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Raloxifene is a Female-specific Proteostasis Therapeutic in the Spinal Cord
Edmund Charles Jenkins1, Gabriella Casalena2, Maria Gomez1
1Icahn School of Medicine at Mount Sinai, Tisch Cancer Institute, Department of Medicine, Division of Hematology/Oncology, New York, NY, USA.
Abstract:
Several neurodegenerative disorders are characterized by proteasome dysfunctions leading to protein aggregations and pathogenesis. Since we showed that estrogen receptor alpha (ERα) activates the proteasome, drugs able to stimulate ERα in the central nervous system (CNS) could hold potential for therapeutic intervention. However, the transcriptional effects of selective estrogen receptor modulators (SERMs), such as tamoxifen and raloxifene, can be tissue specific. A direct comparison of the effects of different SERMs on gene transcription in the CNS has never been performed. Here, we report an RNA-seq analysis of the spinal cord treated with estrogen, tamoxifen, or raloxifene. We find stark SERM and sex-specific differences in gene expression profiles in the spinal cord. Notably, raloxifene, but not estrogen or tamoxifen, modulates numerous deubiquitinating enzymes, proteasome subunits and assembly factors, and these effects translate into decreased protein aggregates. In the SOD1-G93A mouse model of amyotrophic lateral sclerosis, we found that even a low dose of raloxifene causes a significant decrease in mutant SOD1 aggregates in the spinal cord, accompanied by a delay in the decline of muscle strength in females, but not in males. These results strongly indicate SERM-selective as well as sex-specific effects, and emphasize the importance of sex as a biological variable to be considered for the careful selection of specific SERM for use in clinical trials for neurodegenerative diseases.
Insights
Raloxifene, a selective estrogen receptor modulator (SERM), reduces protein aggregates in neurodegenerative diseases. Its effects are SERM- and sex-specific, highlighting the need for careful drug selection in clinical trials.
Area of Science:
- Neurobiology
- Pharmacology
- Genomics
Background:
- Neurodegenerative diseases involve proteasome dysfunction and protein aggregation.
- Estrogen receptor alpha (ERα) activation by drugs could be a therapeutic strategy for the central nervous system (CNS).
- Selective estrogen receptor modulators (SERMs) have tissue-specific transcriptional effects, necessitating CNS-specific comparisons.
Purpose of the Study:
- To compare the effects of estrogen, tamoxifen, and raloxifene on gene transcription in the CNS.
- To investigate SERM- and sex-specific effects on proteasome function and protein aggregation.
- To evaluate raloxifene's efficacy in a mouse model of amyotrophic lateral sclerosis (ALS).
Main Methods:
- RNA-sequencing (RNA-seq) analysis of spinal cord tissue from mice treated with estrogen, tamoxifen, or raloxifene.
- Assessment of proteasome subunit and assembly factor gene expression.
- Quantification of protein aggregates and evaluation of motor function in the SOD1-G93A mouse model.
Main Results:
- Significant SERM- and sex-specific differences in spinal cord gene expression were observed.
- Raloxifene, unlike estrogen or tamoxifen, modulated deubiquitinating enzymes and proteasome components.
- Raloxifene treatment decreased protein aggregates and delayed muscle strength decline in female SOD1-G93A mice.
Conclusions:
- Raloxifene demonstrates therapeutic potential for neurodegenerative diseases by targeting proteasome pathways.
- SERM-selective and sex-specific effects are critical considerations for developing CNS-acting therapies.
- Future clinical trials for neurodegenerative diseases must account for sex as a biological variable in SERM selection.
