C/EBP regulates TFAM expression, mitochondrial function and autophagy in cellular models of Parkinson’s Disease
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2023
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Sierra-Magro A, Bartolome F, Lozano-Muñoz D, Alarcón-Gil J, Gine E, Sanz-SanCristobal M, Alonso-Gil S, Cortes-Canteli M, Carro E, Pérez-Castillo A, Morales-García JA. C/EBPβ Regulates TFAM Expression, Mitochondrial Function and Autophagy in Cellular Models of Parkinson's Disease. Int J Mol Sci. 2023 Jan 11;24(2):1459. doi: 10.3390/ijms24021459. PMID: 36674978; PMCID: PMC9865173.
Abstract
La enfermedad de Parkinson (EP) es un trastorno neurodegenerativo que resulta de la degeneración de las neuronas dopaminérgicas de la sustancia negra pars compacta (SNpc). Dado que sólo se dispone de tratamientos sintomáticos, se necesitan nuevas dianas celulares y moleculares implicadas en el inicio y la progresión de esta enfermedad para desarrollar tratamientos eficaces. Los niveles del factor de transcripción CCAAT/Enhancer Binding Protein β (C/EBPβ) están alterados en pacientes con diversas enfermedades neurodegenerativas, lo que sugiere que puede ser una buena diana terapéutica para el tratamiento de la EP. Mediante la combinación de datos genéticos in silico se generó una lista de genes implicados en la EP que pueden ser regulados por C/EBPβ, entre los que se encuentra el factor de transcripción mitocondrial A (TFAM). En este trabajo, observamos que la sobreexpresión de C/EBPβ aumentaba la actividad promotora de TFAM. Sin embargo, la regulación a la baja de C/EBPβ en diferentes modelos celulares de EP/neuroinflamación produjo un aumento de los niveles de TFAM, junto con otros marcadores mitocondriales. Esto nos llevó a proponer una acumulación de mitocondrias no funcionales posiblemente debido a la alteración de su degradación autofágica en ausencia de C/EBPβ. Entonces, concluimos que C/EBPβ no sólo está involucrado en procesos dañinos que ocurren en la EP, como la inflamación, sino que también está implicado en la función mitocondrial y la autofagia en condiciones similares a la EP.
Parkinson’s disease (PD) is a neurodegenerative disorder that results from the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Since there are only symptomatic treatments available, new cellular and molecular targets involved in the onset and progression of this disease are needed to develop effective treatments. CCAAT/Enhancer Binding Protein β (C/EBPβ) transcription factor levels are altered in patients with a variety of neurodegenerative diseases, suggesting that it may be a good therapeutic target for the treatment of PD. A list of genes involved in PD that can be regulated by C/EBPβ was generated by the combination of genetic and in silico data, the mitochondrial transcription factor A (TFAM) being among them. In this paper, we observed that C/EBPβ overexpression increased TFAM promoter activity. However, downregulation of C/EBPβ in different PD/neuroinflammation cellular models produced an increase in TFAM levels, together with other mitochondrial markers. This led us to propose an accumulation of non-functional mitochondria possibly due to the alteration of their autophagic degradation in the absence of C/EBPβ. Then, we concluded that C/EBPβ is not only involved in harmful processes occurring in PD, such as inflammation, but is also implicated in mitochondrial function and autophagy in PD-like conditions.
Parkinson’s disease (PD) is a neurodegenerative disorder that results from the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Since there are only symptomatic treatments available, new cellular and molecular targets involved in the onset and progression of this disease are needed to develop effective treatments. CCAAT/Enhancer Binding Protein β (C/EBPβ) transcription factor levels are altered in patients with a variety of neurodegenerative diseases, suggesting that it may be a good therapeutic target for the treatment of PD. A list of genes involved in PD that can be regulated by C/EBPβ was generated by the combination of genetic and in silico data, the mitochondrial transcription factor A (TFAM) being among them. In this paper, we observed that C/EBPβ overexpression increased TFAM promoter activity. However, downregulation of C/EBPβ in different PD/neuroinflammation cellular models produced an increase in TFAM levels, together with other mitochondrial markers. This led us to propose an accumulation of non-functional mitochondria possibly due to the alteration of their autophagic degradation in the absence of C/EBPβ. Then, we concluded that C/EBPβ is not only involved in harmful processes occurring in PD, such as inflammation, but is also implicated in mitochondrial function and autophagy in PD-like conditions.