Detoxification of Biogeneic Aldehydes in Parkinson's Disease

生物醛在帕金森病中的解毒作用

• 批准号: 8666526
• 负责人: RANDY STRONG
• 金额: --
• 依托单位: SOUTH TEXAS VETERANS HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8666526
• 关键词: 1-Methyl-4-phenylpyridinium; Accounting; Affect; Age; Aldehydes; Alzheimer' s Disease; Animals; Behavior; Behavioral; Biochemical; Biological Assay; Biological Markers; Brain; Cell Death; Clinical; Corpus striatum structure; Diagnostic; Disease; Disease Progression; Dopamine; Drug Metabolic Detoxication; Environmental Exposure; Epidemiologic Studies; Etiology; Excision; Exhibits; Exposure to; FDA approved; Family; Functional disorder; Funding; Gene Mutation; Genetic; Histopathology; Human; Hydralazine; Hydrophobicity; Impairment; Isoenzymes; Knockout Mice; Link; Maneb; Measurement; Measures; Midbrain structure; Military Personnel; Modeling; Motor; Movement; Mus; Muscle Rigidity; Mutation; Neurodegenerative Disorders; Neurotoxins; Paraquat; Parkinson Disease; Pathogenesis; Patients; Peripheral; Pesticides; Pharmaceutical Preparations; Phenotype; Population; Presynaptic Terminals; Process; Research; Rest Tremor; Risk; Role; Rotenone; Safety; Substantia nigra structure; Symptoms; Testing; Tissues; Toxic Environmental Substances; Toxin; Ubiquitin; Veterans; Wild Type Mouse; Work; adduct; age related; aged; aldehyde dehydrogenase 1; aldehyde dehydrogenases; alpha synuclein; dopaminergic neuron; environmental agent; neurochemistry; neuropathology; neuroprotection; neurotoxic; novel therapeutics; overexpression; preclinical study; prevent; protein aggregate; protein folding; public health relevance; synuclein; therapeutic target; treatment strategy

DESCRIPTION (provided by applicant): Parkinson's disease (PD) is the second most prevalent age-related neurodegenerative disorder, after Alzheimer's disease, affecting up to 5% of the population aged 65 - 85 years the clinical manifestations of PD include slowness of voluntary movement, resting tremor, muscle rigidity and postural instability. The major biochemical abnormality is a profound loss of dopamine in the substantia nigra (SN) and striatum, resulting from loss of dopaminergic neurons in the substantia nigra and their axon terminals in the striatum. Other prominent pathological features include the presence of intraneuronal inclusions consisting of protein aggregates containing a-synuclein and ubiquitin. Despite great strides in research over the past two decades, the etiology and pathogenesis of the disease is still largely unknown. Although families have been identified with single gene mutations that cause PD-like symptoms, they account for a relatively small number of PD cases. The majority of PD cases are classified as idiopathic or of unknown cause. Human and animal studies have established a link between environmental exposure to paraquat, maneb and rotenone in idiopathic or sporadic PD. The mechanisms by which exposure to pesticides with different mechanisms of action may cause PD are not fully understood, and treatment strategies to prevent or slow disease progression have not been identified. However, a growing body of evidence from our lab and others has implicated impaired aldehyde detoxification. Our working hypothesis is that impaired aldehyde detoxification leads to elevated "aldehyde load" including increased levels of DOPAL and 4-HNE. These aldehydes or their metabolites can form adducts with a-synuclein, leading to formation of toxic fibrils and eventually cell death. To test the hypothesis that impaired aldehyde detoxification is mechanistically linked to dopaminergic dysfunction; we created two lines of mice, one with homozygous mutations in the two aldehyde dehydrogenase isozymes, Aldh1a1 and Aldh2, that are known to be present in midbrain dopamine neurons, and the other a line of wild- type mice from their littermates on the identical genetic background. We then examined the effects of Aldh1a1/Aldh2-deficiency on their behavioral and neurochemical phenotypes. Our results show that mice deficient in Aldh1a1/Aldh2 exhibit impairments in motor function that are reversed by L-DOPA, reduced dopamine and metabolites and loss of midbrain dopamine neurons. The overall aim is to test mechanistically determine how increased aldehyde load is connected to dopaminergic dysfunction and evaluate aldehydes as a therapeutic target. Our Specific Aims are: Aim 1: To determine whether impaired aldehyde detoxification increases the sensitivity of dopamine neurons to environmental neurotoxins and biogenic aldehydes; Aim 2 To determine the role of a-synuclein in the neuropathology and behavioral deficits in Aldh1a1/Aldh2 null mice; Aim 3 To determine the efficacy of accelerated aldehyde removal by aldehyde trapping agents on neuroprotection of midbrain dopamine neurons. The results of these studies may identify new therapeutic strategies for the treatment of Parkinson's disease.

描述（由申请人提供）：