Perturbations of the Proteome and of Secreted Metabolites in Primary Astrocytes from the hSOD1(G93A) ALS Mouse Model

International Journal of Molecular Sciences

Maria Lina Massimino¹  Alessandro Bertoli¹  Raphael Severino Bonadio²  Stefano Cagnin²  Caterina Peggion³  Roberto Stella⁴ 

[1] CNR—Neuroscience Institute, 35131 Padova, Italy;Department of Biology and CRIBI Biotechnology Center, University of Padova, 35131 Padova, Italy;Department of Biomedical Sciences, University of Padova, 35131 Padova, Italy;Department of Chemistry, Istituto Zooprofilattico Sperimentale delle Venezie, 35020 Legnaro, Italy;

关键词: spinal cord astrocytes;    ALS;    glutathione metabolism;    proteolysis;    metabolomics;    proteomics;   

DOI  :  10.3390/ijms22137028

来源: DOAJ

【 摘 要 】

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease whose pathophysiology is largely unknown. Despite the fact that motor neuron (MN) death is recognized as the key event in ALS, astrocytes dysfunctionalities and neuroinflammation were demonstrated to accompany and probably even drive MN loss. Nevertheless, the mechanisms priming astrocyte failure and hyperactivation are still obscure. In this work, altered pathways and molecules in ALS astrocytes were unveiled by investigating the proteomic profile and the secreted metabolome of primary spinal cord astrocytes derived from transgenic ALS mouse model overexpressing the human (h)SOD1(G93A) protein in comparison with the transgenic counterpart expressing hSOD1(WT) protein. Here we show that ALS primary astrocytes are depleted of proteins—and of secreted metabolites—involved in glutathione metabolism and signaling. The observed increased activation of Nf-kB, Ebf1, and Plag1 transcription factors may account for the augmented expression of proteins involved in the proteolytic routes mediated by proteasome or endosome–lysosome systems. Moreover, hSOD1(G93A) primary astrocytes also display altered lipid metabolism. Our results provide novel insights into the altered molecular pathways that may underlie astrocyte dysfunctionalities and altered astrocyte–MN crosstalk in ALS, representing potential therapeutic targets to abrogate or slow down MN demise in disease pathogenesis.

【 授权许可】

Unknown