Is There a Role of Nogo-A in the Nigrostriatal System?

Introduction: The myelin associated protein Nogo-A is known to be expressed on the surface of oligodendrocytes and has been described to limit neuronal regeneration and plasticity after injury. More recently, Nogo-A expression was also found in a number of neuronal subpopulations of the adult and developing central nervous system suggesting that Nogo-A serves additional functions in the brain. At present, only little is known about the expression of Nogo-A in the midbrain, a brain structure severely affected in Parkinson disease (PD). For that purpose the present study aimed at characterizing the expression pattern of Nogo-A- immunoreactive (ir) cells in the adult midbrain of control rats and in a 6-hydroxydopamine (6-OHDA) rat model of PD.

Methods: Following unilateral striatal injections of 6-OHDA at 1 week and 1 month, rats were perfusion fixed and the brains were processed for histological analysis.

Results: We found that Nogo-A-ir cells were predominantly distributed in the substantia nigra pars compacta (SNc) and in the ventral tegmental area. Interestingly, a substantial number (about 50%) of tyrosine hydroxylase (TH)-ir neurons in the SN also expressed Nogo-A. Moreover, about 70% of the Nogo-A positive cells coexpressed TH hinting to the idea of a predominant neuronal expression of Nogo-A. In line with this notion, no colocalization was observed for Nogo-A and the astrocytic marker glial fibrillary acidic protein. Our preliminary data revealed that 1 week after 6-OHDA injection, animals displayed a significant loss of dopaminergic neurons as well as Nogo-A-ir cells in the SNc of the lesioned as compared with the unlesioned side (by 40 and 50%, respectively). The number of both TH-ir neurons and Nogo-A-ir cells was observed to be further decreased after 1 month (by 90 and 70%, respectively). Interestingly, by means of double-immunofluorescence staining we detected that this cell loss was predominantly seen in the subpopulation of SNc neurons expressing Nogo-A and TH. Specifically, we found that the percentage of Nogo-A-ir cells also expressing TH was significantly lower both at 1 week (with 40% colocalization) and 1 month after the lesion (with 30% colocalization) as compared with control sides (with 70% colocalizations).

Conclusion: Based on these results we hypothesize that the subpopulation of dopaminergic neurons expressing Nogo-A is particularly vulnerable to the 6-OHDA lesion, which strongly suggests for a function of No-go-A in the nigrostriatal system and that Nogo-A may play a substantial role in PD.