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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
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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.
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Overall design |
Transcriptomes of neuroepithelial stem cells in an undifferentiated (0d) and differentiated state (4d) were generated in triplicates on an Illumina HiSeq 2500.
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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 |
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Submission date |
Jun 01, 2017 |
Last update date |
May 15, 2019 |
Contact name |
Florian Andreas Schober |
E-mail(s) |
florian.schober@ki.se
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Organization name |
Karolinska Institutet
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Department |
Department of Medical Biochemistry and Biophysics (MBB)
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Lab |
Division of Molecular Metabolism
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Street address |
Solnavägen 9
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City |
Solna |
ZIP/Postal code |
171 65 |
Country |
Sweden |
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Platforms (1) |
GPL16791 |
Illumina HiSeq 2500 (Homo sapiens) |
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Samples (12)
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Relations |
BioProject |
PRJNA388960 |
SRA |
SRP108507 |
Supplementary file |
Size |
Download |
File type/resource |
GSE99559_Calvo-Garrido_SQSTM1_processed.txt.gz |
1.3 Mb |
(ftp)(http) |
TXT |
SRA Run Selector |
Raw data are available in SRA |
Processed data are available on Series record |
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