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

Area of Science:

• Neuroscience
• Cell Biology
• Genetics

Background:

• Neurodegenerative disorders are a growing societal burden with poorly understood mechanisms.
• Monogenic diseases offer insights into complex neurodegenerative conditions.
• Loss-of-function mutations in SQSTM1/p62 cause a childhood neurodegenerative disease.

Purpose of the Study:

• To investigate the cellular role of SQSTM1/p62 in neuronal differentiation.
• To understand the impact of p62 loss on neuronal energy metabolism.
• To elucidate mechanisms underlying p62-related neurodegeneration.

Main Methods:

• Utilized neuroepithelial stem cell (NESC) models.
• Generated differentiated neurons from patient-derived cells and via CRISPR/Cas9 gene editing.
• Performed transcriptomic and proteomic analyses.

Main Results:

• p62 is crucial for neuronal differentiation, regulating the metabolic shift from glycolysis to oxidative phosphorylation.
• Loss of p62 impairs the downregulation of lactate dehydrogenase (LDH) expression.
• This metabolic block may involve impaired Hif-1α downregulation and increased oxidative stress sensitivity.

Conclusions:

• p62 plays a vital role in neuronal energy metabolism and neurodifferentiation.
• Dysregulation of the glycolysis-to-oxidative phosphorylation shift due to p62 loss contributes to neurodegeneration.
• Findings highlight p62's importance in regulating metabolic processes essential for neuronal development.