RREB1 regulates neuronal proteostasis and the microtubule network

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Transcription factors are key in neuron development, but their role in maintaining neuronal homeostasis is less understood.
• Neuronal homeostasis is critical for brain function and preventing neurodegenerative diseases.

Purpose of the Study:

• To investigate the role of the transcription factor RREB1 (Ras-responsive element-binding protein 1) in maintaining neuronal survival and homeostasis.
• To elucidate the molecular mechanisms by which RREB1 influences neuronal health.

Main Methods:

• Analysis of a spontaneous mouse mutation affecting the RREB1 gene and its nervous system-enriched transcript.
• Chromatin immunoprecipitation sequencing (ChIP-seq) and RNA sequencing (RNA-seq) to identify RREB1 targets.
• Microscopy to assess dendritic complexity and autophagosome/lysosome content in mutant neurons.

Main Results:

• Loss of RREB1 function in mice led to progressive loss of cerebellar Purkinje cells and ataxia.
• RREB1 targets involved in the microtubule cytoskeleton were dysregulated, causing disrupted dendritic complexity.
• RREB1 deficiency resulted in fewer autophagosomes and lysosomes and accumulation of protein inclusions, indicating impaired proteostasis.

Conclusions:

• RREB1 is essential for neuron survival in the mammalian brain.
• RREB1 maintains neuronal homeostasis by regulating the microtubule network and the endomembrane system, including autophagy and lysosomal function.
• Dysregulation of RREB1 contributes to neurodegeneration and suggests potential therapeutic targets for related disorders.