Dataset Information

SQSTM1/p62-directed metabolic reprogramming is essential for normal neurodifferentiation

ABSTRACT: 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.

OTHER RELATED OMICS DATASETS IN: GSE99559

INSTRUMENT(S): LTQ Orbitrap Elite

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Neuroepithelial Stem Cell, Cell Culture

DISEASE(S): Neurodegeneration

SUBMITTER: Florian Schober

LAB HEAD: Anna Wredenberg

PROVIDER: PXD006647 | Pride | 2019-03-05

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	20161209_01_Qp2_p62-KO_norm_13_.raw	Raw
	20161209_02_Qp2_p62-KO_norm_8_.raw	Raw
	20161209_04_Qp2_Ctrl_norm_25_.raw	Raw
	20161209_10_Qp2_Ctrl_norm_C3_.raw	Raw
	20161209_11_Qp2_Ctrl_norm_36_.raw	Raw

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Publications

SQSTM1/p62-Directed Metabolic Reprogramming Is Essential for Normal Neurodifferentiation.

Calvo-Garrido Javier J Maffezzini Camilla C Schober Florian A FA Clemente Paula P Uhlin Elias E Kele Malin M Stranneheim Henrik H Lesko Nicole N Bruhn Helene H Svenningsson Per P Falk Anna A Wedell Anna A Freyer Christoph C Wredenberg Anna A

Stem cell reports 20190228 4

Neurodegenerative disorders are an increasingly common and irreversible burden on society, often affecting the aging population, but their etiology 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 neurodegen ...[more]

PMID: 30827875

Similar Datasets

Project description:Huntington's disease (HD) is a dominantly inherited genetic disease caused by mutant huntingtin (htt) protein with expanded polyglutamine tracts. A neuropathological hallmark of HD is the presence of neuronal inclusions of mutant htt. p62 is an important regulatory protein in selective autophagy, a process by which aggregated proteins are degraded, and it is associated with several neurodegenerative disorders including HD. Here we investigated the effect of p62 depletion in three HD model mice: R6/2, HD190QG and HD120QG mice. We found that loss of p62 in these models led to longer lifespans and reduced nuclear inclusions, although cytoplasmic inclusions increased with polyglutamine length. In mouse embryonic fibroblasts (MEFs) with or without p62, mutant htt with a nuclear localization signal (NLS) showed no difference in nuclear inclusion between the two MEF types. In the case of mutant htt without NLS, however, p62 depletion increased cytoplasmic inclusions. Furthermore, to examine the effect of impaired autophagy in HD model mice, we crossed R6/2 mice with Atg5 conditional knockout mice. These mice also showed decreased nuclear inclusions and increased cytoplasmic inclusions, similar to HD mice lacking p62. These data suggest that the genetic ablation of p62 in HD model mice enhances cytoplasmic inclusion formation by interrupting autophagic clearance of polyQ inclusions. This reduces polyQ nuclear influx and paradoxically ameliorates disease phenotypes by decreasing toxic nuclear inclusions. Gene expression profiles were analyzed to examine the effects of p62 depletion in mouse with or without mutant huntingtin exon 1 To examine the effect of p62 depletion on the transcriptome of Huntington's disease model mice, we crossed p62 knockout mice with HD model mice. We extracted total RNA from the striatum of these mice at 8 weeks and used for a microaaray analysis. The samples are HD transgenic mice with p62 knockout (HD_p62KO), HD mice with normal p62 (HD_p62WT), non-HD-transgenic mice with p62 knockout (NT_p62KO), and non-HD-transgenic mice with normal p62 (NT_p62WT).