Abstract
A hexanucleotide repeat expansion (HRE) in an intron of gene C9ORF72 is the most common cause of familial amyotrophic lateral sclerosis and frontotemporal dementia. The HRE undergoes noncanonical translation (repeat-associated non-ATG translation) resulting in the production of five distinct dipeptide repeat (DPR) proteins. Arginine-rich DPR proteins have shown to be toxic to motor neurons, and recent evidence suggests this toxicity is associated with disruption of the ubiquitin-proteasome system. Here we report the ability of known 20S proteasome activator, TCH-165, to enhance the degradation of DPR proteins and overcome proteasome impairment evoked by DPR proteins. Furthermore, the 20S activator protects rodent motor neurons from DPR protein toxicity and restores proteostasis in cortical neuron cultures. This study suggests that 20S proteasome enhancers may have therapeutic efficacy in neurodegenerative diseases that display proteostasis defects.
| Original language | English (US) |
|---|---|
| Journal | ACS Chemical Neuroscience |
| DOIs | |
| State | Accepted/In press - 2022 |
Funding
This work was supported by the National Institutes of Health (AG061306 and AG066223). J.J.T.: National Public Health Service grants (NS05225 and NS087077), US Public Health Service grants (NS122908 and NS124802), and Department of the Army W81XWH-21-1-0236. R.G.K.: the Heather Koster Family Charitable Fund and the Les Turner ALS Foundation. The authors also thank Michigan State University and Dr. John Cantlon and Carolyne Cantlon for their contributions to the Neogen Land Grant Prize awarded to A.S.V. to aid in funding this research. We also thank Dr. Don Cleveland and Dr. Qiang Zhu for the kind gift of antipoly-GR antibody.
Keywords
- Amyotrophic lateral sclerosis
- DPR proteins
- UPS impairment
- frontotemporal dementia
- neurodegenerative diseases
- neuroprotection
- proteasome
- proteostasis
ASJC Scopus subject areas
- Cognitive Neuroscience
- Biochemistry
- Physiology
- Cell Biology