Abstract
Parkinson disease (PD) is a common and disabling disorder. No current therapy can slow or reverse disease progression. An important aspect of research in this field is target validation, a systematic approach to evaluating the likelihood that modification of a certain molecule, mechanism or biological pathway may be useful for the development of pharmacological or molecular treatments for the disease. TorsinA, a member of the AAA+ family of chaperone proteins, has been proposed as a potential target of neuroprotective therapy. TorsinA is found in Lewy bodies in human PD, and can suppress toxicity in cellular and invertebrate models of PD. Here, we evaluated the neuroprotective properties of torsinA in mouse models of PD based on intoxication with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) as well as recombinant adeno associated virus (rAAV) induced overexpression of alpha-synuclein (α-syn). Using either transgenic mice with overexpression of human torsinA (hWT mice) or mice in which torsinA expression was induced using an rAAV vector, we found no evidence for protection against acute MPTP intoxication. Similarly, genetic deletion of the endogenous mouse gene for torsinA (Dyt1) using an rAAV delivered Cre recombinase did not enhance the vulnerability of dopaminergic neurons to MPTP. Overexpression of α-syn using rAAV in the mouse substantia nigra lead to a loss of TH positive neurons six months after administration, and no difference in the degree of loss was observed between transgenic animals expressing forms of torsinA and wild type controls. Collectively, we did not observe evidence for a protective effect of torsinA in the mouse models we examined. Each of these models has limitations, and there is no single model with established predictive value with respect to the human disease. Nevertheless, these data do seem to support the view that torsinA is unlikely to be successfully translated as a target of therapy for human PD.
Highlights
Parkinson disease (PD) is a progressive neurodegenerative disease which causes a movement disorder characterized by bradykinesia, resting tremor, rigidity, and postural instability along with non-motor features which include autonomic dysfunction and cognitive impairment
One month after virus injection, the mice were treated with MPTP, using 4 doses of the toxin administered in a single day
In this study we evaluated the effects of the protein torsinA in several mouse models of PD, based either on intoxication with MPTP or overexpression of alpha-synuclein induced by an recombinant adeno associated virus (rAAV)
Summary
Parkinson disease (PD) is a progressive neurodegenerative disease which causes a movement disorder characterized by bradykinesia, resting tremor, rigidity, and postural instability along with non-motor features which include autonomic dysfunction and cognitive impairment. A variety of potential approaches to such ‘‘neuroprotective’’ treatments have been described, but most have not been carefully evaluated in either preclinical models of PD or in human patients [1]. The protein torsinA has been proposed as a potential target of PD therapy, based on evidence from cellular systems, animal models and human postmortem studies. TorsinA was first identified as the cause of a human genetic disorder, DYT1 dystonia [3]. The protein is a member of the AAA+ (ATPases Associated with a variety of cellular Activities) superfamily. Members of this protein family typically form multimeric assemblies, and participate in protein folding and chaperone processes [4,6]. One of the proteins modulated by torsinA, both in vitro and in invertebrate models, is the dopamine transporter (DAT), which is sequestered intracellularly by high levels of torsinA expression [11,12]
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