Susan Slaugenhaupt - Academia.edu (original) (raw)
Papers by Susan Slaugenhaupt
Science Translational Medicine, 2019
Genetic variations in primary cilia genes cause defects during valve morphogenesis that can progr... more Genetic variations in primary cilia genes cause defects during valve morphogenesis that can progress to mitral valve prolapse in the adult.
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Nature, 2015
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Disease Models & Mechanisms
Mucolipidosis type IV (MLIV) is a lysosomal disease caused by mutations in the MCOLN1 gene that e... more Mucolipidosis type IV (MLIV) is a lysosomal disease caused by mutations in the MCOLN1 gene that encodes the endolysosomal transient receptor potential channel mucolipin-1, or TRPML1. MLIV results in developmental delay, motor and cognitive impairments, and vision loss. Brain abnormalities include thinning and malformation of the corpus callosum, white matter abnormalities, accumulation of undegraded intracellular “storage” material and cerebellar atrophy in older patients. Identification of the early events in the MLIV course is key to understanding the disease and deploying therapies. Mcoln1−/- mouse model reproduces all major aspects of the human disease. We have previously reported hypomyelination in the MLIV mouse brain. Here we investigated the onset of hypomyelination and compared oligodendrocyte maturation between the cortex/forebrain and cerebellum. We found significant delays in expression of mature oligodendrocyte markers Mag, Mbp, and Mobp in the Mcoln1−/-cortex manifesti...
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Human Molecular Genetics
Mucolipidosis IV (MLIV) is an orphan disease leading to debilitating psychomotor deficits and vis... more Mucolipidosis IV (MLIV) is an orphan disease leading to debilitating psychomotor deficits and vision loss. It is caused by loss-of-function mutations in the MCOLN1 gene that encodes the lysosomal transient receptor potential channel mucolipin1, or TRPML1. With no existing therapy, the unmet need in this disease is very high. Here, we showed that AAV-mediated CNS-targeted gene transfer of the human MCOLN1 gene rescued motor function and alleviated brain pathology in the MLIV mouse model. Using the AAV-PHP.b vector in symptomatic mice, we showed long-term reversal of declined motor function and significant delay of paralysis. Next, using self-complementary AAV9 clinical candidate vector, we showed that its intracerebroventricular administration in post-natal day 1 mice significantly improved motor function, myelination and reduced lysosomal storage load in the MLIV mouse brain. Based on our data and general advancements in the gene therapy field, we propose scAAV9-mediated CSF-targete...
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Mucolipidosis IV (MLIV, OMIM 252650) is an orphan disease leading to debilitating psychomotor def... more Mucolipidosis IV (MLIV, OMIM 252650) is an orphan disease leading to debilitating psychomotor deficits and vision loss. It is caused by loss-of-function mutations in the MCOLN1 gene that encodes thethe lysosomal transient receptor potential channel mucolipin 1 (TRPML1). With no existing therapy, the unmet need in this disease is very high. Here we show that AAV-mediated gene transfer of the human MCOLN1 gene rescues motor function and alleviates brain pathology in the Mcoln1−/− MLIV mouse model. Using the AAV-PHP.b vector for initial proof-of-principle experiments in symptomatic mice, we showed long-term reversal of declined motor function and significant delay of paralysis. Next, we designed self-complimentary AAV9 vector for clinical use and showed that its intracerebroventricular administration in post-natal day 1 mice significantly improved motor function and myelination and reduced lysosomal storage load in the MLIV mouse brain. We also showed that CNS targeted gene transfer is...
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Structural Heart
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Human molecular genetics, Jan 16, 2018
Mucolipidosis IV (MLIV) is an orphan neurodevelopmental disease that causes severe neurologic dys... more Mucolipidosis IV (MLIV) is an orphan neurodevelopmental disease that causes severe neurologic dysfunction and loss of vision. Currently there is no therapy for MLIV. It is caused by loss of function of the lysosomal channel mucolipin-1, also known as TRPML1. Knockout of the Mcoln1 gene in a mouse model mirrors clinical and neuropathological signs in humans. Using this model, we previously observed robust activation of microglia and astrocytes in early symptomatic stages of disease. Here we investigate the consequence of mucolipin-1 loss on astrocyte inflammatory activation in vivo and in vitro and apply a pharmacological approach to restore Mcoln1-/- astrocyte homeostasis using a clinically approved immunomodulator, fingolimod. We found that Mcoln1-/- mice over-express numerous pro-inflammatory cytokines, some of which were also over-expressed in astrocyte cultures. Changes in the cytokine profile in Mcoln1-/- astrocytes are concomitant with changes in phospho-protein signaling, inc...
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FASEB journal : official publication of the Federation of American Societies for Experimental Biology, Feb 13, 2017
The transient receptor potential cation channel mucolipin 1 (TRPML1) channel is a conduit for lys... more The transient receptor potential cation channel mucolipin 1 (TRPML1) channel is a conduit for lysosomal calcium efflux, and channel activity may be affected by lysosomal contents. The lysosomes of retinal pigmented epithelial (RPE) cells are particularly susceptible to build-up of lysosomal waste products because they must degrade the outer segments phagocytosed daily from adjacent photoreceptors; incomplete degradation leads to accumulation of lipid waste in lysosomes. This study asks whether stimulation of TRPML1 can release lysosomal calcium in RPE cells and whether such release is affected by lysosomal accumulations. The TRPML agonist ML-SA1 raised cytoplasmic calcium levels in mouse RPE cells, hesRPE cells, and ARPE-19 cells; this increase was rapid, robust, reversible, and reproducible. The increase was not altered by extracellular calcium removal or by thapsigargin but was eliminated by lysosomal rupture with glycyl-l-phenylalanine-β-naphthylamide. Treatment with desipramine ...
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European Heart Journal
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Progress in Neurobiology, 2016
Familial dysautonomia (FD) is a rare neurological disorder caused by a splice mutation in the IKB... more Familial dysautonomia (FD) is a rare neurological disorder caused by a splice mutation in the IKBKAP gene. The mutation arose in the 1500s within the small Jewish founder population in Eastern Europe and became prevalent during the period of rapid population expansion within the Pale of Settlement. The carrier rate is 1:32 in Jews descending from this region. The mutation results in a tissue-specific deficiency in IKAP, a protein involved in the development and survival of neurons. Patients homozygous for the mutations are born with multiple lesions affecting mostly sensory (afferent) fibers, which leads to widespread organ dysfunction and increased mortality. Neurodegenerative features of the disease include progressive optic atrophy and worsening gait ataxia. Here we review the progress made in the last decade to better understand the genotype and phenotype. We also discuss the challenges of conducting controlled clinical trials in this rare medically fragile population. Meanwhile, the search for better treatments as well as a neuroprotective agent is ongoing.
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Genomics, 1995
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Human Molecular Genetics, Jul 1, 1993
Electrical excitability of neurons and muscle cells is mediated largely through the actions of th... more Electrical excitability of neurons and muscle cells is mediated largely through the actions of the voltage-gated sodium channel. Initiation and propagation of the action potential is a direct result of the precisely controlled inward flux of sodium through these channels. Much attention has been paid to the sodium channel alpha-subunit, the major, pore-forming component. However, alpha-subunits are associated with one or more smaller beta-subunits, which have been implicated in the critical fine tuning of the gating properties of the channel. To investigate the properties of the beta-subunit, we have isolated a cDNA encoding the human brain beta 1-subunit and assigned the corresponding gene to chromosome 19. We have also examined the effects of expressing the brain beta 1-subunit on the kinetics of a coexpressed muscle sodium channel alpha-subunit. Our results underscore the functional importance of the beta 1-subunit and imply a conserved mechanism for the interaction of the beta 1-subunit with different alpha-subunits.
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Human Molecular Genetics, 1992
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Journal of Personalized Medicine, 2016
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Circulation, Nov 25, 2014
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Genomics, Apr 15, 2001
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Science Translational Medicine, 2019
Genetic variations in primary cilia genes cause defects during valve morphogenesis that can progr... more Genetic variations in primary cilia genes cause defects during valve morphogenesis that can progress to mitral valve prolapse in the adult.
Bookmarks Related papers MentionsView impact
Nature, 2015
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Disease Models & Mechanisms
Mucolipidosis type IV (MLIV) is a lysosomal disease caused by mutations in the MCOLN1 gene that e... more Mucolipidosis type IV (MLIV) is a lysosomal disease caused by mutations in the MCOLN1 gene that encodes the endolysosomal transient receptor potential channel mucolipin-1, or TRPML1. MLIV results in developmental delay, motor and cognitive impairments, and vision loss. Brain abnormalities include thinning and malformation of the corpus callosum, white matter abnormalities, accumulation of undegraded intracellular “storage” material and cerebellar atrophy in older patients. Identification of the early events in the MLIV course is key to understanding the disease and deploying therapies. Mcoln1−/- mouse model reproduces all major aspects of the human disease. We have previously reported hypomyelination in the MLIV mouse brain. Here we investigated the onset of hypomyelination and compared oligodendrocyte maturation between the cortex/forebrain and cerebellum. We found significant delays in expression of mature oligodendrocyte markers Mag, Mbp, and Mobp in the Mcoln1−/-cortex manifesti...
Bookmarks Related papers MentionsView impact
Human Molecular Genetics
Mucolipidosis IV (MLIV) is an orphan disease leading to debilitating psychomotor deficits and vis... more Mucolipidosis IV (MLIV) is an orphan disease leading to debilitating psychomotor deficits and vision loss. It is caused by loss-of-function mutations in the MCOLN1 gene that encodes the lysosomal transient receptor potential channel mucolipin1, or TRPML1. With no existing therapy, the unmet need in this disease is very high. Here, we showed that AAV-mediated CNS-targeted gene transfer of the human MCOLN1 gene rescued motor function and alleviated brain pathology in the MLIV mouse model. Using the AAV-PHP.b vector in symptomatic mice, we showed long-term reversal of declined motor function and significant delay of paralysis. Next, using self-complementary AAV9 clinical candidate vector, we showed that its intracerebroventricular administration in post-natal day 1 mice significantly improved motor function, myelination and reduced lysosomal storage load in the MLIV mouse brain. Based on our data and general advancements in the gene therapy field, we propose scAAV9-mediated CSF-targete...
Bookmarks Related papers MentionsView impact
Mucolipidosis IV (MLIV, OMIM 252650) is an orphan disease leading to debilitating psychomotor def... more Mucolipidosis IV (MLIV, OMIM 252650) is an orphan disease leading to debilitating psychomotor deficits and vision loss. It is caused by loss-of-function mutations in the MCOLN1 gene that encodes thethe lysosomal transient receptor potential channel mucolipin 1 (TRPML1). With no existing therapy, the unmet need in this disease is very high. Here we show that AAV-mediated gene transfer of the human MCOLN1 gene rescues motor function and alleviates brain pathology in the Mcoln1−/− MLIV mouse model. Using the AAV-PHP.b vector for initial proof-of-principle experiments in symptomatic mice, we showed long-term reversal of declined motor function and significant delay of paralysis. Next, we designed self-complimentary AAV9 vector for clinical use and showed that its intracerebroventricular administration in post-natal day 1 mice significantly improved motor function and myelination and reduced lysosomal storage load in the MLIV mouse brain. We also showed that CNS targeted gene transfer is...
Bookmarks Related papers MentionsView impact
Structural Heart
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Human molecular genetics, Jan 16, 2018
Mucolipidosis IV (MLIV) is an orphan neurodevelopmental disease that causes severe neurologic dys... more Mucolipidosis IV (MLIV) is an orphan neurodevelopmental disease that causes severe neurologic dysfunction and loss of vision. Currently there is no therapy for MLIV. It is caused by loss of function of the lysosomal channel mucolipin-1, also known as TRPML1. Knockout of the Mcoln1 gene in a mouse model mirrors clinical and neuropathological signs in humans. Using this model, we previously observed robust activation of microglia and astrocytes in early symptomatic stages of disease. Here we investigate the consequence of mucolipin-1 loss on astrocyte inflammatory activation in vivo and in vitro and apply a pharmacological approach to restore Mcoln1-/- astrocyte homeostasis using a clinically approved immunomodulator, fingolimod. We found that Mcoln1-/- mice over-express numerous pro-inflammatory cytokines, some of which were also over-expressed in astrocyte cultures. Changes in the cytokine profile in Mcoln1-/- astrocytes are concomitant with changes in phospho-protein signaling, inc...
Bookmarks Related papers MentionsView impact
FASEB journal : official publication of the Federation of American Societies for Experimental Biology, Feb 13, 2017
The transient receptor potential cation channel mucolipin 1 (TRPML1) channel is a conduit for lys... more The transient receptor potential cation channel mucolipin 1 (TRPML1) channel is a conduit for lysosomal calcium efflux, and channel activity may be affected by lysosomal contents. The lysosomes of retinal pigmented epithelial (RPE) cells are particularly susceptible to build-up of lysosomal waste products because they must degrade the outer segments phagocytosed daily from adjacent photoreceptors; incomplete degradation leads to accumulation of lipid waste in lysosomes. This study asks whether stimulation of TRPML1 can release lysosomal calcium in RPE cells and whether such release is affected by lysosomal accumulations. The TRPML agonist ML-SA1 raised cytoplasmic calcium levels in mouse RPE cells, hesRPE cells, and ARPE-19 cells; this increase was rapid, robust, reversible, and reproducible. The increase was not altered by extracellular calcium removal or by thapsigargin but was eliminated by lysosomal rupture with glycyl-l-phenylalanine-β-naphthylamide. Treatment with desipramine ...
Bookmarks Related papers MentionsView impact
European Heart Journal
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Progress in Neurobiology, 2016
Familial dysautonomia (FD) is a rare neurological disorder caused by a splice mutation in the IKB... more Familial dysautonomia (FD) is a rare neurological disorder caused by a splice mutation in the IKBKAP gene. The mutation arose in the 1500s within the small Jewish founder population in Eastern Europe and became prevalent during the period of rapid population expansion within the Pale of Settlement. The carrier rate is 1:32 in Jews descending from this region. The mutation results in a tissue-specific deficiency in IKAP, a protein involved in the development and survival of neurons. Patients homozygous for the mutations are born with multiple lesions affecting mostly sensory (afferent) fibers, which leads to widespread organ dysfunction and increased mortality. Neurodegenerative features of the disease include progressive optic atrophy and worsening gait ataxia. Here we review the progress made in the last decade to better understand the genotype and phenotype. We also discuss the challenges of conducting controlled clinical trials in this rare medically fragile population. Meanwhile, the search for better treatments as well as a neuroprotective agent is ongoing.
Bookmarks Related papers MentionsView impact
Genomics, 1995
Bookmarks Related papers MentionsView impact
Human Molecular Genetics, Jul 1, 1993
Electrical excitability of neurons and muscle cells is mediated largely through the actions of th... more Electrical excitability of neurons and muscle cells is mediated largely through the actions of the voltage-gated sodium channel. Initiation and propagation of the action potential is a direct result of the precisely controlled inward flux of sodium through these channels. Much attention has been paid to the sodium channel alpha-subunit, the major, pore-forming component. However, alpha-subunits are associated with one or more smaller beta-subunits, which have been implicated in the critical fine tuning of the gating properties of the channel. To investigate the properties of the beta-subunit, we have isolated a cDNA encoding the human brain beta 1-subunit and assigned the corresponding gene to chromosome 19. We have also examined the effects of expressing the brain beta 1-subunit on the kinetics of a coexpressed muscle sodium channel alpha-subunit. Our results underscore the functional importance of the beta 1-subunit and imply a conserved mechanism for the interaction of the beta 1-subunit with different alpha-subunits.
Bookmarks Related papers MentionsView impact
Bookmarks Related papers MentionsView impact
Bookmarks Related papers MentionsView impact
Human Molecular Genetics, 1992
Bookmarks Related papers MentionsView impact
Journal of Personalized Medicine, 2016
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Circulation, Nov 25, 2014
Bookmarks Related papers MentionsView impact
Genomics, Apr 15, 2001
Bookmarks Related papers MentionsView impact
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