Dr. Mable Lam is a postdoctoral fellow in the laboratory of Dr. Brad Zuchero in the Department of Neurosurgery. She received her PhD from UCSF, where she investigated the cell biology and biochemistry of membrane trafficking in the laboratory of Dr. Peter Walter. These studies motivated her current research to identify membrane trafficking pathways for the formation of myelin, an insulating membrane sheath around axons that accelerates conduction velocity. In the future, she plans to elucidate cellular pathways that drive myelin remodeling during neuroplasticity and myelin regeneration in the context of demyelinating diseases.
Brad Zuchero, Postdoctoral Faculty Sponsor
Current Research and Scholarly Interests
Myelin is required for rapid nerve signaling by insulating axons to accelerate action potential propagation. Myelin-forming cells of the central nervous system, called oligodendrocytes, orchestrate one of the most complex morphological transformations in neurobiology. Each oligodendrocyte can extend multiple processes that selectively wrap axons in tens to hundreds of spiraling membrane layers, forming myelin sheaths that vary in thickness and length. Furthermore, oligodendrocytes can respond to neural activity by adding new sheaths or by changing the geometry of pre-existing sheaths to tune neural circuitry, a process known as adaptive myelination.
What are the membrane trafficking mechanisms that drive adaptive myelination in oligodendrocytes?
How can these mechanisms be stimulated to promote myelin regeneration in disease?
By using transgenic mouse models and primary oligodendrocytes, we have found that SNARE-mediated exocytosis drives membrane addition in myelin sheaths. Current research is focused on how these pathways in oligodendrocytes may be regulated during adaptive myelination.
CNS myelination requires VAMP2/3-mediated membrane expansion in oligodendrocytes.
2022; 13 (1): 5583
Myelin is required for rapid nerve signaling and is emerging as a key driver of CNS plasticity and disease. How myelin is built and remodeled remains a fundamental question of neurobiology. Central to myelination is the ability of oligodendrocytes to add vast amounts of new cell membrane, expanding their surface areas by many thousand-fold. However, how oligodendrocytes add new membrane to build or remodel myelin is not fully understood. Here, we show that CNS myelin membrane addition requires exocytosis mediated by the vesicular SNARE proteins VAMP2/3. Genetic inactivation of VAMP2/3 in myelinating oligodendrocytes caused severe hypomyelination and premature death without overt loss of oligodendrocytes. Through live imaging, we discovered that VAMP2/3-mediated exocytosis drives membrane expansion within myelin sheaths to initiate wrapping and power sheath elongation. In conjunction with membrane expansion, mass spectrometry of oligodendrocyte surface proteins revealed that VAMP2/3 incorporates axon-myelin adhesion proteins that are collectively required to form nodes of Ranvier. Together, our results demonstrate that VAMP2/3-mediated membrane expansion in oligodendrocytes is indispensable for myelin formation, uncovering a cellular pathway that could sculpt myelination patterns in response to activity-dependent signals or be therapeutically targeted to promote regeneration in disease.
View details for DOI 10.1038/s41467-022-33200-4
View details for PubMedID 36151203
BMAL1 loss in oligodendroglia contributes to abnormal myelination and sleep.
Myelination depends on the maintenance of oligodendrocytes that arise from oligodendrocyte precursor cells (OPCs). We show that OPC-specific proliferation, morphology, and BMAL1 are time-of-day dependent. Knockout of Bmal1 in mouse OPCs during development disrupts the expression of genes associated with circadian rhythms, proliferation, density, morphology, and migration, leading to changes in OPC dynamics in a spatiotemporal manner. Furthermore, these deficits translate into thinner myelin, dysregulated cognitive and motor functions, and sleep fragmentation. OPC-specific Bmal1 loss in adulthood does not alter OPC density at baseline but impairs the remyelination of a demyelinated lesion driven by changes in OPC morphology and migration. Lastly, we show that sleep fragmentation is associated with increased prevalence of the demyelinating disorder multiple sclerosis (MS), suggesting a link between MS and sleep that requires further investigation. These findings have broad mechanistic and therapeutic implications for brain disorders that include both myelin and sleep phenotypes.
View details for DOI 10.1016/j.neuron.2023.08.002
View details for PubMedID 37657440
Misfolded proteins bind and activate death receptor 5 to trigger apoptosis during unresolved endoplasmic reticulum stress
Disruption of protein folding in the endoplasmic reticulum (ER) activates the unfolded protein response (UPR)-a signaling network that ultimately determines cell fate. Initially, UPR signaling aims at cytoprotection and restoration of ER homeostasis; that failing, it drives apoptotic cell death. ER stress initiates apoptosis through intracellular activation of death receptor 5 (DR5) independent of its canonical extracellular ligand Apo2L/TRAIL; however, the mechanism underlying DR5 activation is unknown. In cultured human cells, we find that misfolded proteins can directly engage with DR5 in the ER-Golgi intermediate compartment, where DR5 assembles pro-apoptotic caspase 8-activating complexes. Moreover, peptides used as a proxy for exposed misfolded protein chains selectively bind to the purified DR5 ectodomain and induce its oligomerization. These findings indicate that misfolded proteins can act as ligands to activate DR5 intracellularly and promote apoptosis. We propose that cells can use DR5 as a late protein-folding checkpoint before committing to a terminal apoptotic fate.
View details for DOI 10.7554/eLife.52291
View details for Web of Science ID 000518125300001
View details for PubMedID 31904339
View details for PubMedCentralID PMC7041945
The Mars1 kinase confers photoprotection through signaling in the chloroplast unfolded protein response
In response to proteotoxic stress, chloroplasts communicate with the nuclear gene expression system through a chloroplast unfolded protein response (cpUPR). We isolated Chlamydomonas reinhardtii mutants that disrupt cpUPR signaling and identified a gene encoding a previously uncharacterized cytoplasmic protein kinase, termed Mars1-for mutant affected in chloroplast-to-nucleus retrograde signaling-as the first known component in cpUPR signal transmission. Lack of cpUPR induction in MARS1 mutant cells impaired their ability to cope with chloroplast stress, including exposure to excessive light. Conversely, transgenic activation of cpUPR signaling conferred an advantage to cells undergoing photooxidative stress. Our results indicate that the cpUPR mitigates chloroplast photodamage and that manipulation of this pathway is a potential avenue for engineering photosynthetic organisms with increased tolerance to chloroplast stress.
View details for DOI 10.7554/eLife.49577
View details for Web of Science ID 000490547100001
View details for PubMedID 31612858
View details for PubMedCentralID PMC6794094
Confirming a critical role for death receptor 5 and caspase-8 in apoptosis induction by endoplasmic reticulum stress
CELL DEATH AND DIFFERENTIATION
2018; 25 (8): 1530-1531
Several studies implicate specific death receptors (DRs) and caspase-8 in mediating apoptosis in response to endoplasmic reticulum (ER) stress; however, a recent paper challenges this conclusion. Here we validate the importance of DR5 and caspase-8 as critical signal conduits for apoptosis activation upon ER stress.
View details for DOI 10.1038/s41418-018-0155-y
View details for Web of Science ID 000442884000013
View details for PubMedID 29991746
View details for PubMedCentralID PMC6113221