# Pathological Mechanisms of Immune-Mediated Cerebellar Ataxia with Associated Sez6L2 Autoantibodies

> **NIH NIH R21** · UNIVERSITY OF ROCHESTER · 2022 · $423,500

## Abstract

Project Summary/Abstract
 Sez6L2 autoantibodies have been reported in patients with subacute cerebellar ataxia.
Patients present with gait ataxia, slurred speech, and ocular motor symptoms. Some patients also
develop limb ataxia, cognitive deficits, bradykinesia, and/or Parkinsonism. These case studies have
led to the hypothesis that autoimmunity against Sez6L2 can directly cause cerebellar damage leading
to ataxia. Sez6L2 is a transmembrane protein expressed by most neurons in the brain including
Purkinje cells and granule cells of the cerebellum. Currently, no animal studies have been performed
to help understand if Sez6L2 autoantibodies are directly pathologic, whether they are a biomarker of
cell-based autoimmunity to Sez6L2, or whether are simply superfluous to the cerebellar pathology.
We plan to test two mouse models of Sez6L2 autoimmunity in order to understand the mechanisms
underlying cerebellar ataxia with associated Sez6L2 autoantibodies. Aim 1 of this project will
determine whether mice immunized with Sez6L2 protein develop cerebellar ataxia. We will also seek to
understand the disease mechanisms using behavioral assessments, immunohistochemistry, and flow
cytometry analysis of infiltrating immune cell populations. Aim 2 will determine whether Sez6L2
antibodies alone can cause cerebellar ataxia in mice, or block Sez6L2’s complement inhibitory functions
in vitro. We anticipate that these studies will provide strong mechanistic evidence that the antibody
and/or full immune response to Sez6L2 is a pathological cause of ataxia and related symptoms. These
studies, coupled with the presently reported human case studies, should encourage prompt and routine
screening for Sez6L2 autoantibodies in suspected immune-mediated presentations of cerebellar ataxia.
The results on disease mechanisms could also help guide clinicians to the immunotherapies that may
be most effective for patients and help justify the risks of prolonged immunosuppression.

## Key facts

- **NIH application ID:** 10526475
- **Project number:** 1R21NS126845-01A1
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** JENNETTA W HAMMOND
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $423,500
- **Award type:** 1
- **Project period:** 2022-07-01 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10526475

## Citation

> US National Institutes of Health, RePORTER application 10526475, Pathological Mechanisms of Immune-Mediated Cerebellar Ataxia with Associated Sez6L2 Autoantibodies (1R21NS126845-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10526475. Licensed CC0.

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