Cortical Pathology in Vanishing White Matter (2024)

Man, J. H. K., van Gelder, C. A. G. H., Breur, M., Okkes, D., Molenaar, D., van der Sluis, S., Abbink, T., Altelaar, M., van der Knaap, M. S., & Bugiani, M. (2022). Cortical Pathology in Vanishing White Matter. Cells, 11(22), 1-19. Article 3581. https://doi.org/10.3390/cells11223581

Man, Jodie H.K. ; van Gelder, Charlotte A.G.H. ; Breur, Marjolein et al. / Cortical Pathology in Vanishing White Matter. In: Cells. 2022 ; Vol. 11, No. 22. pp. 1-19.

@article{1ca3c409d1bd4421ac0bbb409f378db5,

title = "Cortical Pathology in Vanishing White Matter",

abstract = "Vanishing white matter (VWM) is classified as a leukodystrophy with astrocytes as primary drivers in its pathogenesis. Magnetic resonance imaging has documented the progressive thinning of cortices in long-surviving patients. Routine histopathological analyses, however, have not yet pointed to cortical involvement in VWM. Here, we provide a comprehensive analysis of the VWM cortex. We employed high-resolution-mass-spectrometry-based proteomics and immunohistochemistry to gain insight into possible molecular disease mechanisms in the cortices of VWM patients. The proteome analysis revealed 268 differentially expressed proteins in the VWM cortices compared to the controls. A majority of these proteins formed a major protein interaction network. A subsequent gene ontology analysis identified enrichment for terms such as cellular metabolism, particularly mitochondrial activity. Importantly, some of the proteins with the most prominent changes in expression were found in astrocytes, indicating cortical astrocytic involvement. Indeed, we confirmed that VWM cortical astrocytes exhibit morphological changes and are less complex in structure than control cells. Our findings also suggest that these astrocytes are immature and not reactive. Taken together, we provide insights into cortical involvement in VWM, which has to be taken into account when developing therapeutic strategies.",

keywords = "Astrocytes, Astrocytopathy, Cortex, Leukodystrophy, Proteomics, Vanishing white matter",

author = "Man, {Jodie H.K.} and {van Gelder}, {Charlotte A.G.H.} and Marjolein Breur and Daniel Okkes and Douwe Molenaar and {van der Sluis}, Sophie and Truus Abbink and Maarten Altelaar and {van der Knaap}, {Marjo S.} and Marianna Bugiani",

note = "Funding Information: The research was funded by the ZonMw TOP grant 91217006. S.v.d.S is supported by NWO Gravitation program BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (NWO: 024.004.012). M.B. (Marianna Bugiani) is supported by the ZonMW VENI Grant 016.196.107. Publisher Copyright: {\textcopyright} 2022 by the authors.",

year = "2022",

month = nov,

day = "12",

doi = "10.3390/cells11223581",

language = "English",

volume = "11",

pages = "1--19",

journal = "Cells",

issn = "2073-4409",

publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",

number = "22",

}

Man, JHK, van Gelder, CAGH, Breur, M, Okkes, D, Molenaar, D, van der Sluis, S, Abbink, T, Altelaar, M, van der Knaap, MS & Bugiani, M 2022, 'Cortical Pathology in Vanishing White Matter', Cells, vol. 11, no. 22, 3581, pp. 1-19. https://doi.org/10.3390/cells11223581

Cortical Pathology in Vanishing White Matter. / Man, Jodie H.K.; van Gelder, Charlotte A.G.H.; Breur, Marjolein et al.
In: Cells, Vol. 11, No. 22, 3581, 12.11.2022, p. 1-19.

Research output: Contribution to journal › Article › Academic › peer-review

TY - JOUR

T1 - Cortical Pathology in Vanishing White Matter

AU - Man, Jodie H.K.

AU - van Gelder, Charlotte A.G.H.

AU - Breur, Marjolein

AU - Okkes, Daniel

AU - Molenaar, Douwe

AU - van der Sluis, Sophie

AU - Abbink, Truus

AU - Altelaar, Maarten

AU - van der Knaap, Marjo S.

AU - Bugiani, Marianna

N1 - Funding Information:The research was funded by the ZonMw TOP grant 91217006. S.v.d.S is supported by NWO Gravitation program BRAINSCAPES: A Roadmap from Neurogenetics to Neurobiology (NWO: 024.004.012). M.B. (Marianna Bugiani) is supported by the ZonMW VENI Grant 016.196.107.Publisher Copyright:© 2022 by the authors.

PY - 2022/11/12

Y1 - 2022/11/12

N2 - Vanishing white matter (VWM) is classified as a leukodystrophy with astrocytes as primary drivers in its pathogenesis. Magnetic resonance imaging has documented the progressive thinning of cortices in long-surviving patients. Routine histopathological analyses, however, have not yet pointed to cortical involvement in VWM. Here, we provide a comprehensive analysis of the VWM cortex. We employed high-resolution-mass-spectrometry-based proteomics and immunohistochemistry to gain insight into possible molecular disease mechanisms in the cortices of VWM patients. The proteome analysis revealed 268 differentially expressed proteins in the VWM cortices compared to the controls. A majority of these proteins formed a major protein interaction network. A subsequent gene ontology analysis identified enrichment for terms such as cellular metabolism, particularly mitochondrial activity. Importantly, some of the proteins with the most prominent changes in expression were found in astrocytes, indicating cortical astrocytic involvement. Indeed, we confirmed that VWM cortical astrocytes exhibit morphological changes and are less complex in structure than control cells. Our findings also suggest that these astrocytes are immature and not reactive. Taken together, we provide insights into cortical involvement in VWM, which has to be taken into account when developing therapeutic strategies.

AB - Vanishing white matter (VWM) is classified as a leukodystrophy with astrocytes as primary drivers in its pathogenesis. Magnetic resonance imaging has documented the progressive thinning of cortices in long-surviving patients. Routine histopathological analyses, however, have not yet pointed to cortical involvement in VWM. Here, we provide a comprehensive analysis of the VWM cortex. We employed high-resolution-mass-spectrometry-based proteomics and immunohistochemistry to gain insight into possible molecular disease mechanisms in the cortices of VWM patients. The proteome analysis revealed 268 differentially expressed proteins in the VWM cortices compared to the controls. A majority of these proteins formed a major protein interaction network. A subsequent gene ontology analysis identified enrichment for terms such as cellular metabolism, particularly mitochondrial activity. Importantly, some of the proteins with the most prominent changes in expression were found in astrocytes, indicating cortical astrocytic involvement. Indeed, we confirmed that VWM cortical astrocytes exhibit morphological changes and are less complex in structure than control cells. Our findings also suggest that these astrocytes are immature and not reactive. Taken together, we provide insights into cortical involvement in VWM, which has to be taken into account when developing therapeutic strategies.

KW - Astrocytes

KW - Astrocytopathy

KW - Cortex

KW - Leukodystrophy

KW - Proteomics

KW - Vanishing white matter

UR - http://www.scopus.com/inward/record.url?scp=85142437868&partnerID=8YFLogxK

U2 - 10.3390/cells11223581

DO - 10.3390/cells11223581

M3 - Article

C2 - 36429009

AN - SCOPUS:85142437868

SN - 2073-4409

VL - 11

SP - 1

EP - 19

JO - Cells

JF - Cells

IS - 22

M1 - 3581

ER -

Man JHK, van Gelder CAGH, Breur M, Okkes D, Molenaar D, van der Sluis S et al. Cortical Pathology in Vanishing White Matter. Cells. 2022 Nov 12;11(22):1-19. 3581. doi: 10.3390/cells11223581