title: Neurodegeneration and motor dysfunction in mice lacking cytosolic and mitochondrial aldehyde dehydrogenases: implications for Parkinson's disease.
abstract: Previous studies have reported elevated levels of biogenic aldehydes in the brains of patients with Parkinson's disease (PD). In the brain, aldehydes are primarily detoxified by aldehyde dehydrogenases (ALDH). Reduced ALDH1 expression in surviving midbrain dopamine neurons has been reported in brains of patients who died with PD. In addition, impaired complex I activity, which is well documented in PD, reduces the availability of the NAD(+) co-factor required by multiple ALDH isoforms to catalyze the removal of biogenic aldehydes. We hypothesized that chronically decreased function of multiple aldehyde dehydrogenases consequent to exposure to environmental toxins and/or reduced ALDH expression, plays an important role in the pathophysiology of PD. To address this hypothesis, we generated mice null for Aldh1a1 and Aldh2, the two isoforms known to be expressed in substantia nigra dopamine neurons. Aldh1a1(-/-)×Aldh2(-/-) mice exhibited age-dependent deficits in motor performance assessed by gait analysis and by performance on an accelerating rotarod. Intraperitoneal administration of L-DOPA plus benserazide alleviated the deficits in motor performance. We observed a significant loss of neurons immunoreactive for tyrosine hydroxylase (TH) in the substantia nigra and a reduction of dopamine and metabolites in the striatum of Aldh1a1(-/-)×Aldh2(-/-) mice. We also observed significant increases in biogenic aldehydes reported to be neurotoxic, including 4-hydroxynonenal (4-HNE) and the aldehyde intermediate of dopamine metabolism, 3,4-dihydroxyphenylacetaldehyde (DOPAL). These results support the hypothesis that impaired detoxification of biogenic aldehydes may be important in the pathophysiology of PD and suggest that Aldh1a1(-/-)×Aldh2(-/-) mice may be a useful animal model of PD.
authors.affiliation: Department of Pharmacology, University of Texas Health Science Center at San Antonio, San Antonio, Texas, United States of America.
authors.forename: Margaret Chia-Ying
authors.initials: MC
authors.lastname: Wey
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Fernandez
authors.forename: Paul Anthony
authors.initials: PA
authors.lastname: Martinez
authors.forename: Patricia
authors.initials: P
authors.lastname: Sullivan
authors.forename: David S
authors.initials: DS
authors.lastname: Goldstein
authors.forename: Randy
authors.initials: R
authors.lastname: Strong
mesh_terms: D015102:3,4-Dihydroxyphenylacetic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D000444:Aldehyde Dehydrogenase / Q000235:genetics* / Q000502:physiology; D000818:Animals; D001835:Body Weight; D003072:Cognition Disorders; D003600:Cytosol / Q000201:enzymology*; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D005260:Female; D005838:Genotype; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008928:Mitochondria / Q000201:enzymology*; D009243:NAD / Q000737:chemistry; D019636:Neurodegenerative Diseases / Q000235:genetics* / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D010300:Parkinson Disease / Q000235:genetics; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D009243:NAD; D015102:3,4-Dihydroxyphenylacetic Acid; C007430:3,4-dihydroxyphenylacetaldehyde; D014446:Tyrosine 3-Monooxygenase; D000444:Aldehyde Dehydrogenase; D004298:Dopamine