The Molecular Scale Program aims to explore whether targeting specific regulators can simultaneously enhance mitochondrial function and suppress Tau aggregation. It adopts a proteomic approach to map the differential vulnerability of the neuronal proteome to misfolding and aggregation following energy stress or the expression of proteins with familial Alzheimer’s mutations. Additionally, the program seeks to provide the first description of the role of wild-type and pathological Tau in controlling NMDR trafficking in synaptic plasticity, offering a mechanistic basis for Tau-based therapeutic development. By applying machine-learning approaches to Alzheimer’s patient-derived neurons, the program aims to determine the mitochondrial components that drive Alzheimer’s pathogenesis. Furthermore, it will pre-clinically test combination therapies targeting signalling pathways involved in protein aggregation in Alzheimer’s.

Investigator-led Projects:

– Regulators of tau pathology and mitochondrial function induced by tau seeds

– Fundamental principles linking energy homeostasis and protein folding in Alzheimer’s disease

– Physiological and pathological tau in glutamate receptor homeostasis

– Leveraging machine learning to identify mitochondrial molecular drivers in AD

– Combination therapy targeting aggregation and oxidative stress in Alzheimer’s disease

– Investigating mechanisms underpinning the mitochondrial phenotype in Alzheimer’s disease in induced pluripotent stem cell derived neurons and microglia (CI Ooi and CI Zuryn)

– Designed protein binders for analysing mitochondrial disruption and blood-brain barrier adhesion proteins (CI Collins, CI Lazarou, CI Zuryn, CI Götz, CI Iyer, CI Nisbet, AI Kretzmann, Dr. Michael Healy, A/Prof. Julia Pagan)

– The regulation of NMDA receptor synaptic nanodomains and function by the microtubule-associated protein Tau (AI Anggono, CI Götz, AI Padmanabhan)

– Binders to selectively assess how tau structural states impact cellular health and energy metabolism (AI Hatters, CI Nisbet, AI Shepherd, CI Collins)

– Multipronged neurotrophin delivery strategies to restore proteostasis and bioenergetics (CI Götz, AI Kretzmann, AI Killugudi Swaminatha Iyer, AI Padmanabhan, Dr Gerhard Leinenga, Julia Brandt, Godfrey Njkajja)

– Investigating neuronal and glial mitochondrial dysfunction in tauopathies (CI Nisbet, AI Hatters, CI Lazarou, CI Ooi)

 EMCR-led Projects

– Neuronal survival signalling in energy-stressed brain cells: A path to drug discovery (Dr. Jacinta Conroy, Dr. Michael Healy)

– Functionalisation of a JAM1 nanobody (Dr. Michael Healy, Dr. Liyu Chen)