-step real time RT-PCR analysis. Western blot analysis of the mouse brain showed reduced levels of calpastatin and rabaptin-5 and higher amount of neuronatin in PKU compared to the wild type. These observations in the PKU mouse brain suggest that altered expression of these genes resulting in abnormal proteome. These changes in the PKU mouse brain are likely to contribute cognitive impairment seen in the PKU mouse, if documented also in patients with PKU.

Neurobiology of Disease, 2005

Canavan disease (CD) is a neurodegenerative disorder characterized by the spongy degeneration of ... more Canavan disease (CD) is a neurodegenerative disorder characterized by the spongy degeneration of the white matter of the brain. Aspartoacylase (ASPA) gene mutation resulting enzyme deficiency is the basic cause of CD. Whether the ASPA defect in CD affects the spinal cord has been investigated using the ASPA gene knockout mouse. Luxol fast blue-hematoxylin and eosin staining in the spinal cord of the knockout mouse showed vacuolation in both white matter and gray matter areas of cervical, thoracic, lumbar, and sacral segments of the spinal cord. However, more vacuoles were seen in the gray matter than the white matter of the spinal cord. ASPA activity in the cervical, thoracic, lumbar, and sacrococcygeal regions of the spinal cord was significantly lower in the knockout mouse compared to the wild type. The enzyme defect in the knockout mouse was also confirmed using the Western blot method. These observations suggest that the ASPA gene defect in the mouse leads to spinal cord pathology, and that these changes may be partly involved in the cause of the physiological/behavioral abnormalities seen in the knockout mouse, if documented also in patients with CD.

Molecular Therapy, 2004

Phenylketonuria (PKU) is an inborn error of amino acid metabolism caused by phenylalanine hydroxy... more Phenylketonuria (PKU) is an inborn error of amino acid metabolism caused by phenylalanine hydroxylase (PAH) deficiency. Dietary treatment has been the cornerstone for controlling systemic phenylalanine (Phe) levels in PKU for the past 4 decades. Over the years, it has become clear that blood Phe concentration needs to be controlled for the life of the patient, a difficult task taking into consideration that the diet becomes very difficult to maintain. Therefore alternative models of therapy are being pursued. This review describes the progress made in enzyme replacement therapy for PKU. Two modalities are discussed, PAH and phenylalanine ammonia-lyase PAH. Developing stable and functional forms of both enzymes has proven difficult, but recent success in producing polyethylene glycol-modified forms of active and stable PAH shows promise.

Molecular Genetics and Metabolism, 2003

Canavan disease (CD) is an inherited leukodystrophy, caused by aspartoacylase (ASPA) deficiency, ... more Canavan disease (CD) is an inherited leukodystrophy, caused by aspartoacylase (ASPA) deficiency, and accumulation of N-acetylaspartic acid (NAA) in the brain. The gene for ASPA has been cloned and more than 40 mutations have been described, with two founder mutations among Ashkenazi Jewish patients. Screening of Ashkenazi Jews for these two common mutations revealed a high carrier frequency, approximately 1/40, so that programs for carrier testing are currently in practice. The enzyme deficiency in CD interferes with the normal hydrolysis of NAA, which results in disruption of myelin and spongy degeneration of the white matter of the brain. The clinical features of the disease are macrocephaly, head lag, progressive severe mental retardation, and hypotonia in early life, which later changes to spasticity. A knockout mouse for CD has been generated, and used to study the pathophysiological basis for CD. Findings from the knockout mouse indicate that this monogenic trait leads to a series of genomic interaction in the brain. Changes include low levels of glutamate and GABA. Microarray expression analysis showed low level of expression of GABA-A receptor (GABRA6) and glutamate transporter (EAAT4). The gene Spi2, a gene involved in apoptosis and cell death, showed high level of expression. Such complexity of gene interaction results in the phenotype, the proteome, with spongy degeneration of the brain and neurological impairment of the mouse, similar to the human counterpart. Aspartoacylase gene transfer trial in the mouse brain using adenoassociated virus (AAV) as a vector are encouraging showing improved myelination and decrease in spongy degeneration in the area of the injection and also beyond that site.

Journal of Ethnopharmacology, 2009

Withania somnifera root extract (Ws)/Ashwagandha/Indian ginseng is a traditional herbal medicine,... more Withania somnifera root extract (Ws)/Ashwagandha/Indian ginseng is a traditional herbal medicine, used over 4000 years in India, shown to have effect on neural growth and locomotor function. Although catecholamines and oxidative stress resulting in neurodegeneration and locomotor disorder are the main events in Parkinson's disease (PD), efficacy of the drug on these molecules and physiological abnormality are not clear. The objective of the study was to examine effect of Ws on catecholamines and physiological abnormalities seen in PD using PD model mouse. Mouse were treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) for 4 days to show biochemical and physiological abnormalities similar to patients with PD. PD mice were treated with Ws 100mg/kg body weight for 7 or 28 days. Catecholamines: dopamine (DA), 3,4-dihydroxy-phenylacetic acid (DOPAC) and homovanillic acid (HVA); antioxidants: glutathione (GSH) and glutathione peroxidase (GPx); and lipid peroxidation marker (TBARS) were analyzed in the Ws treated and untreated PD mouse striatum. Mouse treated with MPTP showed reduced levels of DA, DOPAC, HVA, GSH and GPx and induced thiobarbituric acid reactive substance (TBARS) level compared to the control. Physiological abnormalities were seen in the mouse as determined by hang test and rotarod test. Oral treatment of PD mouse Ws root extract (100mg/kg body weight) for 7 days or 28 days increased DA, DOPAC and HVA levels and normalized TBARS levels in the corpus striatum of the PD mouse. The 7 days Ws treated mice showed improved motor function as determined by hang test and rotarod test. Treatment with Ws for 28 days increased GSH and GPx levels in the striatum compared to the Ws untreated PD mouse striatum. These data suggest that Ws is a potential drug in treating catecholamines, oxidative damage and physiological abnormalities seen in the PD mouse.

Journal of Child Neurology, 2003

Patients with slightly increased excretion of N-acetylaspartic acid in urine, together with macro... more Patients with slightly increased excretion of N-acetylaspartic acid in urine, together with macrocephaly, present a dignostic dilemma for Canavan's disease. We describe a 13-year-old male patient with macrocephaly, mild developmental delay, increased signal intensity in the basal ganglia bilaterally, partial cortical blindness, and retinitis pigmentosa. Although the clinical course and magnetic resonance imaging findings did not resemble typical Canavan's disease, N-acetylaspartic acid excretion in the patient's urine was slightly elevated, 99.90 +/- 4.00 microg/mg creatinine, whereas the normal control range was < 83 microg/mg creatinine. Cultured skin fibroblasts from the patient showed no aspartoacylase activity. Cloning of genomic DNA isolated from the patient's fibroblasts showed an intronic mutation, specifically deletion of -2A and -3C at the acceptor site of exon 3 and disrupting the normal splicing of the gene. A second mutation was found in exon 6, 863 A-->G in aspartoacylase complementary DNA, causing a tyrosine-to-cysteine (Y288C) amino acid substitution. Expression of the mutation on exon 6 showed normal aspartoacylase activity. These data suggest that expression of the mutation may help to understand the enzyme defect in a patient with slightly increased N-acetylaspartic acid excretion.

Current Pharmacogenomics, 2004

... Sankar Surendran, Stephen K. Tyring, Kimberlee Michals-Matalon and Reuben Matalon ... Berger,... more ... Sankar Surendran, Stephen K. Tyring, Kimberlee Michals-Matalon and Reuben Matalon ... Berger, UV; Luthi-Carter, R.; Passani, L.; Elkabes, S.; Black, I.; Konradi, C. and Coyle, JT (1999) Glutamate carboxypeptidase II is expressed by astrocytes in the adult rat nervous system. ...

Brain Research Bulletin, 2003

Canavan disease (CD) is an autosomal recessive leukodystrophy characterized by spongy degeneratio... more Canavan disease (CD) is an autosomal recessive leukodystrophy characterized by spongy degeneration of the brain. The clinical features of CD are hypotonia, megalencephaly, and mental retardation leading to early death. While aspartoacylase (ASPA) activity increases with age in the wild type mouse brain, there is no ASPA activity in the CD mouse brain. So far ASPA deficiency and elevated NAA have been ascribed with the CD. Other factors affecting the brain that result from ASPA deficiency may lead pathophysiology of CD. The NMR spectra and amino acid analysis showed lower levels of glutamate and ␥-aminobutyric acid in the CD mouse brain compared to the wild type. Microarray gene expression on CD mouse brain showed glutamate transporter-EAAT4 and ␥-aminobutyric acid-A receptor, subunit ␣6 (GABRA6) were lower 9.7-and 119.1-fold, respectively. Serine proteinase inhibitor 2 (Spi2) was 29.9-fold higher in the CD mouse brain compared to the wild type. The decrease of GABRA6 and high expression of Spi2 in CD mouse brain were also confirmed by real-time RT-PCR. This first report showing abnormal expression of EAAT4, GABRA6, Spi2 combined with lower levels of glutamate and GABA are likely to be associated with the pathophysiology of CD.

Brain Research, 2004

Aspartoacylase (ASPA)-deficient patients [Canavan disease (CD)] reportedly have increased urinary... more Aspartoacylase (ASPA)-deficient patients [Canavan disease (CD)] reportedly have increased urinary excretion of N-acetylaspartylglutamate (NAAG), a neuropeptide abundant in the brain. Whether elevated excretion of urinary NAAG is due to ASPA deficiency, resulting in an abnormal level of brain NAAG, is examined using ASPA-deficient mouse brain. The level of NAAG in the knockout mouse brain was similar to that in the wild type. The NAAG hydrolyzing enzyme, glutamate carboxypeptidase II (GCP II), activity was normal in the knockout mouse brain. These data suggest that ASPA deficiency does not affect the NAAG or GCP II level in the knockout mouse brain, if documented also in patients with CD. D

Biochemical and Biophysical Research Communications, 2004

Orexins/hypocretins are recently discovered neuropeptides, synthesized mainly in the lateral hypo... more Orexins/hypocretins are recently discovered neuropeptides, synthesized mainly in the lateral hypothalamus of the brain. Orexins regulate various functions including sleep and apetite. We recently reported increased amount of orexin A in the phenylketonuria (PKU) mouse brain. Whether this is caused by overexpression of the precursor for orexins, prepro-orexin was studied in the PKU mouse brain. Microarray expression analysis revealed overexpression of orexin gene in the brain of PKU mouse. Quantitative realtime RT-PCR showed increased level of prepro-orexin mRNA in the PKU mouse brain. In addition, expression of genes associated with cell signal and growth regulation was also affected in the PKU mouse brain, as observed by microarray analysis. These data suggest that up-regulation of orexin mRNA expression is the possible factor for inducing high orexin A in the brain of PKU mouse. The metabolic environment in the brain of PKU mouse affects normal expression of other genes possibly to result in pathophysiology seen in the PKU mouse, if documented also in patients with PKU.

American Journal of Medical Genetics, 2002

Four patients from three families with the clinical features of DOOR syndrome (onychoosteodystrop... more Four patients from three families with the clinical features of DOOR syndrome (onychoosteodystrophy, dystrophic thumbs, sensorineural deafness, and increased urinary levels of 2-oxoglutarate) are the subjects of this report. Our report deals with the autosomal recessive form of the disease, wherein the activity of 2-oxoglutarate decarboxylase (E1 0 ) in fibroblasts and white blood cells of the patients is decreased. The activity of E1 0 in all patients' fibroblasts and white blood cells was significantly lower compared to the controls. This study demonstrates for the first time that E1 0 deficiency is an important biochemical marker for the autosomal recessive form of DOOR syndrome.

Brain Research Developmental Brain Research, Oct 15, 2004