Characterization of the Subventricular-Thalamo-Cortical Circuit in the NP-C Mouse Brain, and New Insights Regarding Treatment

Min Hee Park; Byung Jo Choi; Min Seock Jeong; Ju Youn Lee; In Kyung Jung; Kang Ho Park; Hye Won Lee; Tomoyuki Yamaguchi; Hugo H. Marti; Beom Hee Lee; Edward H. Schuchman; Hee Kyung Jin; Jae sung Bae

doi:10.1016/j.ymthe.2019.05.008

Characterization of the Subventricular-Thalamo-Cortical Circuit in the NP-C Mouse Brain, and New Insights Regarding Treatment

Min Hee Park, Byung Jo Choi, Min Seock Jeong, Ju Youn Lee, In Kyung Jung, Kang Ho Park, Hye Won Lee, Tomoyuki Yamaguchi, Hugo H. Marti, Beom Hee Lee, Edward H. Schuchman, Hee Kyung Jin, Jae sung Bae

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Abstract

Gliosis in Niemann-Pick type C (NP-C) disease is characterized by marked changes in microglia and astrocytes. However, the gliosis onset and progression in NP-C has not been systematically studied, nor has the mechanism underlying this finding. Here, we found early gliosis in the subventricular zone (SVZ) of NP-C mice. Neural progenitor damage by Npc1 mutation suppressed vascular endothelial growth factor (VEGF) expression and further induced microglia activation followed by astrogliosis. Interestingly, excessive astrogliosis in the SVZ induced neural progenitor retention and/or migration into thalamus via astrocyte-derived VEGF, resulting in acceleration of thalamic and cortical gliosis through thalamo-cortical pathways. Transplantation of VEGF-overexpressing neural stem cells into the SVZ improved whole-brain pathology of NP-C mice. Overall, our data provide a new pathological perspective on NP-C neural pathology, revealing abnormalities in the subventricular-thalamo-cortical circuit of NP-C mouse brain and highlighting the importance of the SVZ microenvironment as a therapeutic target for NP-C disease. Park et al. show early gliosis in the subventricular zone (SVZ) of Niemann-Pick type C mice. SVZ gliosis leads to abnormal migration of neural progenitors to the thalamus, and it accelerates thalamic gliosis and further cortical gliosis through thalamo-cortical pathways.

Original language	English
Pages (from-to)	1507-1526
Number of pages	20
Journal	Molecular Therapy
Volume	27
Issue number	8
DOIs	https://doi.org/10.1016/j.ymthe.2019.05.008
State	Published - 7 Aug 2019

Keywords

Niemann-Pick type C disease
gliosis
neural progenitor retention and/or migration
subventricular zone
thalamo-cortical pathway
vascular endothelial growth factor

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10.1016/j.ymthe.2019.05.008

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Park, M. H., Choi, B. J., Jeong, M. S., Lee, J. Y., Jung, I. K., Park, K. H., Lee, H. W., Yamaguchi, T., Marti, H. H., Lee, B. H., Schuchman, E. H., Jin, H. K., & Bae, J. S. (2019). Characterization of the Subventricular-Thalamo-Cortical Circuit in the NP-C Mouse Brain, and New Insights Regarding Treatment. Molecular Therapy, 27(8), 1507-1526. https://doi.org/10.1016/j.ymthe.2019.05.008

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title = "Characterization of the Subventricular-Thalamo-Cortical Circuit in the NP-C Mouse Brain, and New Insights Regarding Treatment",

abstract = "Gliosis in Niemann-Pick type C (NP-C) disease is characterized by marked changes in microglia and astrocytes. However, the gliosis onset and progression in NP-C has not been systematically studied, nor has the mechanism underlying this finding. Here, we found early gliosis in the subventricular zone (SVZ) of NP-C mice. Neural progenitor damage by Npc1 mutation suppressed vascular endothelial growth factor (VEGF) expression and further induced microglia activation followed by astrogliosis. Interestingly, excessive astrogliosis in the SVZ induced neural progenitor retention and/or migration into thalamus via astrocyte-derived VEGF, resulting in acceleration of thalamic and cortical gliosis through thalamo-cortical pathways. Transplantation of VEGF-overexpressing neural stem cells into the SVZ improved whole-brain pathology of NP-C mice. Overall, our data provide a new pathological perspective on NP-C neural pathology, revealing abnormalities in the subventricular-thalamo-cortical circuit of NP-C mouse brain and highlighting the importance of the SVZ microenvironment as a therapeutic target for NP-C disease. Park et al. show early gliosis in the subventricular zone (SVZ) of Niemann-Pick type C mice. SVZ gliosis leads to abnormal migration of neural progenitors to the thalamus, and it accelerates thalamic gliosis and further cortical gliosis through thalamo-cortical pathways.",

keywords = "Niemann-Pick type C disease, gliosis, neural progenitor retention and/or migration, subventricular zone, thalamo-cortical pathway, vascular endothelial growth factor",

author = "Park, {Min Hee} and Choi, {Byung Jo} and Jeong, {Min Seock} and Lee, {Ju Youn} and Jung, {In Kyung} and Park, {Kang Ho} and Lee, {Hye Won} and Tomoyuki Yamaguchi and Marti, {Hugo H.} and Lee, {Beom Hee} and Schuchman, {Edward H.} and Jin, {Hee Kyung} and Bae, {Jae sung}",

note = "Publisher Copyright: {\textcopyright} 2019 The American Society of Gene and Cell Therapy",

year = "2019",

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doi = "10.1016/j.ymthe.2019.05.008",

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AU - Park, Min Hee

AU - Choi, Byung Jo

AU - Jeong, Min Seock

AU - Lee, Ju Youn

AU - Jung, In Kyung

AU - Park, Kang Ho

AU - Lee, Hye Won

AU - Yamaguchi, Tomoyuki

AU - Marti, Hugo H.

AU - Lee, Beom Hee

AU - Schuchman, Edward H.

AU - Jin, Hee Kyung

AU - Bae, Jae sung

PY - 2019/8/7

Y1 - 2019/8/7

N2 - Gliosis in Niemann-Pick type C (NP-C) disease is characterized by marked changes in microglia and astrocytes. However, the gliosis onset and progression in NP-C has not been systematically studied, nor has the mechanism underlying this finding. Here, we found early gliosis in the subventricular zone (SVZ) of NP-C mice. Neural progenitor damage by Npc1 mutation suppressed vascular endothelial growth factor (VEGF) expression and further induced microglia activation followed by astrogliosis. Interestingly, excessive astrogliosis in the SVZ induced neural progenitor retention and/or migration into thalamus via astrocyte-derived VEGF, resulting in acceleration of thalamic and cortical gliosis through thalamo-cortical pathways. Transplantation of VEGF-overexpressing neural stem cells into the SVZ improved whole-brain pathology of NP-C mice. Overall, our data provide a new pathological perspective on NP-C neural pathology, revealing abnormalities in the subventricular-thalamo-cortical circuit of NP-C mouse brain and highlighting the importance of the SVZ microenvironment as a therapeutic target for NP-C disease. Park et al. show early gliosis in the subventricular zone (SVZ) of Niemann-Pick type C mice. SVZ gliosis leads to abnormal migration of neural progenitors to the thalamus, and it accelerates thalamic gliosis and further cortical gliosis through thalamo-cortical pathways.

AB - Gliosis in Niemann-Pick type C (NP-C) disease is characterized by marked changes in microglia and astrocytes. However, the gliosis onset and progression in NP-C has not been systematically studied, nor has the mechanism underlying this finding. Here, we found early gliosis in the subventricular zone (SVZ) of NP-C mice. Neural progenitor damage by Npc1 mutation suppressed vascular endothelial growth factor (VEGF) expression and further induced microglia activation followed by astrogliosis. Interestingly, excessive astrogliosis in the SVZ induced neural progenitor retention and/or migration into thalamus via astrocyte-derived VEGF, resulting in acceleration of thalamic and cortical gliosis through thalamo-cortical pathways. Transplantation of VEGF-overexpressing neural stem cells into the SVZ improved whole-brain pathology of NP-C mice. Overall, our data provide a new pathological perspective on NP-C neural pathology, revealing abnormalities in the subventricular-thalamo-cortical circuit of NP-C mouse brain and highlighting the importance of the SVZ microenvironment as a therapeutic target for NP-C disease. Park et al. show early gliosis in the subventricular zone (SVZ) of Niemann-Pick type C mice. SVZ gliosis leads to abnormal migration of neural progenitors to the thalamus, and it accelerates thalamic gliosis and further cortical gliosis through thalamo-cortical pathways.

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SN - 1525-0016

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EP - 1526

JO - Molecular Therapy

JF - Molecular Therapy

IS - 8

ER -

Characterization of the Subventricular-Thalamo-Cortical Circuit in the NP-C Mouse Brain, and New Insights Regarding Treatment

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