Parkinsonism Without Dopamine Neuron Degeneration in Aged L-Dopa-Responsive Dystonia Knockin Mice

• Type of Material: Article
• Authors: Samuel J. Rose, Emory University; Porter Harrast, Emory University; Christine Donsante, Emory University; Xueliang Fan, Emory University; Valerie Joers, Emory University; MariadeLourdes Tansey, Emory University; Hyder Jinnah, Emory University; Ellen Hess, Emory University
• Language: English
• Date: 2017-12-01
• Publisher: Wiley
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2017 International Parkinson and Movement Disorder Society
• Final Published Version (URL): http://dx.doi.org/10.1002/mds.27169
• Title of Journal or Parent Work: Movement Disorders
• ISSN: 0885-3185
• Volume: 32
• Issue: 12
• Start Page: 1694
• End Page: 1700
• Grant/Funding Information: This work was supported by the United States National Institute of Health (NS059645, NS088528) and the Pediatric Neurotransmitter Disease Association.
• Keywords: Clinical Neurology; Parkinson's disease; basal ganglia; dopamine; Neurosciences & Neurology; Life Sciences & Biomedicine; dystonia; Science & Technology; tyrosine hydroxylase
• Research Categories: Health Sciences, Pharmacology; Biology, Neuroscience

Abstract

Background: Recent neuroimaging studies implicate nigrostriatal degeneration as a critical factor in producing late-onset parkinsonism in patients with l-dopa-responsive dystonia-causing mutations. However, postmortem anatomical studies do not reveal neurodegeneration in l-dopa-responsive dystonia patients. These contrasting findings make it unclear how parkinsonism develops in l-dopa-responsive dystonia mutation carriers. Methods: We prospectively assessed motor dysfunction, responses to dopaminergic challenge, and dopamine neuron degeneration with aging in a validated knockin mouse model bearing a l-dopa-responsive dystonia-causing mutation found in humans. Results: As l-dopa-responsive dystonia mice aged, dystonic movements waned while locomotor activity decreased and initiation of movements slowed. Despite the age-related reduction in movement, there was no evidence for degeneration of midbrain dopamine neurons. Presynaptically mediated dopaminergic responses did not change with age in l-dopa-responsive dystonia mice, but responses to D1 dopamine receptor agonists decreased with age. Conclusions: We have demonstrated for the first time the co-occurrence of dystonia and Parkinson's-like features (mainly consisting of hypokinesia) in a genetic mouse model. In this model we show that these features evolve without dopaminergic neurodegeneration, suggesting that postsynaptic plasticity, rather than presynaptic degeneration, may contribute to the development of parkinsonism in patients with l-dopa-responsive dystonia. © 2017 International Parkinson and Movement Disorder Society.