Distinct forebrain regions define a dichotomous astrocytic profile in multiple system atrophy

Schneider Y, Gauer C, Andert M, Hoffmann A, Riemenschneider MJ, Krebs W, Chalmers N, Lötzsch C, Naumann U, Xiang W, Rothhammer V, Beckervordersandforth R, Schlachetzki JC, Winkler J (2024)

Publication Type: Journal article

Publication year: 2024

Journal

Acta Neuropathologica Communications BioMed Central

Book Volume: 12

Article Number: 1

Journal Issue: 1

DOI: 10.1186/s40478-023-01699-3

Abstract

The growing recognition of a dichotomous role of astrocytes in neurodegenerative processes has heightened the need for unraveling distinct astrocytic subtypes in neurological disorders. In multiple system atrophy (MSA), a rare, rapidly progressing atypical Parkinsonian disease characterized by increased astrocyte reactivity. However the specific contribution of astrocyte subtypes to neuropathology remains elusive. Hence, we first set out to profile glial fibrillary acidic protein levels in astrocytes across the human post mortem motor cortex, putamen, and substantia nigra of MSA patients and observed an overall profound astrocytic response. Matching the post mortem human findings, a similar astrocytic phenotype was present in a transgenic MSA mouse model. Notably, MSA mice exhibited a decreased expression of the glutamate transporter 1 and glutamate aspartate transporter in the basal ganglia, but not the motor cortex. We developed an optimized astrocyte isolation protocol based on magnetic-activated cell sorting via ATPase Na+/K+ transporting subunit beta 2 and profiled the transcriptomic landscape of striatal and cortical astrocytes in transgenic MSA mice. The gene expression profile of astrocytes in the motor cortex displayed an anti-inflammatory signature with increased oligodendroglial and pro-myelinogenic expression pattern. In contrast, striatal astrocytes were defined by elevated pro-inflammatory transcripts accompanied by dysregulated genes involved in homeostatic functions for lipid and calcium metabolism. These findings provide new insights into a region-dependent, dichotomous astrocytic response—potentially beneficial in the cortex and harmful in the striatum—in MSA suggesting a differential role of astrocytes in MSA-related neurodegenerative processes.

Authors with CRIS profile

Yanni Schneider Department of Molecular Neurology Carina Gauer Lehrstuhl für Biochemie und Molekulare Medizin Marie Andert Professur für Molekulare Neurologie Alana Hoffmann Department of Molecular Neurology Nicholas Chalmers Professur für Molekulare Medizin mit dem Schwerpunkt Molekulare Bildgebung Ulrike Naumann Department of Neurology Wei Xiang Department of Molecular Neurology Ruth Beckervordersandforth-Bonk Lehrstuhl für Biochemie und Pathobiochemie Jürgen Winkler Professur für Molekulare Neurologie

Involved external institutions

University of California, San Diego US United States (USA) (US) Universitätsklinikum Regensburg DE Germany (DE)

How to cite

APA:

Schneider, Y., Gauer, C., Andert, M., Hoffmann, A., Riemenschneider, M.J., Krebs, W.,... Winkler, J. (2024). Distinct forebrain regions define a dichotomous astrocytic profile in multiple system atrophy. Acta Neuropathologica Communications, 12(1). https://doi.org/10.1186/s40478-023-01699-3

MLA:

Schneider, Yanni, et al. "Distinct forebrain regions define a dichotomous astrocytic profile in multiple system atrophy." Acta Neuropathologica Communications 12.1 (2024).

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