Daryl A. Bosco, Ph.D. is an Associate Professor in the Neurology Department and holds a joint appointment in the Biochemistry and Molecular Pharmacology Department at the University of Massachusetts Medical School (UMMS) in Worcester, MA, USA. Dr. Bosco received her doctorate in Bio-organic Chemistry from Brandeis University in Waltham Massachusetts, where she used NMR spectroscopy to study enzyme dynamics. She was then a post-doctoral fellow at the Scripps Research Institute in La Jolla California, where she studied the effect of oxidative cholesterol metabolites on the misfolding and aggregation of alpha-synuclein, a Parkinson’s disease-associated protein. Prior to joining the faculty at UMMS, Dr. Bosco was an Instructor of Neurology at Harvard Medical School and a Visiting Scholar at Brandeis University, where she worked on various aspects of amyotrophic lateral sclerosis (ALS).
The goals of Dr. Bosco’s current research program are to identify the pathogenic mechanisms underlying neurodegenerative diseases, namely ALS and frontotemporal dementia (FTD). The Bosco laboratory has a longstanding interest in studying how stress contributes to neurodegeneration, particularly in the context of stress granules and protein-misfolding. Recently, the laboratory has started investigating disease-relevant phenotypes within both motor neurons and microglia derived from human induced pluripotent stem cells harboring various disease-linked mutations. In addition to cell culture systems, the Bosco laboratory uses a multidisciplinary approach that also includes protein biochemistry, biophysics, human and mouse models for their investigations.
Vital cellular processes are impaired in ALS motor neurons and microglia derived from human iPS cells
Human induced pluripotent stem cells (iPSCs) have emerged as a valuable system for modeling human disease, particularly for disorders such as amyotrophic lateral sclerosis (ALS) that can be caused by distinct genetic mutations. Advantages of iPSC models include the ability to differentiate human cells into disease-relevant cell types, and to study mutant proteins at endogenous levels. Our research has focused on understanding the pathogenic mechanisms underlying ALS-linked genes such as FUS and PFN1. FUS is an RNA-binding protein that shuttles between the nucleus and cytoplasm to perform a myriad of RNA processing functions. Here, we will present data demonstrating nuclear pore defects and impaired nucleocytoplasmic transport within neurons derived from iPSCs expressing ALS-FUS. Our data raise the possibility that these nuclear pore-related defects stem from interactions between FUS and a class of nucleoporins referred to as F/G Nups. While motor neurons are the primary cell type that degenerate in ALS, this degeneration occurs in a non-cell autonomous manner, with contributions from other cell types such as microglia. Microglia are the resident immune cells of the CNS that play an important role in maintaining homeostasis. However, this role appears to be compromised in the context of aging and across multiple neurodegenerative disorders including ALS. Intriguingly, profilin-1 (PFN1), an actin binding protein, is expressed at relatively high levels in microglia and has been suggested to be important for the phagocytic function of these cells. Here, we show that our iPSC-derived microglia-like cells express microglia signature genes, respond to lipopolysaccharide stimulation and phagocytose mouse-brain synaptosomes. Our data indicate that expression of ALS-PFN1 represses normal microglia function, similar to what is observed in microglia from the aged brain. Studies are underway to further elucidate how these disease-relevant phenotypes arise, and to identify factors that can modulate or rescue these adverse effects.