RESUMEN
Increased mitochondrial mass, commonly termed mitochondrial proliferation, is frequently observed in many human diseases directly or indirectly involving mitochondrial dysfunction. Mitochondrial proliferation is thought to counterbalance a compromised energy metabolism, yet it might also be detrimental through alterations of mitochondrial regulatory functions such as apoptosis, calcium metabolism or oxidative stress. Here, we show that prominent mitochondrial proliferation occurs in Cramping mice, a model of hereditary neuropathy caused by a mutation in the dynein heavy chain gene Dync1h1. The mitochondrial proliferation correlates with post-prandial induction of full-length (FL) and N-terminal truncated (NT) isoforms of the transcriptional co-activator PGC-1α. The selective knock-out of FL-PGC-1α isoform, preserving expression and function of NT-PGC-1α, led to a complete reversal of mitochondrial proliferation. Moreover, FL-PGC-1α ablation potently exacerbated the mitochondrial dysfunction and led to severe weight loss. Finally, FL-PGC-1α ablation triggered pronounced locomotor dysfunction, tremors and inability to rear in Cramping mice. In summary, endogenous FL-PGC-1α activates mitochondrial proliferation and salvages neurological and metabolic health upon disease. NT-PGC-1α cannot fulfil this protective action. Activation of this endogenous salvage pathway might thus be a valuable therapeutic target for diseases involving mitochondrial dysfunction.
Asunto(s)
Metabolismo Energético/genética , Mitocondrias/metabolismo , Isoformas de Proteínas/genética , Factores de Transcripción/genética , Animales , Apoptosis/genética , Proliferación Celular , Dineínas Citoplasmáticas/genética , Modelos Animales de Enfermedad , Humanos , Ratones , Ratones Noqueados , Mitocondrias/genética , Mitocondrias/patología , Estrés Oxidativo/genética , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma , Fenotipo , Isoformas de Proteínas/metabolismo , Factores de Transcripción/metabolismoRESUMEN
Mitochondrial dysfunction is a common hallmark of ageing-related diseases involving neurodegeneration. Huntington's disease (HD) is one of the most common monogenetic forms of neurodegenerative disorders and shares many salient features with the major sporadic disease of neurodegeneration, such as amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD) and Parkinson's disease (PD). Recent evidence from the study of transgenic and knockout animal models of HD has stimulated new perspectives on mitochondrial dysfunction in HD and possibly other neurodegenerative diseases. The transcriptional co-activator PGC-1α, originally described as a metabolic master regulator in peripheral tissues such as brown adipose tissue (BAT) and muscle, has emerged as a molecular link between transcriptional dysregulation and mitochondrial dysfunction in the brain. PGC-1α knockout mice display many phenotypic similarities to transgenic mouse models of HD and the gene-expression analysis of tissues from HD patients revealed a disruption of the PGC-1α regulatory pathway. Hence, mitochondrial and transcriptional dysregulation in HD - previously thought to be unrelated mechanisms of neurodegeneration - appear to be directly linked at the molecular level. The clinical and therapeutic potential of targeting the PGC-1α in HD is further highlighted by the finding that common genetic variations in the PGC-1α gene significantly modify the disease onset, delaying the onset of motor symptoms by several years. The present review provides an overview of the advances in the understanding of the role of the PGC-1α system in HD pathogenesis and explores the implications for ALS, AD and PD.
Asunto(s)
Sistemas de Liberación de Medicamentos , Proteínas de Choque Térmico/metabolismo , Enfermedades Neurodegenerativas/fisiopatología , Factores de Transcripción/metabolismo , Envejecimiento , Animales , Modelos Animales de Enfermedad , Perfilación de la Expresión Génica , Proteínas de Choque Térmico/genética , Humanos , Ratones , Ratones Noqueados , Enfermedades Neurodegenerativas/tratamiento farmacológico , Enfermedades Neurodegenerativas/genética , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma , Transactivadores/genética , Transactivadores/metabolismo , Factores de Transcripción/genéticaRESUMEN
The molecular motor dynein and its associated regulatory subunit dynactin have been implicated in several neurodegenerative conditions of the basal ganglia, such as Huntington's disease (HD) and Perry syndrome, an atypical Parkinson-like disease. This pathogenic role has been largely postulated from the existence of mutations in the dynactin subunit p150(Glued). However, dynactin is also able to act independently of dynein, and there is currently no direct evidence linking dynein to basal ganglia degeneration. To provide such evidence, we used here a mouse strain carrying a point mutation in the dynein heavy chain gene that impairs retrograde axonal transport. These mice exhibited motor and behavioural abnormalities including hindlimb clasping, early muscle weakness, incoordination and hyperactivity. In vivo brain imaging using magnetic resonance imaging showed striatal atrophy and lateral ventricle enlargement. In the striatum, altered dopamine signalling, decreased dopamine D1 and D2 receptor binding in positron emission tomography SCAN and prominent astrocytosis were observed, although there was no neuronal loss either in the striatum or substantia nigra. In vitro, dynein mutant striatal neurons displayed strongly impaired neuritic morphology. Altogether, these findings provide a direct genetic evidence for the requirement of dynein for the morphology and function of striatal neurons. Our study supports a role for dynein dysfunction in the pathogenesis of neurodegenerative disorders of the basal ganglia, such as Perry syndrome and HD.