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.
Status | Active |
---|---|
Effective start/end date | 2/15/24 → 1/31/29 |
Funding
- National Institute on Aging: $690,893.00
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