Project: Genomic Instability in Alzheimer’s Disease and Related Disorders: a Single-Cell Approach

Acronym	INSTALZ (Reference Number: 143)
Duration	01/10/2015 - 30/09/2019
Project Topic	The general objective of this proposal is to study the role of neuronal genomic instability in the pathogenesis of Alzheimer’s disease (AD) and related primary Tauopathies in order to provide significant insights and better diagnostic, preventive and therapeutic strategies. The proposal builds on preliminary findings highlighting a novel and direct role for Tau in genome stability and suggesting that somatic genomic variation acts as a causal player in neuropathology. The proposal is subdivided into four specific research objectives: (1) Determine the nature and extent of genomic and transcriptomic instability in human AD and primary Tauopathy brains; (2) Identify mosaic causal mutations in human AD and primary Tauopathy brains; (3) Study the role of Tau protein/pathology in DNA/RNA protection and damage; (4) Study the role of Tau protein/pathology in mitotic chromosomal instability. A multidisciplinary consortium that will use single-cell genome and transcriptome sequencing in human brain tissue as well as experimental Tauopathy-relevant models including mice and Drosophila will achieve these objectives. The project is particularly ambitious at the technological level as it plans to implement highly powerful and novel next-generation sequencing methodologies to single cells which is needed to address the groundbreaking objectives stated above. This proposal addresses the call “Genetic, epigenetic and environmental risk and protective factors for neurodegenerative diseases” and tackles the highly prevalent age-related brain diseases AD and related disorders characterized by Tau pathology. It aims at understanding how altered stability of the neuronal genome in the developing and adult brain determines the risk to develop these chronic disorders in late-adulthood. The expected impact is to genetically explain the pathogenesis of a consistent part of sporadic AD cases, for which no pathogenic cause is known yet and to decipher underlying molecular mechanisms that will lead to new early therapeutic tools.
Network	JPco-fuND
Call	Neurodegenerative diseases: risk and protective factors, longitudinal cohort approaches and advanced experimental models

Project partner

Number	Name	Role	Country
1	Université de Lille 2	Coordinator	France
2	Inserm	Partner	France
3	Sanger Institute	Partner	United Kingdom
4	KU Leuven	Partner	Belgium
5	Copenhagen University	Partner	Denmark
6	The Royal Institute of Technology	Partner	Sweden