Transgenic rodent models of Parkinson's disease.
In the case of Parkinson's disease (PD), classical animal models have utilized dopaminergic neurotoxins such as 6-hydroxydopamine (6OHDA) and 1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine (MPTP). More recently, human genetic linkage studies have identified several genes in familial forms of PD. Transgenic models have been made that explore the function of PD-linked genes (e.g. alpha-synuclein, DJ-1, LRRK2, Parkin, UCH-L1, PINK1). Recent evidence suggests mitochondrial dysfunction may play a major role in PD. Manipulation of mitochondrial respiratory genes (e.g. mitochondrial transcription factor A or TFAM) also elicits a PD phenotype in mice. Transgenic mice (MitoPark) were developed that have TFAM selectively knocked out in dopaminergic neurons. The nigral dopamine neurons of MitoPark mice show respiratory chain dysfunction, accompanied by the development of intraneuronal inclusions and eventual cell death. In early adulthood, the MitoPark mice show a slowly progressing loss of motor function that accompanies these cellular changes. The MitoPark mouse enables further study of the role of mitochondrial dysfunction in DA neurons as an important mechanism in the development of PD. Transgenic technology has allowed new insights into mechanisms of neurodegeneration for a number of neurological disorders. This paper will summarize recent studies on several transgenic models of PD.
Harvey
B K
BK
Intramural Research Program, National Institute on Drug Abuse, National Institutes of Health, Baltimore 21224, MD, USA.
Wang
Y
Y
Hoffer
B J
BJ
D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics; D004195:Disease Models, Animal; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic / Q000235:genetics*; D024101:Mitochondrial Proteins / Q000235:genetics; D009154:Mutation; D015513:Oncogene Proteins / Q000235:genetics; D010300:Parkinson Disease / Q000209:etiology / Q000235:genetics*; D000071617:Protein Deglycase DJ-1; D011494:Protein Kinases / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D044767:Ubiquitin-Protein Ligases / Q000235:genetics; D000099202:PTEN-Induced Putative Kinase
D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D024101:Mitochondrial Proteins; D015513:Oncogene Proteins; D000071617:Protein Deglycase DJ-1; D011494:Protein Kinases; D014157:Transcription Factors; D044767:Ubiquitin-Protein Ligases; D000099202:PTEN-Induced Putative Kinase; C422562:mitochondrial transcription factor A; C111567:parkin protein; C105131:PARK7 protein, human