# The curious case of PARP1 in CNS myelin formation and repair

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA AT DAVIS · 2022 · $500,083

## Abstract

The curious case of PARP1 in CNS myelin formation and repair
 Current anti-inflammatory drugs diminish immune attacks yet are ineffective in preventing neurological
progression of multiple sclerosis (MS), the most common demyelinating disorder of the central nervous system
(CNS) with no cure affecting ~ 400,000 people in the USA. Remyelination failure, primarily resulted from
impaired differentiation of oligodendrocytes from oligodendrocyte progenitor cells (i.e. impaired OPC
differentiation), is one of the major causes for MS neurological progression. Remyelination-promoting therapy
represents a promising option in combination with current immunosuppressive medications, for treating MS.
However, few medications are available for targeting myelin repair. Our long-term goal is to discover
remyelination-promoting strategies for treating demyelinating disorders. The objective of this proposal is to
address if and how poly(ADP-ribose) polymerase 1 (PARP1) regulates OPC differentiation and myelination
and determine therapeutic values of PARP1-mediated pathways in myelin repair. PARP1 is a multi-faceted
nuclear protein that has been extensively scrutinized in cancer biology. Upon activation, PARP1 catalyzes the
covalent addition of poly(ADP-ribose) units to its target proteins, a process called PARylation which can be
reversed by the enzyme poly(ADP-ribose) glycohydrolase (PARG). The clinical rationale underlying this
proposal is that oligodendroglial lineage cells in the active but not chronic MS lesions display elevated PARP1
activity, suggesting that PARP1 may be a potential target for remyelination-promoting therapy. However, our
current knowledge of PARP1 in oligodendroglial biology and pathology is extremely limited and its therapeutic
value in remyelination has yet to be determined. The central hypothesis is that PARP1, acting through its
enzymatic activity, is an intrinsic dual-model driver of OPC differentiation and myelination which could be
harnessed to promote myelin repair. Our central hypothesis is built on the conceptual and methodological
foundations laid by our preliminary data of genetic and pharmacological manipulations in vitro and in vivo. The
hypothesis will be test in three specific aims: 1) determine the effect of PARP1 depletion on OPC differentiation
and myelination; 2) define the mechanisms underlying PARP1-regulated OPC differentiation and myelination;
and 3) determine the effects of loss- and gain-of-function of PARP1-mediated PARylation on myelin repair. We
will pursue these three aims by employing unique transgenic models generated in our laboratory. The
proposed research is significant because it will interrogate the therapeutic potential of PARP1 in myelin repair
and lay the conceptual groundwork to develop remyelination-promoting strategies. The expected outcomes will
have an important positive impact because they will establish the first conceptual picture regarding the function
and mechanism of PARP1 in CNS myelin fo...

## Key facts

- **NIH application ID:** 10445766
- **Project number:** 1R01NS123165-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA AT DAVIS
- **Principal Investigator:** Fuzheng Guo
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $500,083
- **Award type:** 1
- **Project period:** 2022-07-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10445766

## Citation

> US National Institutes of Health, RePORTER application 10445766, The curious case of PARP1 in CNS myelin formation and repair (1R01NS123165-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10445766. Licensed CC0.

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