Cholesterol secosterol aldehyde adduction and aggregation of Cu,Zn-superoxide dismutase: Potential implications in ALS

Autor(es)

Dantas, Lucas S. ^[1] ; Chaves-Filho, Adriano B. ^[1] ; Coelho, Fernando R. ^[1] ; Genaro-Mattos, Thiago C. ^{[2, 3, 4]} ; Tallman, Keri A. ^{[2, 3]} ; Porter, Ned A. ^{[2, 3]} ; Augusto, Ohara ^[1] ; Miyamoto, Sayuri ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Inst Quim, Dept Bioquim, Ave Prof Lineu Prestes 748, Bloco 10 Super, BR-05508000 Sao Paulo, SP - Brazil

^[2] Vanderbilt Univ, Dept Chem, Vanderbilt Inst Chem Biol, Nashville, TN - USA

^[3] Vanderbilt Univ, Vanderbilt Kennedy Ctr Res Human Dev, 221 Kirkland Hall, Nashville, TN 37235 - USA

^[4] Univ Nebraska Med Ctr, Munroe Meyer Inst, Omaha, NE - USA

• Tipo de documento: Artigo Científico
• Fonte: REDOX BIOLOGY; v. 19, p. 105-115, OCT 2018.
• Citações Web of Science: 3

Resumo

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by degeneration of upper and lower motor neurons. While the fundamental causes of the disease are still unclear, the accumulation of Cu,Zn-superoxide dismutase (SOD1) immunoreactive aggregates is associated with familial ALS cases. Cholesterol 5,6 secosterol aldehydes (Seco A and Seco B) are reported to contribute to neurodegenerative disease pathology by inducing protein modification and aggregation. Here we have investigated the presence of secosterol aldehydes in ALS SOD1-G93A rats and their capacity to induce SOD1 aggregation. Secosterol aldehydes were analyzed in blood plasma, spinal cord and motor cortex of ALS rats at the pre-symptomatic and symptomatic stages. Seco B was significantly increased in plasma of symptomatic ALS rats compared to pre-symptomatic animals, suggesting an association with disease progression. In vitro experiments showed that both Seco A and Seco B induce the formation of high molecular weight (HMW) SOD1 aggregates with amorphous morphology. SOD1 adduction to to-alkynyl-secosterols analyzed by click assay showed that modified proteins are only detected in the HMW region, indicating that secosterol adduction generates species highly prone to aggregate. Of note, SOD1-secosterol adducts containing up to five secosterol molecules were confirmed by MALDI-TOF analysis. Interestingly, mass spectrometry sequencing of SOD1 aggregates revealed preferential secosterol adduction to Lys residues located at the electrostatic loop (Lys 122, 128 and 136) and nearby the dimer interface (Lys 3 and 9). Altogether, our results show that secosterol aldehydes are increased in plasma of symptomatic ALS rats and represent a class of aldehydes that can potentially modify SOD1 enhancing its propensity to aggregate. (AU)

• Processo FAPESP: 10/50891-0 - Ácido docosahexaenóico e colesterol: caracterização e detecção de produtos de oxidação, modificação de proteínas e implicações na esclerose lateral amiotrófica
• Beneficiário: Sayuri Miyamoto
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 13/07937-8 - Redoxoma
• Beneficiário: Ohara Augusto
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs