Homocysteine induces oxidative cytotoxicity in Cu,Zn-superoxide dismutase mutant motor neuronal cell

Abstract

Mutations in human Cu,Zn-superoxide dismutase (SOD1) cause approximately 20% of familial amyotrophic lateral sclerosis (FALS) cases. The mechanism of late-onset disease manifestation despite the innate mutation has no clear explanation. The relationship between homocysteine (HC) and amyotrophic lateral sclerosis (ALS) has not been investigated, in spite of the similarity in their pathogenesis. We investigated the effect of HC on the motor neuronal cell-line transfected with SOD1 of either wild-type or one of two mutant forms (G93A and A4V). In the MTT assay, HC induced significant cytotoxicity in A4V, but not in G93A, as compared with wild-type, even at the physiological concentration of 10 microM. This HC-induced cytotoxicity was inhibited by the antioxidant trolox and the Cu (I) chelator bathocuproinedisulfonate. Here we show that the vulnerability of the A4 V mutant involves the cytotoxic copper-mediated pathway, and that HC may be a lifelong precipitating factor in some forms of FALS, suggesting the possible treatment modality with vitamin supplements.

Elevated Levels of Methylmalonate and Homocysteine in Parkinson’s Disease, Progressive Supranuclear Palsy and Amyotrophic Lateral Sclerosis

“…Direct neurotoxicity of Hcy to neuronal cells has been demonstrated [24] . Several mechanisms by which Hcy induces neurotoxicity like excitotoxicity by stimulating NMDA receptors [25] , increased production of ␤ -amyloid aggregates, promotion of neuronal apoptosis [26] and an increase of oxidative stress [36] have been suggested. Regardless, elevated serum levels of Hcy expose patients to an increased risk of arteriosclerosis [35] .…”

Epigallocatechin gallate prevents oxidative-stress-induced death of mutant Cu/Zn-superoxide dismutase (G93A) motoneuron cells by alteration of cell survival and death signals

“…They include oxidative stress, excitotoxicity due to glutamate, calcium-mediated toxicity, genetic defects, autoimmunity, and accumulation of abnormal proteins (Victor and Ropper, 2001). However, increasing evidence indicates that oxidative stress is an important mechanism implicated in neurodegenerative diseases (Al-Chalabi and Leigh, 2000;Kim et al, 2002;Kim et al, 2003;McCord, 1994;Rosen et al, 1993;Son et al, 2003;Sung et al, 2002;Strange et al, 2003;Wang et al, 2002). And, even the precise mechanisms of oxidative stress are not completely characterized, there are growing interests in establishing therapeutic and dietary strategies to protect motor neurons from oxidative-stress-induced damage.…”

“…Although several mechanisms such as enhancement of protein nitrosylation by mutant SOD1, enhanced peroxidase activity, exposure of toxic copper at the active site, and accumulation and aggregation of abnormal proteins have recently been proposed, the precise pathogenic mechanism induced by these mutations has not yet been clearly established (Al-Chalabi and Leigh, 2000;Kim et al, 2002Kim et al, , 2003Kim et al, , 2004McCord, 1994;Rosen et al, 1993;Son et al, 2003;Sung et al, 2002;Strange et al, 2003;Wang et al, 2002).…”

Effects of homocysteine on adipocyte differentiation and CD36 gene expression in 3T3-L1 adipocytes

“…The effect of Hcy on uptake and clearance of Ox-LDL by adipose tissue now needs to be investigated in vivo. Mujumdar et al 2002;Sung et al 2002;Li et al 2008;Wang et al 2011a. b: Mujumdar et al 2002.…”