Abstract
Recent failures in clinical trials for disease modification in Parkinson’s disease have highlighted the need for a non-human primate model of the synucleinopathy underpinning dopaminergic neuron degeneration. The present study was defined to begin the development of such a model in cynomolgus macaque. We have validated surgical and vector parameters to define a means to provide a robust over-expression of alpha-synuclein which is associated with Lewy-like pathology and robust degeneration of the nigrostriatal pathway. Thus, an AAV1/2 vector incorporating strong transcription and transduction regulatory elements was used to deliver the gene for the human A53T mutation of alpha-synuclein. When injected into 4 sites within each substantia nigra (7 μl per site, 1.7 x 1012 gp/ml), this vector provided expression lasting at least 4 months, and a 50% loss of nigral dopaminergic neurons and a 60% reduction in striatal dopamine. Further studies will be required to develop this methodology into a validated model of value as a drug development platform.
Highlights
Evidence continues to support that Parkinson’s disease (PD) is an alpha-synucleinopathy [1,2,3]
The current studies were designed to assess the potential for AAV1/2 to overexpress human A53T aSyn, and drive neurodegeneration, within the nigrostriatal tract of cynomolgus macaques as measured 17 weeks following surgical delivery
We show that AAV1/2 with chicken beta actin (CBA)/CMV promoters and transduction regulation provides sustained transgene expression over this period of doi:10.1371/journal.pone.0167235.g003
Summary
Evidence continues to support that Parkinson’s disease (PD) is an alpha-synucleinopathy [1,2,3]. Irrespective of etiology and varying upstream mechanisms, deposition of alpha-synuclein (aSyn) is a defining pathological feature of PD and is increasingly being understood to be involved in synaptic dysfunction [4,5,6] and axonal transport deficits [7, 8] and produces ER-Golgi stress [9, 10], to name a few key cell biological processes. Accumulation of aSyn has been found upon postmortem examination in the olfactory bulb, amygdala, nucleus basalis, substantia nigra, locus coeruleus, dorsal motor nucleus of vagus and the cerebral cortex [11, PLOS ONE | DOI:10.1371/journal.pone.0167235. Development of an AAV Alpha Synuclein Macaque Model of Parkinson’s Disease design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the ’author contributions’ section
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