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Transgenic rodent models of Parkinson's disease.

ABSTRACT: 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.

SUBMITTER: Harvey BK

PROVIDER: S-EPMC2613245 | biostudies-literature | 2008

REPOSITORIES: biostudies-literature

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Transgenic rodent models of Parkinson's disease.

Harvey B K BK Wang Y Y Hoffer B J BJ

Acta neurochirurgica. Supplement 20080101

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 ...[more]

PMID: 18642640

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Project description:Compelling evidence suggests that inhibition of the complex I of the electron transport chain and elevated oxidative stress are the earliest events during the pathogenesis of Parkinson's disease (PD). Therefore, anti-oxidants, especially those from natural sources, hold good promise in treating PD as demonstrated mostly by the studies in rodent models.Herein, we determined if polydatin (piceid), a natural polyphenol, could exert anti-oxidative activity and attenuate dopaminergic neurodegeneration in three commonly used rodent models of PD. Male Sprague Dawley rats given rotenone subcutaneously for 5 weeks developed all the essential features of PD, including a strong increase in catalepsy score and a decrease in motor coordination activity, starting at 4 weeks. Selective increase in oxidative damage was found in the striatal region as compared to the hippocampus and cortex, accompanied by massive degeneration of dopaminergic neurons in the substantia nigra (SNc). Co-administration of piceid orally was able to attenuate rotenone-induced motor defects in a dose dependent manner, with 80 mg/kg dosage showing even better effect than L-levodopa (L-dopa). Piceid treatment significantly prevented the rotenone-induced changes in the levels of glutathione, thioredoxin, ATP, malondialdehyde (MDA) and the manganese superoxide dismutases (SOD) in striatum. Furthermore, piceid treatment rescued rotenone-induced dopaminergic neurodegeneration in the SNc region. Similar protective effect of piceid was also observed in two additional models of PD, MPTP in mice and 6-OHDA in rats, showing corrected motor functions, SOD and MDA activities as well as p-Akt and activated caspase-3 levels.In three rodent models of PD, piceid preserves and corrects several major anti-oxidant pathways/parameters selectively in the affected SNc region. This implies its potent anti-oxidant activity as one major underscoring mechanism for protecting the vulnerable SNc neurodegeneration in these models. Taken together, these findings strongly suggest a therapeutic potential of piceid in treating PD.

Project description:Parkinson's disease (PD) is a chronic, progressive movement disorder of adults and the second most common neurodegenerative disease after Alzheimer's disease. Neuropathologic diagnosis of PD requires moderate-to-marked neuronal loss in the ventrolateral substantia nigra pars compacta and ?-synuclein (?S) Lewy body pathology. Nigrostriatal dopaminergic neurodegeneration correlates with the Parkinsonian motor features, but involvement of other peripheral and central nervous system regions leads to a wide range of non-motor features. Nigrostriatal dopaminergic neurodegeneration is shared with other parkinsonian disorders, including some genetic forms of parkinsonism, but many of these disorders do not have Lewy bodies. An ideal animal model for PD, therefore, should exhibit age-dependent and progressive dopaminergic neurodegeneration, motor dysfunction, and abnormal ?S pathology. Rodent models of PD using genetic or toxin based strategies have been widely used in the past several decades to investigate the pathogenesis and therapeutics of PD, but few recapitulate all the major clinical and pathologic features of PD. It is likely that new strategies or better understanding of fundamental disease processes may facilitate development of better animal models. In this review, we highlight progress in generating rodent models of PD based on impairments of four major cellular functions: mitochondrial oxidative phosphorylation, autophagy-lysosomal metabolism, ubiquitin-proteasome protein degradation, and endoplasmic reticulum stress/unfolded protein response. We attempt to evaluate how impairment of these major cellular systems contribute to PD and how they can be exploited in rodent models. In addition, we review recent cell biological studies suggesting a link between ?S aggregation and impairment of nuclear membrane integrity, as observed during cellular models of apoptosis. We also briefly discuss the role of incompetent phagocytic clearance and how this may be a factor to consider in developing new rodent models of PD.

Project description:Alzheimer's disease (AD), the most common tauopathy, is an age-dependent, progressive neurodegenerative disease. Epidemiological studies implicate the role of genetic background in the onset and progression of AD. Despite mutations in familial AD, several risk factors have been implicated in sporadic AD, of which the onset is unknown. In AD, there is a sequential and hierarchical spread of tau pathology to other brain areas. Studies have strived to understand the factors that influence this characteristic spread. Using transgenic rat models with different genetic backgrounds, we reported that the genetic background may influence the manifestation of neurofibrillary pathology. In this study we investigated whether genetic background has an influence in the spread of tau pathology, using hippocampal inoculations of insoluble tau from AD brains in rodent models of tauopathy with either a spontaneously hypertensive (SHR72) or Wistar-Kyoto (WKY72) genetic background. We observed that insoluble tau from human AD induced AT8-positive neurofibrillary structures in the hippocampus of both lines. However, there was no significant difference in the amount of neurofibrillary structures, but the extent of spread was prominent in the W72 line. On the other hand, we observed significantly higher levels of AT8-positive structures in the parietal and frontal cortical areas in W72 when compared to SHR72. Interestingly, we also observed that the microglia in these brain areas in W72 were predominantly phagocytic in morphology (62.4% in parietal and 47.3% in frontal), while in SHR72 the microglia were either reactive or ramified (67.2% in parietal and 84.7% in frontal). The microglia in the hippocampus and occipital cortex in both lines were reactive or ramified structures. Factors such as gender or age are not responsible for the differences observed in these animals. Put together, our results, for the first time, show that the immune response modulating genetic variability is one of the factors that influences the propagation of tau neurofibrillary pathology.

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Transgenic rodent models of Parkinson's disease.

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Transgenic rodent models of Parkinson's disease.

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