Research Interests
Unraveling the Physiological Pathways Crucial for Neuronal Survival in the Adult Nervous System
The adult nervous system is comprised of a wide array of specialized cells, including different types of neurons, oligodendrocytes, astrocytes, and microglia. The production of these specialized cells is tightly orchestrated both temporally and spatially during development to enable the construction of functional neural circuits. It is striking that while oligodendrocytes, astrocytes, and microglia can be replenished throughout life, there are no bulk mechanisms to repopulate neurons in the nervous system. Thus, the neurons we are born with need to survive for our entire lifetime. The vast majority of neurodegenerative diseases are sporadic and do not have a genetic component. We reason that by understanding the processes by which neurons are kept alive as we age, we may gain deeper insight into how sporadic neurodegenerative diseases arise and, accordingly, inform strategies for therapeutic development and earlier diagnosis.
The molecular handle that has helped us make inroads into this problem are two members of a small family of six-transmembrane proteins called the GDEs. This family has three members (GDE2, GDE3, and GDE6), and they all contain an external enzymatic domain that is homologous to bacterial glycerophosphodiester phosphodiesterases (GDPD). We discovered that GDE2, GDE3, and GDE6 are the only known membrane enzymes in vertebrates that work on the cell surface to cleave the glycosylphosphatidylinositol (GPI)-anchor that tethers some proteins to the plasma membrane [Rao et al., Park et al.]. Cleavage of the GPI-anchor can activate or inhibit GPI-anchored protein function depending on cellular context. We focus on GDE2 and GDE3 as they are expressed in mammalian systems. GDE2 is primarily expressed in neurons and subsets of terminally differentiated oligodendrocytes, while GDE3 is expressed in oligodendrocyte precursor cells and astrocytes.
Our previous work identified important roles for GDE2 and GDE3 in embryonic development. Neuronal GDE2 regulates the generation of different subtypes of neurons in the developing spinal cord and cortex and coordinates oligodendrocyte maturation. GDE3 on the other hand, regulates oligodendrocyte proliferation and is involved in astrocyte-neuronal communications important for synaptic function. Our recent work shows that GDE2 uses mechanisms distinct from its embryonic function to regulate neuronal survival in the adult. Loss of GDE2 recapitulates cellular, molecular, and behavioral changes observed in neurodegenerative diseases such as Alzheimer’s Disease (AD), Amyotrophic Lateral Sclerosis (ALS), and ALS/ Frontotemporal Dementia (FTD). Moreover, GDE2 distribution and function are disrupted in samples from patients with AD, ALS, and ALS/FTD.
Find out more about GDE2 in neurodegeneration: Cave et al., Nakamura et al., Westerhaus et al., Daudelin et al., Zhang et al.
These findings provide us with a unique opportunity to investigate the physiological pathways that, when disrupted, lead to cellular changes known to be causal for neurodegeneration in disease. Click the links below to find out more about current directions in the lab.
