Role of the Immunoproteasome in TSC Pathogenesis and Therapeutics
Abstract
The discovery of the immunoproteasome provides a new opportunity for therapeutic development for tuberous sclerosis complex (TSC). Immunoproteasome inhibition may bring multiple benefits for TSC treatment. The Principal Investigator’s lab has recently demonstrated that Tsc1 mutation induces a proteasomal switch from the standard type proteasome to the immunoproteasome in mouse and human cells and mouse tissues. The immunoproteasome is highly increased in hippocampal neurons and glia of TSC patients. The immunoproteasome expression correlates with neuroinflammation, a condition closely associated with neurocognitive dysfunction, epilepsy, and autism that are often observed with TSC patients. Recent studies showed that selective inhibition of the immunoproteasome significantly prevents or delays seizure-like events in rat. The whole body depletion of the immunoproteasome did not have any apparent abnormality in viability, fertility, and behavioral phenotypes in mice, further supporting the advantage of immunoproteasome inhibitors over other drugs. Once our study using the genetic depletion mouse model is successfully accomplished, the availability of the selective inhibitor for the immunoproteasome will facilitate preclinical studies and future drug development. Proteasome inhibitors, such as bortezomib and carfilzomib that inhibit both the standard type proteasome and the immunoproteasome, have been developed as therapeutic targets for human diseases, such as multiple myeloma, and tested for a TSC mouse model. However, severe side effects of those drugs have limited therapeutic efficacy and applications. One of the most severe side effects is the development of peripheral neuropathies. In contrast, the immunoproteasome-specific inhibitor ONX-0914 has been shown to penetrate into the central nervous system with a significantly reduced neurotoxicity. The therapeutic benefit of the immunoproteasome inhibitors is further supported by the finding that complete depletion of the immunoproteasome from the mouse whole body did not cause any apparent abnormality and health problem. These prior studies strongly support the necessity of our study to define clearly the role of the immunoproteasome in TSC pathogenesis and as a promising therapeutic target for TSC-related neuropathy.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910132
Entities
People
- Do-hyung Kim
Organizations
- United States Army
- University of Minnesota