The Parkinson's-Reversing Breakthrough

Is There A Cure for Parkinson Disease

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A locus for a rare familial form of PD maps to chromosome 1p36 and is termed PINK1 (phosphatase and tensin homolog induced kinase-1) (187). The function of PINK1 is thought to be in the protection of mitochondria from oxidative stress (188,189). In addition, PINK1 may serve to control interactions with regulatory factors involved in apoptosis (189). Transgenic mice affecting PINK1 have not yet been reported.


Nurr1 is a transcription factor that is highly expressed in early development, and disruption of this gene results in the failure to develop nigrostriatal dopaminergic neurons in postnatal life (190,191). Nurr1 expression decreases with age and in patients with PD, suggesting that this protein may play a role in maintaining dopamine cell function and integrity (192). Transgenic mice disrupting Nurr1 expression show lack of development of nigrostriatal dopaminergic neurons based on tyrosine hydroxylase immunoreactivity (193-197). Although the time course of midbrain dopaminergic cell death in PD is unclear, the Nurr1 transgenic strains may provide insight into understanding dopamine cell development, potential susceptibility to PD in the context of dopamine dysfunction, and elucidation of the role of Nurrl may act to guide stem cells as a therapeutic replacement for lost neurons.

Other Transgenic Mice and Vector Infusion

The function of the basal ganglia is dependent on a wide range of proteins involved in dopamine biosynthesis, metabolism, uptake, and neurotransmission. To elucidate the role of numerous proteins in basal ganglia development, function, dysfunction, and their potential role in PD and its treatments, a wide spectrum of transgenic animals have been developed. These include transgenic mice targeting tyrosine hydrox-ylase, DAT, monoamine oxidase A and B, catechol-O-methyl-transferase (COMT), dopamine receptors, and vesicular monoamine transporter 2 (vmat-2). These mice are instrumental in elucidating the regulation of dopamine neurotransmission and its link to motor behavior. In addition, genes and proteins involved in other features of basal ganglia function or susceptibility to toxicity, but not directly involved in dopamine neurotransmission, have also been developed, including those for neu-rotrophic factors [such as brain-derived neurotrophic factor (BDNF), glial-derived neurotrophic factor (GDNF), and their receptors]; immune response components (IL-6, TNF-alpha); and other neurotransmitter systems, including those for glutamate, adenosine, and acetylcholine. It is important to recognize the importance of these various genetic models and their potential impact in understanding normal and diseased basal ganglia function and identifying new therapeutic treatments.

It should be noted that with the advent of new vector technologies based on infectious viruses, including lentivirus and adenovirus, genes of interest are introduced directly into the brain using stereotaxic targeting. This allows genes to be introduced to adult animals avoiding the potential confounder in transgenic lines where some gene manipulations are embryonic lethal, fail to thrive postnatal, or other systems may compensate in development for a specific gene deficiency. For example, induction of neurodegeneration can be achieved by direct targeting of alpha-synuclein or tau into the midbrain dopaminergic neurons (198-201). Genes beneficial to neuron protection and repair can also be delivered directly to their site of action in the brain. These include those genes encoding neurotrophic factors like GDNF or dopamine biosynthesis (202-206). Targeting to specific regions to regulate basal ganglia function such as inhibition of the subthalamic nucleus has been reported with some success (207). Studies are still underway to evaluate different parameters of delivery, stability, toxicity, and long-term efficacy, as well as evaluation in nonhuman primate models prior to clinical applications. A number of clinical trials using viral vectors are currently in early phase studies.

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