The Expression of CNS-Specific PPARGC1A Transcripts Is Regulated by Hypoxia and a Variable GT Repeat Polymorphism

Molecular Neurobiology, 2020 · DOI: https://doi.org/10.1007/s12035-019-01731-5 · Published: August 30, 2019

Simple Explanation

PPARGC1A encodes PGC-1α, a transcriptional co-activator involved in multiple transcriptional programs, including those relevant to neurodegenerative diseases. The study identifies CNS-specific transcripts of PPARGC1A and examines how their expression is regulated in neuronal cells. A variable GT repeat polymorphism in the CNS promoter region influences promoter activity, and hypoxia also regulates CNS-specific transcript expression.

Study Duration

Not specified

Participants

Human neuronal cell lines, rat model of ischemia, DNA from 2000 subjects

Evidence Level

Not specified

Key Findings

1
A naturally occurring variable GT repeat polymorphism increases promoter activity in neuronal cell lines.
2
The CNS promoter is induced by FOXA2 and co-activated by PGC-1α, resulting in robust activation.
3
The CNS promoter is targeted by the canonical hypoxia response involving HIF1A, modulated by the size of the GT polymorphism.

Research Summary

This study investigates the regulation of CNS-specific PPARGC1A transcripts in human neuronal cell lines and a rat model of ischemia. The findings reveal that a GT repeat polymorphism and hypoxia influence the expression of these transcripts, suggesting a role in ischemia. The study also identifies FOXA2 as a selective activator of the CNS-specific promoter, further highlighting its role in neuronal function.

Practical Implications

Inter-individual Variability

The GT repeat polymorphism may explain inter-individual variability in CNS transcript expression and response to hypoxia.

Therapeutic Target

Understanding the regulation of CNS-specific PPARGC1A transcripts could lead to new therapeutic targets for neurodegenerative diseases and ischemia.

Dopaminergic Neuron Maintenance

FOXA2's role in activating the CNS-specific promoter suggests a link to the development and maintenance of dopaminergic mid-brain neurons.

Study Limitations

1
The study primarily used cell lines and a rat model; further studies in humans are needed.
2
The precise mechanisms of interaction between HIF1A and the GT repeat size require further investigation.
3
The effects of ischemia on individual brain regions need further study due to limited sample numbers.

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