Abstract
Parkinson’s disease is characterized by motor and nonmotor symptoms that gradually appear as a consequence of the selective loss of dopaminergic neurons in the substantia nigra pars compacta. Currently, no treatment can slow Parkinson’s disease progression. Inasmuch, there is a need to develop animal models that can be used to understand the pathophysiological mechanisms underlying dopaminergic neuron death. The initial goal of this study was to determine if canine adenovirus type 2 (CAV-2) vectors are effective gene transfer tools in the monkey brain. A second objective was to explore the possibility of developing a large nonhuman primate that expresses one of the most common genetic mutations causing Parkinson’s disease. Our studies demonstrate the neuronal tropism, retrograde transport, biodistribution, and efficacy of CAV-2 vectors expressing GFP and leucine-rich repeat kinase 2 (LRRK2G2019S) in the Macaca fascicularis brain. Our data also suggest that following optimization CAV-2-mediated LRRK2G2019S expression could help us model the neurodegenerative processes of this genetic subtype of Parkinson’s disease in monkeys.
Highlights
Parkinson’s disease is a complex neurodegenerative disorder clinically characterized by a triad of motor symptoms, including tremor, rigidity, and bradykinesia (Poewe et al, 2017)
Similar to the results found in other species, we demonstrated here that canine adenovirus type 2 (CAV-2) preferentially infects neurons and is transported to efferent sites when injected into the
The mean age of PD onset for LRRK2G2019S mutation carriers is 57.5 years (Healy et al, 2008), which is similar to the age of onset of idiopathic PD, and suggest that age-related factors can play a role in the genesis of symptoms in these patients
Summary
Parkinson’s disease is a complex neurodegenerative disorder clinically characterized by a triad of motor symptoms, including tremor, rigidity, and bradykinesia (Poewe et al, 2017). 9 million individuals are directly affected by Parkinson’s disease, making it the second most prevalent neurodegenerative disease among the elderly. The etiology and pathogenic mechanisms of Parkinson’s disease remain poorly understood with only a small proportion having an identifiable monogenic cause (with an overall prevalence lower than 5%; Poewe et al, 2017). Autosomal dominant mutations in PARK8, the gene coding for leucine-rich repeat kinase 2 (LRRK2), are the most common cause of familial Parkinson’s disease (Paisán-Ruíz et al, 2004; Zimprich et al, 2004). LRRK2 is expressed in brain areas receiving dopaminergic innervation, such as the striatum, hippocampus, cortex, and cerebellum, while lower levels have
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