These studies highlight the importance of postmortem study data and their conclusions. They guide our clinical formulations, and thus our experimental and therapeutic approaches. Finally, studies with DJ-1 are in very early stages. Its distribution has been analyzed in postmortem brain of control and PD subjects in two recent studies. DJ-1

does not colocalize with LBs, but with tau inclusions; it is mainly expressed by astrocytes; and it appears to be sensitive to oxidative stress:11,42 At present, a functional interpretation of these data is lacking. The role of LBs in DA cell death There remains much debate over whether LBs are neuroprotective, constitute Inhibitors,research,lifescience,medical an age-related epiphenomenon, or are cytotoxic; Inhibitors,research,lifescience,medical postmortem end points may supply some answers. Recently, Conway et al43,44 suggested that, accelerated formation of nonfibrillar α-synuclein oligomers is the critical process in PD pathogenesis, ie, LB formation is neuroprotective by sequestering toxic protein species. Once this issue is resolved, Inhibitors,research,lifescience,medical drug therapy can be aimed at promoting the healthy process. Two observations from pathological examination of human brain contribute to this dialogue: SNpc DA neurons containing LB appear to be “healthier” than neighboring neurons,45 whereas

the nigral DA neurons undergoing apoptotic-like cell death do not contain somal LBs. Tompkins and Hill45 suggested that the majority of SNpc neurons die before or without forming LBs and that SNpc neurons that survive the initial pathological insult suffer damage that leads to LB formation. It is not uncommon to observe “incidental” LBs at autopsy of aged asymptomatic individuals. An alternative explanation Inhibitors,research,lifescience,medical for this finding Inhibitors,research,lifescience,medical is

that these individuals have not lived long enough to develop a parkinsonian phenotype. Also, if LBs were protective, one might speculate that controls should have more LBs than PD patients, which is clearly not the case. Alternatively, LBs may occur as an epiphenomenon of the primary pathology and have little or no effect on neuronal viability. In contrast to the observations by Tompkins and Hill,45 Resveratrol Gibb and I .ees46 reported that SNpc neurons with and without somal LBs generally appear to be similarly affected by the disease process. Moreover, cell size and nucleolar size do not differ between LB-positive and LB-negative SNpc neurons.47 Also, dendritic morphological abnormalities found in parkinsonian SNpc arc similar in LB- and non-LB-containing neurons.48 Finally, neurofilament mRNA levels also show a similar level of reduction for both LB- and non-LB-containing neurons.49 We favor the PD184352 cell line hypothesis that the presence of LBs is an indicator of neuronal distress, although it is impossible to deduce from postmortem work whether I ,Bs are, as such, neurotoxic.