Dysregulation of Steroid Hormone Receptors in Motor Neurons and Glia Associates with Disease Progression in ALS Mice

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease targeting motor neurons which shows sexual dimorphism in its incidence, age of onset, and progression rate. All steroid hormones, including androgens, estrogens, and progestogens, have been implicated in modulating ALS. Increasing evidence suggests that steroid hormones provide neuroprotective and neurotrophic support to motor neurons, either directly or via surrounding glial cell interactions, by activating their respective nuclear hormone receptors and initiating transcriptional regulatory responses. The SOD1(G93A) transgenic mouse also shows sex-specific differences in age of onset and progression, and remains the most widely used model in ALS research. To provide a more comprehensive understanding of the influences of steroid hormone signaling in ALS, we systemically characterized sex hormone receptor expression at transcript and protein levels, cellular localization, and the impact of disease course in lumbar spinal cords of male and female SOD1(G93A) mice. We found that spinal motor neurons highly express nuclear androgen receptor (AR), estrogen receptor (ER)alpha, ER beta, and progesterone receptor with variations in glial cell expression. AR showed the most robust sex-specific difference in expression and was downregulated in male SOD1(G93A) mouse spinal cord, in association with depletion in 5 alpha-reductase type 2 isoform, which primarily metabolizes testosterone to 5 alpha-dihydrotestosterone. ER alpha was highly enriched in reactive astrocytes of SOD1(G93A) mice and ER beta was strongly upregulated. The 5 alpha-reductase type 1 isoform was upregulated with disease progression and may influence local spinal cord hormone levels. In conclusion, steroid hormone receptor expression is dynamic and cell-type specific in SOD1(G93A) mice which may provide targets to modulate progression in ALS.