Many neurodegenerative diseases, including ALS, are characterized by mitochondrial dysfunction and defects in the ubiquitin-proteasome pathway. However, why the central nervous system is more prone to these defects than other tissues is unknown. In addition, several of the CNS-associated diseases show sexual disparity but, again, the mechanistic source of this observation is unclear. The current application addresses both the increased sensitivity of the CNS to proteostasis and mitochondrial defects and sex disparity. The Germain group first described an estrogen receptor alpha (ERa) driven axis of the mitochondria unfolded protein response (UPRmt), which promotes the activity of the proteasome, as well as the transcription of mitochondrial genes. More recently, the Germain and Manfredi labs characterized this pathway in the SOD1-G93A model of familial ALS, a model in which males show earlier disease onset than females. We found that females maintain the ability to activate the ER axis of the UPRmt longer than males. These observations raise the possibility that interventions aimed at activating the ERa axis of the UPRmt early on in the disease course may delay the progression of ALS and potentially other CNS-associated diseases. Data presented in this application demonstrate that treatment with the FDA-approved selective estrogen modulator (SERM) raloxifene, but not estrogen or tamoxifen up- regulates expression of both the activity of the proteasome at multiple levels and mitochondria genes. Further, we found that raloxifene delays disease progression in this model, in females specifically, despite the fact that the serum level achieved in our trial was 10-fold lower than what is possible to achieve clinically in humans treated chronically with raloxifene. This suggests that raloxifene is unique in its remarkable ability to increase two of the key pathways associated with diseases affecting the spinal cord, such as ALS, and possibly other components of the CNS. Moreover, our findings also suggest that if levels of raloxifene closer to those achieved with human regimens can be achieve in mice, the protective effect of raloxifene could be much improved. Based on these results, we propose the three following specific aims.
Aim 1 : Understanding the molecular basis of the differential effect of estrogen, tamoxifen and raloxifene on the transcriptional activity of the ER in the spinal cord and expand the analysis of their effects on other parts of the CNS.
Aim 2 : Optimize raloxifene delivery,, alone or in combination with the proteasome activator oleuropein and extend the beneficial effect to males.
Aim 3 : Extending raloxifene-based therapy to a mutant Ubiquilin2 mouse model of ALS/FTD. The program proposed here is an aggressive and ambitious attempt at testing the neuroprotective effects of raloxifene in ALS. As thousands of Americans suffer from this devastating disease, which has no effective therapy, we feel that the ambitious approaches proposed are well justified.
Selective estrogen receptors modulators (SERM) have been shown to be neuroprotective, but their efficacy in neurodegenerative diseases has not been fully understood and tested. This application focuses on the ability of the SERM raloxifene to activate both the proteasome activity and mitochondrial genes and delay disease progression in mouse models of amyotrophic lateral sclerosis.
