Frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) are two severely disabling and fatal neurodegenerative disorders for which no effective treatment is currently available. Both disorders constitute the two extremes of a neurodegenerative disease continuum in which the large majority of patients present TDP-43 pathology in affected brain and spinal cord regions, independent of the genetic cause. Unfortunately, there is a current paucity of knowledge concerning the presymptomatic disease etiology and how the respective genetic alterations converge into a common pathophysiological disease phenotype with age. It is therefore imperative to improve our mechanistic appreciation of the closely related TDP-43 proteinopathies. The primary aim of this project is to contribute to the elucidation of the molecular processes underlying this convergence. We will pursue this goal by obtaining a comprehensive and longitudinal appreciation of the quantitative post-genomic consequences of genetic alterations underlying the FTD-ALS disease spectrum with TDP-43 pathology. We will apply novel disease-relevant mouse models using a coherent and synergistic combination of state-of-the-art proteomic and transcriptomic technologies. Using combined analyses of different tissues at different ages, we intend to unravel the disease signature already at presymptomatic stages. Understanding the molecular 'architecture' of central signaling events, at a high-dimensionality level and at early stages in disease, will create a pioneering platform for improved biomarker discovery, a more accurate clinical diagnosis, and development of prophylactic and therapeutic agents in the future.