The ubiquitin-selective ATPase p97 is involved in proteasomal as well as lysosomal protein degradation pathways and thus a central element of eukaryotic proteostasis. Mutations in the human VCP gene encoding p97 are causative of two fatal protein aggregation diseases, Inclusion Body Myopathy with Paget´s disease of the bone and Fronto-temporal Dementia (IBMPFD) and familial Amyotrophic Lateral Sclerosis (fALS). However, the pathogenic consequences caused by mutational impairment of p97 are still poorly understood. This project is therefore focused on the identification of disease-relevant p97 cofactors, substrate proteins and cellular functions. To that end, we will employ different proteomic strategies and microscopy-based RNAi screens on a high content imaging platform.