# Evaluating the functional consequences of Alzheimer's disease-associated variant CICP36L

> **NIH NIH F31** · BAYLOR COLLEGE OF MEDICINE · 2022 · $46,752

## Abstract

Project Summary
Alzheimer's disease (AD) is the most common neurodegenerative disorder affecting more than 44 million people
worldwide. While more than 95% of AD cases are late-onset AD (LOAD), the exact pathogenic mechanism of
LOAD remains unclear. As AD is a highly heritable disease, identifying risk variants associated with LOAD will
be critical for understanding the pathogenesis and identifying therapeutic targets for AD. The overarching goal
of this study is to determine if a partial loss of function mutation in CAPICUA (CIC), a gene in which complete
loss of function causes intellectual disability, can contribute to AD. CIC encodes a transcriptional repressor that
forms a co-repressor complex with Ataxin1 (ATXN1), or its paralog, Ataxn1-like (ATXN1L). Interaction with both
is critical for CIC protein stability. While the ATXN1/1L-CIC complex is essential in survival, heterozygous loss of
CIC by severe truncating mutations in patients cause intellectual disability. Additionally, we recently found
impaired ATXN1-CIC function to be implicated in AD pathology. When we knock out ATXN1 in mice, it leads to
>50% reduction of CIC protein due to the decreased stability and activates a transcriptional cascade that
increases −secretase (BACE1), a key enzyme in generating pathogenic amyloid beta (A) species. This
ultimately leads to accelerated AD pathology. The link between loss of ATXN1-CIC complex function and increase
in BACE1 mediated AD pathology led to the overall hypothesis that mutations in CIC that lead to a partial loss of
the ATXN1-CIC complex function will potentiate AD pathology. We identified a rare heterozygous missense
variant, CICP36L, which appeared only in the LOAD patients but not in the controls. CICP36L is located within a
highly conserved ATXN1 binding domain. To determine this mutation’s effect on ATXN1-CIC interaction, I
expressed tagged CICP36L in cells, performed co-immunoprecipitation, and found that the interaction of CICP36L
with ATXN1 is reduced by ~60% compared to CICWT. This suggests that CICP36L could lead to decreased CIC
stability and reduced ATXN1-CIC complex function. Therefore, I hypothesize that the CICP36L variant leads to
a partial loss of function of the ATXN1-CIC complex and potentiates AD pathology via upregulation of
BACE1. To understand the functional consequence in a physiologically relevant system, I generated CicP36L
knock-in mice using CRISPR/Cas9 and demonstrated that CICP36L reduces CIC stability in P0 brain lysate,
supporting the hypothesis that CICP36L could lead to a partial loss of ATXN1‑CIC complex function. In this
proposal, I will further determine the in vivo functional consequences of the CICP36L variant (Aim1) and determine
the impact of the CICP36L variant on AD pathology (Aim2). At the end of the study, we will determine if CICP36L is
an AD risk variant. This work will highlight the need to search for rare AD-associated variants that genome-wide
association studies could miss and poten...

## Key facts

- **NIH application ID:** 10464611
- **Project number:** 1F31AG077918-01
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Hamin Lee
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $46,752
- **Award type:** 1
- **Project period:** 2022-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10464611

## Citation

> US National Institutes of Health, RePORTER application 10464611, Evaluating the functional consequences of Alzheimer's disease-associated variant CICP36L (1F31AG077918-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10464611. Licensed CC0.

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