- Objectives: To date, most studies of Shc family proteins have focused on the near-ubiquitously expressed ShcA. The role of the neuron-specific Shc proteins, ShcB and ShcC, is only beginning to be defined. In our work, we have emphasised study of Shc expression in normal brain and in response to stress, analysing the interactions of ShcC with signalling proteins/pathways, and the possible implications of these interactions for brain pathology, neuroprotection, and changes associated with ageing. Methodology: Analysis of current knowledge of Shc proteins in brain, including data obtained in our laboratories. Results: Expression of Shc proteins in the mammalian brain is tightly regulated. The factors responsible for transcribing or repressing the genes encoding the Shc proteins are still unclear. Shc expression undergoes dramatic and differential changes during development, remains relatively stable in adulthood, but is apparently affected with ageing. The mature brain expresses almost exclusively ShcC and ShcB. The induction of the p64ShcC anti-apoptotic ShcC isoform following stress is attenuated in advanced age, and this may contribute to an increased vulnerability of the ageing brain. The appearance of ShcA in the adult CNS is generally associated with pathological processes, including trauma, neurodegeneration, and brain tumours. In some cases, re-expression of ShcA may reflect a neuroregenerative response. In other cases, uncontrolled ShcA expression may activate cell proliferation, promoting tumourigenesis. Indeed, in all cases of highly aggressive astrocytomas, we observed a high level of ShcA protein, with the level of ShcA correlating with tumour grade. In low-grade astrocytomas, ShcC and ShcA were concurrently expressed. At present, it is unclear whether these observations reflect causal or correlative relationships. We also discuss a possible role for Shc proteins in Alzheimer's disease. Conclusions: The isoforms of the Shc proteins have differential functions in normal brain and may be involved in brain pathology. Thus, they may represent specific targets for pharmacological interventions. Modulation of the level and activity of Shc protein in brain offers the potential for neuroprotection.