# A LNK–CBL–HNRPA2B1–GPX4 signaling axis mediates dopaminergic neuron vulnerability to ferroptosis in Parkinson's disease

## TL;DR

This study identifies a new signaling pathway involving LNK, CBL, HNRNPA2B1, and GPX4 that makes brain cells vulnerable to damage in Parkinson's disease and suggests a potential treatment.

## Contribution

The discovery of a novel LNK–CBL–HNRNPA2B1–GPX4 signaling axis that mediates ferroptosis in Parkinson's disease.

## Key findings

- LNK expression is elevated in Parkinson's disease and correlates with motor severity.
- Lifitegrast, an FDA-approved drug, inhibits LNK and provides neuroprotection in PD models.
- LNK promotes HNRNPA2B1 degradation, reducing GPX4 stability and enhancing ferroptosis.

## Abstract

The upstream mechanisms governing neuronal susceptibility to ferroptosis in Parkinson's disease (PD) remain incompletely defined. This study investigates the molecular pathways mediating dopaminergic neuron vulnerability to ferroptosis in PD. The Lymphocyte adaptor protein (LNK) is identified as an upstream regulator, with its expression being significantly increased in peripheral blood of PD patients and positively associating with motor impairment severity. Similar upregulation occurs in murine PD models, coinciding with enhanced neuronal susceptibility. LNK interacts with the E3 ubiquitin ligase casitas B-lineage lymphoma proto-oncogene (CBL), promoting nuclear translocation and K27-linked polyubiquitination-driven degradation of the RNA-binding protein heterogeneous nuclear ribonucleoprotein A2/B1 (HNRNPA2B1). As an N6-methyladenosine (m6A) reader, HNRNPA2B1 stabilizes GPX4 transcripts, and its depletion reduces GPX4 levels, impairing glutathione-dependent lipid peroxidation defense. A pharmacological screen identifies lifitegrast an FDA-approved ophthalmic LFA-1 antagonist, as a putative small molecule modulator capable of interacting with the LNK SH2 domain and attenuating LNK-associated signaling in cellular assays. In PD models, lifitegrast administration or genetic ablation of LNK was observed to mitigate dopaminergic neurodegeneration. These findings define the LNK–CBL–HNRNPA2B1–GPX4 axis in ferroptotic regulation and support LNK as a potential therapeutic target in PD.

Image 1

•LNK expression is elevated in Parkinson's disease and correlates with motor severity.•Novel LNK–CBL–HNRNPA2B1–GPX4 axis regulates neuronal ferroptosis vulnerability.•LNK promotes HNRNPA2B1 degradation, reducing GPX4 stability and enhancing ferroptosis.•FDA-approved lifitegrast inhibits LNK and provides neuroprotection in PD models.

LNK expression is elevated in Parkinson's disease and correlates with motor severity.

Novel LNK–CBL–HNRNPA2B1–GPX4 axis regulates neuronal ferroptosis vulnerability.

LNK promotes HNRNPA2B1 degradation, reducing GPX4 stability and enhancing ferroptosis.

FDA-approved lifitegrast inhibits LNK and provides neuroprotection in PD models.