Deterioration of neuroregenerative plasticity in association with testicular atrophy and dysregulation of the hypothalamic-pituitary-gonadal (HPG) axis in Huntington's disease: A putative role of the huntingtin gene in steroidogenesis

摘要

Huntington's disease (HD) is an autosomal dominant progressive neurodegenerative disorder mainly affecting the structure and functions of the striatum, cerebral cortex and hippocampus leading to movement disorders, cognitive dysfunctions and emotional disturbances. The onset of HD has been linked to a pathogenic CAG repeat expansion in the huntingtin (HTT) gene that encodes for the polyglutamine (polyQ) stretches in the huntingtin (Htt) protein. Notably, the neuropathogenic events of the mutant HTT gene appear to be primed during adulthood and magnified along the ageing process. While the normal Htt protein is vital for the neuronal differentiation and neuroprotection, experimental HD models and postmortem human HD brains have been characterized by neurodegeneration and defects in neuroregenerative plasticity in the basal ganglia and limbic system including the hippocampus. Besides gonadal dysfunctions, reduced androgen levels and abnormal hypothalamic-pituitary-gonadal (HPG) axis have increasingly been evident in HD. Recently, ageing-related changes in levels of steroid sex hormones have been proposed to play a detrimental effect on the regulation of hippocampal neurogenesis in the adult brain. Considering its adult-onset nature, a potential relationship between dysregulation in the synthesis of sex steroid hormones and the pathogenesis of the mutant HTT gene appears to be an important clinical issue in HD. While the hippocampus and testis are the major sites of steroidogenesis, the presence of Htt in both areas is conclusively evident. Hence, the expression of the normal HTT gene may take part in the steroidogenic events in aforementioned organs in the physiological state, whereas the mutant HTT gene may cause defects in steroidogenesis in HD. Therefore, this review article comprehends the potential relationship between the gonadal dysfunctions and abnormal hippocampal plasticity in HD and represents a hypothesis for the putative role of the HTT gene in the regulation of steroidogenesis in gonads and in the brain.