Figure 1  Knock-down of endogenous α-syn in midbrain dopamine neurons reproduces a PD-like pattern of nigrostriatal degeneration. rAAV- α-syn-shRNA treatment produces exaggerated degeneration of ventral tier substantia nigra (vtSN) dopamine neurons and denervation of the putamen (Pt) that exceeds that in the caudate (Cd), reproducing the pattern of degeneration observed in Parkinson's disease [A,B,E,G,H, transduced hemisphere on right side of micrographs, staining for tyrosine hydroxylase (TH)]. This pattern is not observed with rAAV-scr-shRNA treatment (C,D,F,I,J, arrows in (J) indicate injection site). Dorsal tier substantia nigra (dtSN) neurons surviving α-syn-shRNA treatment (white asterisk in H) were transduced by the vector, but resistant to degeneration (K, brown stain for GFP vector tag). While rAAV- α-syn-shRNA of both High and Low titers produced equivalent loss of TH+ vtSN neurons, greater numbers of neuromelanin-positive neurons surviving in this region following Low titer treatment (M) indicates phenotype suppression with cell survival, and the low number of these cells in the High titer treatment (L) suggests greater overt cell loss [black asterisk in (H) indicates vtSN region shown in (L) and equivalent region in (M) with greater (Low shRNA titer M) and lesser (High titer in L) numbers of surviving neuromelanin neurons (brown pigment)]. Abbreviations: Cd, caudate nucleus; Pt, putamen; ic, internal capsule; dtSN, dorsal tier substantia nigra; vtSN, ventral tier substantia nigra; Calibration bar in (A) = 100 μm and applies to (A–F); bar in (G) = 500 μm and applies to (G–J); bar in (M) = 100 μm and applies to (K–L).