To begin to further characterize the consequences of knockdown of endogenous α-syn and determine whether effects seen in rats were reproducible in a species more closely related to humans, we generated an α-syn shRNA specific for St.Kitts green monkeys (Chlorocebus sabaeus). We injected α-syn shRNA or scrambled shRNA, of two different titers, into the SN of individual monkeys (N = 4 total), waited 3 months, and examined DA neuron numbers, morphology, striatal innervation, and striatal DA content. α-Syn shRNA produced region-specific, titer-related, degeneration of SN tyrosine hydroxylase-positive (TH+) neurons and innervation of the striatum, reproducing the pattern of nigrostriatal degeneration observed in PD: SN degeneration was exaggerated in ventral tier neurons (vtSN; Gibb and Lees, 1991) with relative sparing of adjacent ventral tegmental area (VTA) DA neurons, and loss of TH+ fibers in the putamen (Pt) exceeded denervation of the caudate nucleus (Cd) (Kish et al., 1988; Figure 1). Stereologic quantification of TH+ neurons confirmed the qualitative observations: loss of TH+ neurons was greatest in vtSN with the VTA exhibiting relatively little neuron loss. However, the general pattern of TH+ neuron loss was not different in the High and Low titer α-syn shRNA conditions. These neurons also contain neuromelanin, and when counts of neuromelanin-only positive cells were added to the analysis, titer-related differences emerged. The Low titer shRNA condition was associated with the preservation of significantly more neuromelanin-only neurons, suggesting that while loss of TH+ phenotype was equivalent across titers, overt loss of neurons was greater in the High titer condition. The presence of TH-negative, neuromelanin-positive neurons is suggestive of ongoing pathology, an observation that also is seen in early PD. Importantly, co-localization of green fluorescent protein (GFP) as a marker of viral transduction within surviving midbrain DA neurons confirmed that dorsal SN and VTA neurons were transduced, but showed less degeneration (Figure 1). Titer-related differences in striatal DA depletion also were detected. Deficits in DA in the caudate nucleus and putamen were exaggerated in the α-syn shRNA High titer condition and a significant increase in the homovanillic acid (HVA)/DA ratio was only detected in the High titer subject. Increase in the HVA/DA ratio is known to be associated with a compensatory response to ongoing significant degeneration of DA neurons (Zigmond et al., 1990).