Elucidation of the mechanisms by which Ms4a genes regulate neurodegeneration in Alzheimer’s Disease and related disorders - Project Summary/Abstract Current therapeutic interventions for treating neurodegenerative disorders, including Alzheimer’s Disease (AD), frontotemporal dementia (FTD), multiple sclerosis (MS), and Amyotrophic lateral sclerosis (ALS), are highly limited in both number and efficacy, suggesting novel approaches are needed. Historically, most research effort has focused on developing strategies for treating each of these diseases individually, but these endeavors have largely failed in advancing efficacious therapeutics for these debilitating diseases. We have recently generated exciting, unpublished data that offers the promise to overcome this gap in neurodegenerative research. We have found that genetic deletion of one of the members of the membrane spanning 4a (Ms4a) family of genes, Ms4a6c, significantly improves cognitive, behavioral, and cellular phenotypes in mouse models of AD, FTD, ALS, and MS. Moreover, we and others have demonstrated that polymorphisms in Ms4a genes are strongly and reproducibly linked to altered susceptibility to neurodegenerative disorders, including ALS and AD. The genetic link between Ms4a genes and neurodegeneration has been best studied in AD, where current data suggest that as many as 10% of all AD cases worldwide may be explained by polymorphism in Ms4a genes. Together, this research suggests that therapeutic strategies targeting Ms4a genes are likely to be beneficial in treating many neurodegenerative disorders. However, to date we have only examined in detail the effect of deleting a single Ms4a family member on neurodegeneration. Although Ms4a6c deletion results in significant improvement in all phenotypes that we have examined across multiple neurodegenerative disorders, the phenotypic rescue remains incomplete and there is still some evidence of disease in Ms4a6c knockout mice. The Ms4a gene family consists of 17 members, and in addition to Ms4a6c, other Ms4a family members, including Ms4a4a, Ms4a4e, and Ms4a6e have also been strongly genetically linked to altered risk of developing neurodegenerative disorders. In addition, we have found that similarly to Ms4a6c, the expression of many Ms4a genes is upregulated in multiple mouse models of neurodegeneration. Together, these observations suggest that deletion of other Ms4a family members might also improve neurodegenerative phenotypes, and we have generated significant pilot data in support of this hypothesis. Our first aim will therefore take advantage of novel mouse genetic reagents we have generated to enable us to probe the effect of deleting other Ms4a family members individually or deleting multiple Ms4a family members simultaneously on neurodegenerative phenotypes. In our second aim, we will build on considerable pilot data to elucidate the mechanisms by which Ms4a genes regulate neurodegeneration, a process which to date remains entirely unexplored. Together, these aims will provide significant insight into the role that Ms4a genes play across neurodegenerative diseases and take us one significant step closer to developing therapeutic approaches targeting these genes.
