Endoplasmic reticulum stress leads to accumulation of wild-type SOD1 aggregates associated with sporadic amyotrophic lateral sclerosis

Abstract

The identification of aberrant SOD1 WT species accumulating in the spinal cord during aging could reveal pathogenic species involved in sporadic (s)ALS. Using a combination of biochemical approaches, we discovered that disulfide–cross-linked SOD1 WT aggregates rise before other abnormal protein species during aging and are significantly increased in sALS spinal cord tissue. We also found that endoplasmic reticulum stress stimulates accumulation of these species, with involvement of tryptophan-32 oxidation. These results establish a connection between SOD1 WT aggregation and a major proteostasis network affected in ALS.

Document Details

• Document Type: Pub Defense Publication
• Publication Date: Jul 23, 2018
• Source ID: 10.1073/pnas.1801109115

Entities

People

• Claudio Hetz
• Danilo B. Medinas
• Daryl A. Bosco
• Francisca Martínez Traub
• Pablo Rozas
• Robert H. Brown
• Ute Woehlbier

Organizations

• ALS Therapy Alliance
• Air Force Office of Scientific Research
• Buck Institute for Research on Aging
• CONICYT
• FONDEF
• Harvard T.H. Chan School of Public Health
• Millennium Institute
• Muscular Dystrophy Association
• National Fund for Scientific and Technological Development
• The Michael J. Fox Foundation
• United States Department of Defense
• Universidad Mayor

Tags

Fields of Study

• Environmental science

Readers

• Molecular Biology and Genetics
• Neuroscience
• Traumatic Brain Injury (TBI) and Cognitive Aging in the Guam and Border Populations Affected by Alzheimer's Disease and Tau-Associated Dementias.