Goldsmith Research
233 South 10th Street
BLSB, Room 306
Philadelphia, PA 19107
Autophagy is a highly conserved cellular sorting and recycling system that regulates the clearance of proteins, damaged or unwanted organelles, and protein aggregates in development, homeostasis and following stress. In neurons, autophagy is critical for both function and survival. In aging and in many neurodegenerative diseases, autophagy is delayed or impaired, yet understanding how disrupted autophagy introduces vulnerabilities to neuronal health is still incompletely understood.
Our lab utilizes iPSC-derived neurons and glia to study how the genetic mutations associated with Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) impact autophagy. We apply a range of biochemical and molecular biology techniques, complemented with high-resolution live imaging in cells. Our exploratory research utilizes proteomics to uncover new roles for autophagy in neurons and glia. Learning about the function and regulation of autophagy in neurons and glia will help us to understand the critical molecular and cellular consequences downstream of disrupted autophagy in neurodegenerative disease, illuminating early steps in disease progression and novel biomarkers or therapeutic targets.
Research Projects
Regulation of mitochondrial health and function downstream of disrupted autophagy in ALS/FTD
iPSC-derived lower motor neurons, stained for motor neuron specific markers, neuron specific markers, and autophagosomes
Mutations in UBQLN2 associated with ALS/FTD lead to accumulations of ubiquitinated proteins that clog up the autophagy pathway. In particular, we see an impairment in the basal clearance of mitochondria containing mitochondrial DNA by autophagy. We are using iPSC-derived glutamatergic neurons and lower motor neurons to understand the impact of these disruptions to mitochondrial health and function, as well as the repercussions on neuroinflammation.
Impact of AD associated mutations on autophagy
Many different AD-associated mutations or variants are predicted to impact autophagy. We are investigating how the ApoE4 variant and the PSEN1 mutation associated with AD affects autophagy biogenesis, cargo selection, trafficking and maturation in glutamatergic and GABAergic iPSC-derived neurons.
Understanding autophagy differences and similarities in neurons and glia
iPSC-derived glutamatergic neurons, stained for neuron specific markers and autophagosomes
iPSC-derived cell systems provide a powerful tool to directly compare how autophagy cargo and autophagy regulation differs in different neuron types (excitatory, inhibitory and motor neurons) and glial cell types (microglia and astrocytes). This may have direct therapeutic implications when thinking about how to engage autophagy as a target for the treatment of neurodegenerative disease.