Neurodegeneration occurring in many pathologies such as Parkinson’s disease (PD), Alzheimer’s disease (AD), and other dementias is a severe health burden with major impact on patients, relatives and societies. It affects millions of people in the world, but treatment options are insufficient and mainly address symptoms underlining the urgent need for new effective therapies to halt and counteract neuronal loss. Due to several failures, research for a cure in neurodegenerative diseases has decreased, however, and new anti-neurodegenerative mechanisms are needed. Although neurodegenerative diseases arise from different underlying causes like misfolded amyloid proteins in AD and α-synuclein in PD, their pathomechanisms overlap suggesting that new interventions against neurodegeneration rather than the individual diseases can be developed. For example, neuroinflammation, dysfunctional energy supply and protein degradation processes as well as insufficient regeneration occur in multiple neurodegenerative pathologies. NeuRoPROBE aims to validate new molecular targets for novel therapeutic approaches in neurodegeneration. It focuses on the ligand-sensing transcription factors nuclear receptor-related 1 (Nurr1) and tailless homologue (TLX) which appear to have critical roles in neuronal health, but their pharmacological control and target validation have not been established. Nurr1is found in (mainly dopaminergic) neurons where it seems to have a protective and anti-neuroinflammatory role. Reduced Nurr1 expression/activity has been observed in neurodegenerative diseases including AD and PD patients and preclinical animal studies support great therapeutic potential. TLX is almost exclusively expressed in neural stem cells (NSCs) and appears to be responsible for maintaining NSCs proliferation to enable neurogenesis. Observations from patients and animal studies point to critical roles of TLX in learning, cognitive function and mental health. Therapeutic modulation of the transcription factors Nurr1 and TLX may thus evolve as a very attractive novel strategy to counteract neurodegeneration but pharmacological control of their activity and hence target validation for therapeutic approaches is hindered by the lack of potent and selective synthetic modulators. NeuRoPROBE aims to close this gap by developing high-quality chemical toolboxes and applying them in phenotypic models of neurodegeneration to study pharmacological control of Nurr1 and TLX.
