Genetic variability commonly affecting neurodegeneration and neuroinflammation

Abstract

Loss of nerve cells and axons is a common feature of common complex neurodegenerative disorders, such as Alzheimer’s and Parkinson’s diseases. However, also Multiple Sclerosis (MS), primarily an autoimmune disorder, has a prominent neurodegenerative component. In complex disorders, many components affecting disease development and disease progression in combination make up the overall risk. In general, we divide these factors into inherited genetic factors and environmental factors. In addition, there are sometimes complex gene-environment interactions that make it difficult to identify individual risk components.

In this thesis, I have focused on a translational approach to find genetic determinants of nerve cell survival in a simplified experimental model of nerve injury-induced neurodegeneration. The aim has been to find novel genes/pathways whose relevance subsequently can be tested in human disease. Through various genetic mapping approaches I demonstrate a strong inverse correlation between neuronal survival and expression and protein levels of an enzyme involved in detoxification of certain oxidation by-products. This enzyme, Glutathione S-Transferase alpha 4 (Gsta4), is highly efficient in catalysing the reduction of the neurotoxic aldehyde 4-hydroxynonenal (HNE), which is generated during lipid peroxidation and has previously been implicated in the pathogenesis of various neurodegenerative disorders.

The relevance of this mechanism was also tested in a model of traumatic brain injury, where Gsta4 levels inversely correlate with degree of neuronal loss as well. In addition, rats with higher Gsta4 levels have a more favourable outcome after injection of HNE directly into the cortex. Taken together, these two studies provide strong support for the notion that the identified pathway is highly important for ability to cope with oxidative stress and in turn of relevance for nerve cell survival in different types of acute injury.

Finally, a possible role for Gsta4 is tested in experimental autoimmune encephalomyelitis (EAE), a model of MS. No discernible clinical effect was observed between congenic rats with higher Gsta4 expression and the parental strain. However, lower Gsta4 expression was associated with a stronger autoantibody response. Protein modifications by HNE have in other inflammatory models been documented to induce a stronger antibody response, which is consistent with the obtained results. Intrathecal antibody production is an important diagnostic marker in MS, and hypothetically the HNE pathway can play a role for disease course through both neurotoxicity and amplification of the immune response. This was tested in a large case control cohort of MS, where suggested associations both to clinical and immune phenotypes were found. In summary, the results presented encourage further studies on the Gsta4-HNE pathway both in conditions of acute nerve injury and autoimmune neuroinflammation.