Quaking and its Target Gene, Lipocalin Prostaglandin D2 Synthase, are Important Regulators of Microglial Phagocytosis during Neurodegeneration

Takese Tasseen McKenzie, BS (Advisor: Jian Hu, PhD)

Microglia are resident phagocytes of the central nervous system, and their dysregulation is a key contributor to neurodegenerative diseases affecting 57 million people worldwide. These diseases include Alzheimer’s Disease (AD), the leading cause of dementia, and Multiple Sclerosis (MS), the most prevalent primary demyelinating disease. Despite extensive research, there are no effective therapies that completely halt disease progression in AD or MS. The dysregulation of microglial phagocytosis presents an attractive therapeutic target; however, this requires further understanding of the regulators involved in this process.

Quaking (Qki), an RNA-binding protein and a transcriptional co-activator, is a master regulator of microglial phagocytosis, but its role in neurodegeneration remains to be fully elucidated. In my dissertation, I found that in dysfunctional microglia associated with amyloid-beta (Aβ), a key hallmark of AD pathology, Qki is significantly downregulated. Using the 5xFAD amyloidosis mouse model of Alzheimer’s Disease, I uncovered that deletion of microglial Qki increased Aβ plaque accumulation and neuroinflammation but reduced neuronal density and mouse survival. These findings identify the downregulation of Qki as a potential mechanism of neurodegeneration and the expression of Qki as a marker of microglial functional state in AD. 

Lipocalin prostaglandin D2 synthase (L-PGDS), a secreted oligodendrocyte protein and a transcriptional target of Qki, is among the most dysregulated genes in MS lesions. Oligodendrocytes are best known for generating myelin, but their paracrine functions in demyelinating disease remain poorly understood. In the second half of my dissertation, I characterize downregulation of L-PGDS as a potential mechanism driving demyelination in MS. Using the cuprizone model of demyelination, I show that loss of L-PGDS impairs microglial phagocytosis of myelin debris, disrupts remyelination, and induces an aging-associated transcriptional program. Conversely, recombinant L-PGDS enhances microglial phagocytosis and upregulates genes involved in phagosome formation. Additionally, L-PGDS activates AKT signaling, a key regulator of actin dynamics and phagocytosis. These findings define a novel oligodendrocyte–microglia signaling axis that promotes myelin clearance and repair and suggest that impaired oligodendrocyte secretory function contributes to multiple sclerosis pathogenesis.

In summary, my dissertation has identified two mechanisms underlying microglial dysfunction in neurodegeneration. First, Aβ downregulates microglial Qki, and the loss of Qki impairs microglial phagocytosis of Aβ, thereby accelerating neurodegeneration in AD. Second, demyelination significantly downregulates L-PGDS, a Qki target gene, and the loss of L-PGDS disrupts the paracrine signaling axis between oligodendrocytes and microglia, thereby impairing remyelination.

Advisory Committee:

• Jian Hu, PhD, Chair
• Hugo Bellen,
• Guangwei Du, PhD
• Boyi Gan, PhD
• Kyun Kyoung Lee, PhD
• Sheng Zhang, PhD

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