Dysregulation of PGC-1α-Dependent Transcriptional Programs in Neurological and Developmental Disorders: Therapeutic Challenges and Opportunities
| Autor: | Stephanie N. Fox, Stephanie M. Boas, Laura J. McMeekin, Rita M. Cowell |
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| Rok vydání: | 2020 |
| Předmět: |
Cell type
Parkinson's disease Transcription Genetic Developmental Disabilities nuclear respiratory factor 2 nuclear respiratory factor 1 Disease Review interneuron Biology Neuroprotection nuclear-encoded mitochondrial genes mitochondrial transcription factor A Parkinson’s Disease Huntington's disease dopaminergic neuron medicine Transcriptional regulation Huntington’s Disease Humans NRF1 lcsh:QH301-705.5 spiny projection neuron neuronal vulnerability General Medicine TFAM medicine.disease Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha Genes Mitochondrial lcsh:Biology (General) Gene Expression Regulation Nervous System Diseases Neuroscience |
| Zdroj: | Cells Cells, Vol 10, Iss 352, p 352 (2021) |
| ISSN: | 2073-4409 |
| Popis: | Substantial evidence indicates that mitochondrial impairment contributes to neuronal dysfunction and vulnerability in disease states, leading investigators to propose that the enhancement of mitochondrial function should be considered a strategy for neuroprotection. However, multiple attempts to improve mitochondrial function have failed to impact disease progression, suggesting that the biology underlying the normal regulation of mitochondrial pathways in neurons, and its dysfunction in disease, is more complex than initially thought. Here, we present the proteins and associated pathways involved in the transcriptional regulation of nuclear-encoded genes for mitochondrial function, with a focus on the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1α). We highlight PGC-1α’s roles in neuronal and non-neuronal cell types and discuss evidence for the dysregulation of PGC-1α-dependent pathways in Huntington’s Disease, Parkinson’s Disease, and developmental disorders, emphasizing the relationship between disease-specific cellular vulnerability and cell-type-specific patterns of PGC-1α expression. Finally, we discuss the challenges inherent to therapeutic targeting of PGC-1α-related transcriptional programs, considering the roles for neuron-enriched transcriptional coactivators in co-regulating mitochondrial and synaptic genes. This information will provide novel insights into the unique aspects of transcriptional regulation of mitochondrial function in neurons and the opportunities for therapeutic targeting of transcriptional pathways for neuroprotection. |
| Databáze: | OpenAIRE |
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