Using selective autophagy to determine protein aggregation’s contribution to neurodegenerative disease
More than a century has passed since toxic inclusions were first identified in the brains of patients with neurodegenerative diseases, yet the pathogenic contribution of these aggregates is still uncertain. Nonetheless, elucidating the importance of protein accumulation in disease pathogenesis can help establish an essential therapeutic strategy for these incurable disorders. Our work presents a promising strategy to delay disease onset across different neurodegenerative disorders by augmenting the clearance rates of these aggregated proteins. We find that targeting the levels of selective adaptor Autophagy-linked FYVE (Alfy) in vivo leads to enhanced clearance of aggregated proteins, which dramatically prevents the onset of neuropathological and behavioral deficits across mouse models of disease.
Developing novel models of neurodegenerative disease
Fundamental to translational neuroscience is the use of model systems that appropriately capture aspects of human disease. Our work looks critically at the current gaps in neurodegenerative disease models, with a particular focus on Parkinson’s disease. Studies using human genetics and animal models have associated the disease with autophagy and mitochondrial dysfunction, but the precise relationships, and opportunities for treatment, remain incompletely resolved. In the mouse, we are establishing a new model of Parkinson’s disease as well as a way to monitor mitochondrial stability in vivo, with the goal of elucidating disease mechanisms and targets of therapeutic intervention.
Understanding the role of TDP-43 in cognition
By the age of 65, more than 1 out of every 3 people suffer from cognitive impairment due to neurodegenerative disease. There is currently no treatment that targets the underlying causes of pathogenesis. However, the abnormal cytosolic accumulation of TDP-43, an essential DNA/RNA-binding protein, is reported across a broad range of neurological diseases and correlates with the severity of cognitive deficits. Our aim is to elucidate the mechanistic underpinning of this correlation by understanding how TDP-43 impacts synaptic function.
TDP-43 translocation and puncta formation upon crowding. Credit: Risa Kimura
Characterizing the effects of macromolecular crowding on protein aggregation and neurodegeneration
If we could shrink ourselves down to the nanometer scale and be transported into a cell, we would discover an exceptionally large, dynamic crowd with molecules and organelles of various sizes and structures. Within this myriad of cellular constituents, macromolecules like proteins are challenged to locate, assemble, and disassemble with their binding partners at the correct place and time. We are interested in understanding how intracellular crowding affects protein-protein interaction dynamics and how such processes may go awry in neurodegenerative disease.
Medium spiny neurons directly reprogrammed from HD patient fibroblasts. Credit: In collaboration with Andrew Yoo’s group at WashU
Translating our observations from mouse to human
The Yoo Lab from Washington University in St. Louis has developed direct conversion techniques that transform fibroblasts collected from a patient’s skin into medium spiny neurons (MSNs). These neurons retain age and disease associated phenotypes, which is unlike other stem cell models. This retention allows benefit for studying neurodegenerative diseases with late-age onset. In the lab, we use this model to learn how autophagy regulates neurodegeneration in a human system.