Emerging role of PAD4 mediated TDP-43 citrullination in the neuropathology of LATE and Alzheimer’s Disease Related Dementias

Grants and Contracts Details

Description

Title: “Emerging role of PAD4 mediated TDP-43 citrullination in the neuropathology of LATE-NC and Alzheimer’s Disease Related Dementias”. Abstract: TAR DNA-binding protein 43 (TDP-43) pathology is associated with a spectrum of clinical dementias. The TDP-43 pathology is present in more than half of clinically diagnosed Alzheimer''s (AD) patients and one-third of the aging population diagnosed with Limbic-Predominant Age- related TDP-43 Encephalopathy (LATE). Despite the importance of age-related TDP-43 proteinopathy in public health, there is a lack of proper models, targets, and disease-modifying strategies against TDP-43 pathology. Our laboratory has discovered that citrullination (citR) is a novel posttranslational modification of TDP-43 induced by peptidyl arginine deiminase 4 (PAD4). We identified increased PAD4 expression and citR TDP-43 during early Neuropathological Changes in LATE, AD+LATE human brain, and TDP-43 mouse models. To date, we know very little about the role of PAD4 in TDP-43 proteinopathies. We discovered that conversion of arginine (positive) to citrulline (neutral) dramatically changes TDP-43 protein biophysical properties. Meanwhile, the impact of citR moieties on TDP-43 protein phase separation and downstream biological events remains elusive. This proposal will address these significant gaps and define how PAD4-induced citR promotes the TDP-43 pathological phenotype in the human brain, TDP- 43 mouse models, and neuronal cells. PAD4-mediated TDP-43 citrullination impairs TDP-43 nucleocytoplasmic shuttling and accelerates cytoplasmic accumulation, thereby driving the TDP-43 toxic gain-of-function phenotype and cognitive decline in LATE. In Aim 1, we will establish how genetic PADi4 (gene) gain- and loss-of-function and Ca2+-coordinated PAD4 activation restricts TDP-43 epitope citrullination, regulates TDP-43 nuclear import and cytoplasmic accumulation in primary neurons. We will also assess the role of PAD4 in TDP-43 cytoplasmic accumulation, synaptic dysfunction, and neurobehavioral deficits in a TDP-43 mouse model. Aim 2 will define the role of citrullination on TDP-43 protein structure and biology. We will utilize pseudo-citR mimetics to investigate region-specific effects of citrullination on TDP-43 nuclear import, solid-liquid phase transitons, and solubility in primary neurons. We will also determine how the citR moieties regulate TDP-43 protein phase separation kinetics. Aim 3 will determine if citR TDP-43 epitope restriction signatures follow the regional vulnerability of the human brain to PAD4 activation. The proposed studies will identify how the PAD4 pathway and citrullination affect TDP-43 protein properties and function, leading to the neuropathology of TDP- 43 proteinopathies in LATE and ADRD.
StatusActive
Effective start/end date2/15/241/31/29

Funding

  • National Institute on Aging: $690,893.00

Fingerprint

Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.