Jared Sterneckert Group
iPS Cells and Neurodegenerative Diseases
© CRTD
Industrialized nations face a formidable health threat: a rapid increase in patients suffering from neurodegenerative diseases. Among them, amyotrophic lateral sclerosis (ALS) is particularly devastating because patients suffer progressive paralysis and death due to the loss of motor neurons (MNs). Two hallmarks of ALS pathology are (1) degeneration tends to start at the distal axon and, subsequently, progress back to the soma (referred to as “dying-back”), and (2) MNs in ALS patients are often marked by cytoplasmic protein aggregates. Disease symptoms are so devastating that a fascinating observation is often obscured: in the absence of ALS, MN axons are highly regenerative – including in mammals! Interestingly, similar observations have been made about dopaminergic neuron axons in Parkinson’s disease, suggesting that regeneration plays a critical, but unappreciated, role in neurodegenerative diseases. We argue that this is very important because it suggests that neuronal function in patients can, indeed, be regenerated. Our group uses human induced pluripotent stem (iPS) cells to understand how neurodegenerative diseases disrupt axon regenerative capacity. In addition, we seek to develop new strategies to protect neurons and promote renewal using therapeutic interventions such as antisense oligonucleotides, bait RNAs, and small molecules.
Future Projects and Goals
- Understanding the role of membraneless compartments in axon regeneration and how neurodegenerative diseases alter these compartments, thereby disrupting their function and seeding protein aggregation
- Understanding the role of the immune system in regulating axon regeneration, and how this is disrupted by disease pathology
- Identifying therapeutic strategies (e.g., antisense oligonucleotides, bait RNAs, or small molecules) to promote axon regeneration
Methodological and Technical Expertise
- Reprogramming to generate iPSC lines
- Directed differentiation of iPSCs
- Gene editing
- Imaging, including live-cell imaging and FRAP
- Virus-mediated gene expression/knockdown
- Small molecule screening