Project Summary/Abstract Age-related neurodegenerative disorders represent a major financial and emotional burden to society, but to date no preventative strategies have been developed. Frontotemporal dementia (FTD) and Amyotrophic lateral sclerosis (ALS) are relentlessly progressive diseases which involve the degeneration of neurons important for behavior and muscle movement, respectively. A hexanucleotide repeat expansion in a non-protein-coding region of the gene C9ORF72 was recently discovered to be the most common cause of FTD and ALS, responsible for 10% of all diagnoses. Two prevailing hypotheses have been suggested to explain how this mutation leads to progressive loss of neurons. The gain of function (GOF) hypothesis proposes that toxic molecules produced from the repeat expansion disrupt neural function and lead to their destruction. The loss of function (LOF) hypothesis proposes that the C9ORF72 protein plays an important role in support of neural function and survival and that reduced expression of this gene directly or indirectly sensitizes neurons to disease. New evidence indicates that the mouse ortholog of C9ORF72 functions in the immune system to limit inflammation and autoimmunity, although the exact mechanisms require further study. The first AIM of this proposal will be to identify pathways and cell types that contribute to inflammation when the C9ORF72 ortholog is reduced and to determine whether induced pluripotent stem cell-derived microglia-like cells from humans with the C9ORF72 repeat expansion display similar inflammatory phenotypes. The second AIM of this proposal seeks to test the validity of the LOF hypothesis in live organisms by injecting virus containing the hexanucleotide repeat expansion into mice that express normal or reduced levels of the C9ORF72 ortholog. If lower levels of the C9ORF72 ortholog sensitize animals to toxic features of the repeat expansion, this would provide support for developing therapies aimed at boosting levels of C9ORF72 or inhibiting pathways affected by its reduction. The candidate will train with experts in diverse fields to develop the technical skills necessary to complete these AIMs and to identify disease relevant pathways which can be pursued in the independent phase of this proposal. Continued training with the candidate’s advisor and expert collaborators will prepare him to succeed in his goal to run an independent research group in which he mentors investigators of all levels and pursues hypotheses aimed at understanding etiologies of neurodegenerative disease.