Neuro-glial crosstalk during ferroptosis

• Applicant: Dr. Marcus Conrad
• Subject Area: Cell Biology ; Biochemistry
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 461385412

Ferroptosis is a pervasive form of regulated necrotic cell death tiggered by uncontrolled lipid peroxidation and has recently been implicated as a root cause of several neurodegenerative diseases (NDs). NDs encompass a variety of human disorders characterized by the early and progressive loss of neurons in the central or peripheral nervous system. With steadily increasing life expectancy, age-related NDs such as Alzheimer’s disease (AD) are becoming increasingly common worldwide. Despite the serious health problems for patients suffering from NDs, there is still no curative treatment available to date. Spatiotemporal deletion of the key ferroptosis regulator, glutathione peroxidase 4 (Gpx4), in mouse cortical neurons results in widespread loss of neurons accompanied by massive neuroinflammation through infiltration of innate and adaptive immune cells and progressive cognitive decline. These preliminary findings reveal considerable similarities with human neuropathology, and further corroborate the notion that ferroptosis may be the underlying cause of neuronal cell death, even in the absence of any known genetic susceptibilities in the GPX4 gene in AD. Since a recently identified homozygous missense variant in the GPX4 gene causes the ultrarare disease Sedaghatian-type spondylometaphyseal dysplasia (SMDS), which is characterised by neurodegeneration, the investigation of the molecular determinants and complex networks underlying the still unexplored pathophysiological consequences of ferroptosis is of utmost interest. To further elucidate the factors that are the consequences of neuronal ferroptosis and potentially involved in the manifestation of neurodegeneration, we aim to identify and validate single cell transcriptomic and comprehensive (epi)lipidome signatures, triggered by neuronal ferroptosis and associated pathological changes in the brain, with a particular focus on the neuron-glial axis. Since children affected by SMDS exhibit neurological symptoms reminiscent of progressive cortical atrophy seen in adult-onset AD patients, we will develop a novel mouse model that recapitulates SMDS as a viable tool to study genotype-phenotype correlations in GPX4 neuroprotection on a mechanistic level. Last, we aim to provide an in vivo proof-of-concept for a novel therapeutic approach for yet-untreatable neurodegenerative diseases.

• DFG Programme: Priority Programmes
• Subproject of: SPP 2306: Ferroptosis: from Molecular Basics to Clinical Applications