Age-related Purkinje cell death is steroid dependent: RORα haplo-insufficiency impairs plasma and cerebellar steroids and Purkinje cell survival

Abstract

A major problem of ageing is progressive impairment of neuronal function and ultimately cell death. Since sex steroids are neuroprotective, their decrease with age may underlie age-related neuronal degeneration. To test this, we examined Purkinje cell numbers, plasma sex steroids and cerebellar neurosteroid concentrations during normal ageing (wild-type mice, WT), in our model of precocious ageing (Rora+/sg, heterozygous staggerer mice in which expression of the neuroprotective factor RORα is disrupted) and after long-term hormone insufficiency (WT post-gonadectomy). During normal ageing (WT), circulating sex steroids declined prior to or in parallel with Purkinje cell loss, which began at 18 months of age. Although Purkinje cell death was advanced in WT long-term steroid deficiency, this premature neuronal loss did not begin until 9 months, indicating that vulnerability to sex steroid deficiency is a phenomenon of ageing Purkinje neurons. In precocious ageing (Rora+/sg), circulating sex steroids decreased prematurely, in conjunction with marked Purkinje cell death from 9 months. Although Rora+/sg Purkinje cells are vulnerable through their RORα haplo-insufficiency, it is only as they age (after 9 months) that sex steroid failure becomes critical. Finally, cerebellar neurosteroids did not decrease with age in either genotype or gender; but were profoundly reduced by 3 months in male Rora+/sg cerebella, which may contribute to the fragility of their Purkinje neurons. These data suggest that ageing Purkinje cells are maintained by circulating sex steroids, rather than local neurosteroids, and that in Rora+/sg their age-related death is advanced by premature sex steroid loss induced by RORα haplo-insufficiency.

Differential recruitment of coregulators to the RORA promoter adds another layer of complexity to gene (dys) regulation by sex hormones in autism

“…In addition to our finding that RORA regulates the transcription of genes involved in the enzymatic conversion of male to female hormones, neurohistological studies by other groups have reported that loss of Purkinje neurons in male Rora-deficient staggerer mice occurs much earlier in life in comparison to female staggerer mice [ 42 , 43 ], revealing a sexually dimorphic response to Rora deficiency. We recently demonstrated that male and female sex hormones inversely regulate RORA expression in human neuronal cells by suppressing and enhancing RORA expression, respectively [ 16 ].…”

Lifespan of neurons is uncoupled from organismal lifespan

“…In our transplants, the number of mouse PCs did not decrease in older rats, further suggesting that lifespan of the transplanted neurons was not dictated by their mouse genetic background, but by the rat microenvironment. In mice, agedependent loss of PCs has been related to a decrease in concentration of circulating sex steroid hormones (27). However, the increased survival of mouse PCs after xenotransplantation is unlikely to depend on differences in sex steroid, as levels and oscillations of those hormones are similar in aging mice and rats (28,29).…”

Unraveling the physiological roles of retinoic acid receptor-related orphan receptor α

“…PCs are representative models for investigating dendrite development, as well as the function of circulating sex steroids and neurosteroids in neuronal death. Neuronal loss in Rorα +/sg leads to a decline in circulating sex steroids and cerebellar neurosteroids, thus inducing PC death during normal aging 51 . Embryonic knockdown using a miRNA against RORα results in PC mislocation and primitive dendrites.…”