... Clark, S., Schwalbe, J., Stasko, MR, Yarowsky, PJ, Costa, AC (2006). Fluoxetine rescues defic... more ... Clark, S., Schwalbe, J., Stasko, MR, Yarowsky, PJ, Costa, AC (2006). Fluoxetine rescues deficient neurogenesis in hippocampus of the Ts65Dn mouse model for Down syndrome. Experimental Neurology, 200, 256 261. Contestabile, A., Fila, T., Bartesaghi, R., Ciani, E. (2009). ...
Journal of Neuropathology and Experimental Neurology, 2010
Alphab-crystallin (CRYAB) is a small heat shock protein with a chaperoning activity that is prese... more Alphab-crystallin (CRYAB) is a small heat shock protein with a chaperoning activity that is present in the postnatal healthy human brain in oligodendrocytes and in a few astrocytes. The involvement of CRYAB in cell differentiation, proliferation, signaling, cytoskeletal assembly, and apoptosis in various model systems has suggested that it might also play a role in the developing human brain. We analyzed the distribution and the levels of this molecular chaperone in healthy and polygenetically compromised (Down syndrome [DS]) human telencephalon at midgestation. We demonstrate that CRYAB is expressed in a temporospatial pattern by numerous radial glial cells and some early oligodendrocyte progenitors, including dividing cells, as well as a few astroglial cells in both healthy and DS fetal brains. We also found abundant phosphorylation of CRYAB at Ser-59, which mediates its antiapoptotic and cytoskeletal functions. There was only marginal phosphorylation at Ser-45.In contrast to our earlier study in young DS subjects, upregulation of phosphorylated CRYAB occurred rarely in DS fetuses. The distribution, the timing of appearance, and the results of colocalization studies suggest that CRYAB assists in the biological processes associated with developmental remodeling/differentiation and proliferation of select subpopulations of progenitor cells in human fetal brain at midgestation.
Journal of neuropathology and experimental neurology, 2001
Tripeptidyl peptidase I (TPP I) is a lysosomal exopeptidase that cleaves tripeptides from the fre... more Tripeptidyl peptidase I (TPP I) is a lysosomal exopeptidase that cleaves tripeptides from the free N-termini of oligopeptides. Mutations in this enzyme are associated with the classic late-infantile form of neuronal ceroid lipofuscinosis (CLN2), an autosomal recessive disorder leading to severe brain damage. To gain more insight into CLN2 pathogenesis and the role of TPP I in human tissues in general, we analyzed the temporal and spatial distribution of TPP I in the brain and its localization in internal organs under normal and pathological conditions. We report that TPP I immunoreactivity appears in neurons late in gestation and increases gradually in the postnatal period, matching significantly the final differentiation and maturation of neural tissue. Endothelial cells, choroid plexus, microglial cells, and ependyma showed TPP I immunostaining distinctly earlier than neurons. Acquisition of the adult pattern of TPP I distribution in the brain at around the age of 2 years correlat...
Journal of Neuropathology and Experimental Neurology, 2006
Carbonic anhydrase II (CA II) is one of 14 isozymes of carbonic anhydrases, zinc metalloenzymes t... more Carbonic anhydrase II (CA II) is one of 14 isozymes of carbonic anhydrases, zinc metalloenzymes that catalyze the reversible hydration of carbon dioxide to bicarbonate. Mutations in CA II in humans lead to osteopetrosis with renal tubular acidosis and cerebral calcifications, a disorder often associated with mental retardation. Recently, new avenues in CA II research have opened as a result of discoveries that the enzyme increases bicarbonate and proton fluxes and may play an important role in brain tissue. In the human brain, CA II was localized to oligodendrocytes, myelin, and choroid plexus epithelium. Because this conclusion was based on a few fragmentary reports, we analyzed in more detail the expression of the enzyme in human telencephalon. By immunoblotting, we found a gradual increase in CA II levels from 17 weeks' gestation to childhood and adolescence. By immunohistochemistry, CA II was found to be present not only in oligodendrocytes and choroid plexus epithelium (declining with aging in both these locations), but also in a subset of neurons mostly with GABAergic phenotype, in a few astrocytes, and transiently during brain development in the endothelial cells of microvessels. The enzyme also occurred in oligodendrocyte processes in contact with myelinating axons, myelin sheaths, and axolemma, but was either absent or appeared in minute amounts in compact myelin. These findings suggest the possible involvement of CA II in a wide spectrum of biologic processes in the developing and adult human brain and may contribute to better understanding of the pathogenesis of cerebral calcifications and mental retardation caused by CA II deficiency.
There are 35 missense mutations among 68 different mutations in the TPP1 gene, which encodes trip... more There are 35 missense mutations among 68 different mutations in the TPP1 gene, which encodes tripeptidyl peptidase I (TPPI), a lysosomal aminopeptidase associated with classic late-infantile neuronal ceroid lipofuscinosis (CLN2 disease). To elucidate the molecular mechanisms underlying TPPI deficiency in patients carrying missense mutations and to test the amenability of mutant proteins to chemical chaperones and permissive temperature treatment, we introduced individually 14 disease-associated missense mutations into human TPP1 cDNA and analyzed the cell biology of these TPPI variants expressed in Chinese hamster ovary cells. Most TPPI variants displayed obstructed transport to the lysosomes, prolonged half-life of the proenzyme, and residual or no enzymatic activity, indicating folding abnormalities. Protein misfolding was produced by mutations located in both the prosegment (p.Gly77Arg) and throughout the length of the mature enzyme. However, the routes of removal of misfolded proteins by the cells varied, ranging from their efficient degradation by the ubiquitin/proteasome system to abundant secretion. Two TPPI variants demonstrated enhanced processing in response to folding improvement treatment, and the activity of one of them, p.Arg447His, showed a fivefold increase under permissive temperature conditions, which suggests that folding improvement strategies may ameliorate the function of some misfolding TPPI mutant proteins.
... Clark, S., Schwalbe, J., Stasko, MR, Yarowsky, PJ, Costa, AC (2006). Fluoxetine rescues defic... more ... Clark, S., Schwalbe, J., Stasko, MR, Yarowsky, PJ, Costa, AC (2006). Fluoxetine rescues deficient neurogenesis in hippocampus of the Ts65Dn mouse model for Down syndrome. Experimental Neurology, 200, 256 261. Contestabile, A., Fila, T., Bartesaghi, R., Ciani, E. (2009). ...
Journal of Neuropathology and Experimental Neurology, 2010
Alphab-crystallin (CRYAB) is a small heat shock protein with a chaperoning activity that is prese... more Alphab-crystallin (CRYAB) is a small heat shock protein with a chaperoning activity that is present in the postnatal healthy human brain in oligodendrocytes and in a few astrocytes. The involvement of CRYAB in cell differentiation, proliferation, signaling, cytoskeletal assembly, and apoptosis in various model systems has suggested that it might also play a role in the developing human brain. We analyzed the distribution and the levels of this molecular chaperone in healthy and polygenetically compromised (Down syndrome [DS]) human telencephalon at midgestation. We demonstrate that CRYAB is expressed in a temporospatial pattern by numerous radial glial cells and some early oligodendrocyte progenitors, including dividing cells, as well as a few astroglial cells in both healthy and DS fetal brains. We also found abundant phosphorylation of CRYAB at Ser-59, which mediates its antiapoptotic and cytoskeletal functions. There was only marginal phosphorylation at Ser-45.In contrast to our earlier study in young DS subjects, upregulation of phosphorylated CRYAB occurred rarely in DS fetuses. The distribution, the timing of appearance, and the results of colocalization studies suggest that CRYAB assists in the biological processes associated with developmental remodeling/differentiation and proliferation of select subpopulations of progenitor cells in human fetal brain at midgestation.
Journal of neuropathology and experimental neurology, 2001
Tripeptidyl peptidase I (TPP I) is a lysosomal exopeptidase that cleaves tripeptides from the fre... more Tripeptidyl peptidase I (TPP I) is a lysosomal exopeptidase that cleaves tripeptides from the free N-termini of oligopeptides. Mutations in this enzyme are associated with the classic late-infantile form of neuronal ceroid lipofuscinosis (CLN2), an autosomal recessive disorder leading to severe brain damage. To gain more insight into CLN2 pathogenesis and the role of TPP I in human tissues in general, we analyzed the temporal and spatial distribution of TPP I in the brain and its localization in internal organs under normal and pathological conditions. We report that TPP I immunoreactivity appears in neurons late in gestation and increases gradually in the postnatal period, matching significantly the final differentiation and maturation of neural tissue. Endothelial cells, choroid plexus, microglial cells, and ependyma showed TPP I immunostaining distinctly earlier than neurons. Acquisition of the adult pattern of TPP I distribution in the brain at around the age of 2 years correlat...
Journal of Neuropathology and Experimental Neurology, 2006
Carbonic anhydrase II (CA II) is one of 14 isozymes of carbonic anhydrases, zinc metalloenzymes t... more Carbonic anhydrase II (CA II) is one of 14 isozymes of carbonic anhydrases, zinc metalloenzymes that catalyze the reversible hydration of carbon dioxide to bicarbonate. Mutations in CA II in humans lead to osteopetrosis with renal tubular acidosis and cerebral calcifications, a disorder often associated with mental retardation. Recently, new avenues in CA II research have opened as a result of discoveries that the enzyme increases bicarbonate and proton fluxes and may play an important role in brain tissue. In the human brain, CA II was localized to oligodendrocytes, myelin, and choroid plexus epithelium. Because this conclusion was based on a few fragmentary reports, we analyzed in more detail the expression of the enzyme in human telencephalon. By immunoblotting, we found a gradual increase in CA II levels from 17 weeks' gestation to childhood and adolescence. By immunohistochemistry, CA II was found to be present not only in oligodendrocytes and choroid plexus epithelium (declining with aging in both these locations), but also in a subset of neurons mostly with GABAergic phenotype, in a few astrocytes, and transiently during brain development in the endothelial cells of microvessels. The enzyme also occurred in oligodendrocyte processes in contact with myelinating axons, myelin sheaths, and axolemma, but was either absent or appeared in minute amounts in compact myelin. These findings suggest the possible involvement of CA II in a wide spectrum of biologic processes in the developing and adult human brain and may contribute to better understanding of the pathogenesis of cerebral calcifications and mental retardation caused by CA II deficiency.
There are 35 missense mutations among 68 different mutations in the TPP1 gene, which encodes trip... more There are 35 missense mutations among 68 different mutations in the TPP1 gene, which encodes tripeptidyl peptidase I (TPPI), a lysosomal aminopeptidase associated with classic late-infantile neuronal ceroid lipofuscinosis (CLN2 disease). To elucidate the molecular mechanisms underlying TPPI deficiency in patients carrying missense mutations and to test the amenability of mutant proteins to chemical chaperones and permissive temperature treatment, we introduced individually 14 disease-associated missense mutations into human TPP1 cDNA and analyzed the cell biology of these TPPI variants expressed in Chinese hamster ovary cells. Most TPPI variants displayed obstructed transport to the lysosomes, prolonged half-life of the proenzyme, and residual or no enzymatic activity, indicating folding abnormalities. Protein misfolding was produced by mutations located in both the prosegment (p.Gly77Arg) and throughout the length of the mature enzyme. However, the routes of removal of misfolded proteins by the cells varied, ranging from their efficient degradation by the ubiquitin/proteasome system to abundant secretion. Two TPPI variants demonstrated enhanced processing in response to folding improvement treatment, and the activity of one of them, p.Arg447His, showed a fivefold increase under permissive temperature conditions, which suggests that folding improvement strategies may ameliorate the function of some misfolding TPPI mutant proteins.
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