Aldehyde dehydrogenase-2 deficiency aggravates neuroinflammation , nociception, and motor impairment in a mouse model of multiple sclerosis

Author(s)

Evangelista, Bianca G. ; Giardini, Aline C. ; Hosch, Natalia G. ; Sant'Anna, Morena B. ; Martins, Barbara B. ; Neto, Beatriz S. ; Chacur, Marucia ; Pagano, Rosana L. ; Picolo, Gisele ; Zambelli, Vanessa O.

• Document type: Journal article
• Source: Free Radical Biology and Medicine; v. 225, p. 9-pg., 2024-11-05.

Abstract

Aldehyde dehydrogenase-2 deficiency (ALDH2*2) found in 36 % of Han Chinese, affects approximately 8 % of the world population. ALDH2 is a mitochondrial key enzyme in detoxifying reactive aldehydes to less reactive forms. Studies demonstrate a potential link between ALDH2*2 mutation and neurodegenerative diseases. Multiple sclerosis (MS) is an incurable and disabling neurodegenerative autoimmune disease that induces motor, and cognitive impairment, and hypersensitivity, including chronic pain. Accumulating evidence suggests that reactive aldehydes, such as 4-hydroxynonenal (4-HNE), contribute to MS pathogenesis. Here, using knock-in mice carrying the inactivating point mutation in ALDH2, identical to the mutation found in Han Chinese, we showed that the impairment in ALDH2 activity heightens motor disabilities, and hypernociception induced by experimental autoimmune encephalomyelitis (EAE). The deleterious clinical signs are followed by glial cell activation in the spinal cord and increased 4-HNE levels in the spinal cord and serum. Importantly, the pharmacological ALDH2 activation by Alda-1 ameliorates EAE-induced hypernociception and motor impairment in both wild-type and ALDH2*2KI mice. Reduced hypernociception was associated with less early growth response protein 1 (EGR1), neuronal and glial activation, and reactive aldehyde accumulation in the spinal cord and serum. Taken together, our data suggest that the mitochondrial enzyme ALDH2 plays a role in regulating clinical, cellular, and molecular responses associated with EAE. This indicates that ALDH2 could serve as a molecular target for MS control, with ALDH2 activators, like Alda-1 as potential neuroprotective candidates. Furthermore, ALDH2*2 carriers may be at increased risk of developing more accentuated MS symptoms. (AU)

• FAPESP's process: 21/02897-4 - Effect of photobiomodulation treatment on mitochondrial dynamics: analysis of the dorsal root ganglion in a type 1 Diabetes mellitus model
• Grantee: Marucia Chacur
• Support Opportunities: Regular Research Grants
• FAPESP's process: 15/01254-1 - Evaluating the effect of crotoxin-nanostructured silica SBA-15 complex in chronic pain: immunomodulatory, antinociceptive and antiinflammatory aspects
• Grantee: Gisele Picolo
• Support Opportunities: Regular Research Grants
• FAPESP's process: 13/07467-1 - CeTICS - Center of Toxins, Immune-Response and Cell Signaling
• Grantee: Hugo Aguirre Armelin
• Support Opportunities: Research Grants - Research, Innovation and Dissemination Centers - RIDC
• FAPESP's process: 15/26079-8 - Participation of descending serotonergic analgesia pathway and changes in inflammatory and neurodegenerative response in the treatment of neuropathic pain by transcranial direct-current stimulation
• Grantee: Rosana de Lima Pagano
• Support Opportunities: Regular Research Grants