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Series GSE99559 Query DataSets for GSE99559
Status Public on Jan 31, 2019
Title SQSTM1/p62-directed metabolic reprogramming is essential for normal neurodifferentiation
Organism Homo sapiens
Experiment type Expression profiling by high throughput sequencing
Summary Neurodegenerative disorders are an increasingly common and irreversible burden on society, often affecting the ageing population, but their aetiology and disease mechanisms are poorly understood. Studying monogenic neurodegenerative diseases, with known genetic cause, provides an opportunity to understand cellular mechanisms also affected in more complex disorders. We recently reported that loss-of-function mutations in the autophagy adaptor protein, SQSTM1/p62, lead to a slowly progressive neurodegenerative disease presenting in childhood. To further elucidate the neuronal involvement, we studied the cellular consequences of loss of p62 in a neuroepithelial stem (NES) cell model and differentiated neurones, derived from reprogrammed p62 patient cells, or by CRISPR/Cas9-directed gene editing in NES cells. Transcriptomic and proteomic analyses suggest that p62 is essential for neuronal differentiation by controlling the metabolic shift from aerobic glycolysis to oxidative phosphorylation required for neuronal maturation. This shift is blocked by the failure to sufficiently downregulate lactate dehydrogenase expression due to the loss of p62, possibly through impaired Hif-1α downregulation and increased sensitivity to oxidative stress. The findings implicate an important role for p62 in neuronal energy metabolism and particularly in the regulation of the shift between glycolysis and oxidative phosphorylation, required for normal neurodifferentiation.
 
Overall design Transcriptomes of neuroepithelial stem cells in an undifferentiated (0d) and differentiated state (4d) were generated in triplicates on an Illumina HiSeq 2500.
 
Contributor(s) Calvo-Garrido J, Maffezzini C, Schober FA, Clemente P, Uhlin E, Kele M, Stranneheim H, Lesko N, Bruhn H, Svenningsson P, Falk A, Wedell A, Freyer C, Wredenberg A
Citation(s) 30827875
Submission date Jun 01, 2017
Last update date May 15, 2019
Contact name Florian Andreas Schober
E-mail(s) florian.schober@ki.se
Organization name Karolinska Institutet
Department Department of Medical Biochemistry and Biophysics (MBB)
Lab Division of Molecular Metabolism
Street address Solnavägen 9
City Solna
ZIP/Postal code 171 65
Country Sweden
 
Platforms (1)
GPL16791 Illumina HiSeq 2500 (Homo sapiens)
Samples (12)
GSM2646211 NES control 1 0d
GSM2646212 NES control 2 0d
GSM2646213 NES control 3 0d
Relations
BioProject PRJNA388960
SRA SRP108507

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Supplementary file Size Download File type/resource
GSE99559_Calvo-Garrido_SQSTM1_processed.txt.gz 1.3 Mb (ftp)(http) TXT
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Raw data are available in SRA
Processed data are available on Series record

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