# Alpha-Synuclein Dynamics in Cerebral Ischemia

## TL;DR

This review explores how alpha-synuclein affects brain injury from cerebral ischemia and its potential as a target for new treatments.

## Contribution

The paper provides a comprehensive review of alpha-synuclein's dual roles and therapeutic targeting in cerebral ischemia.

## Key findings

- Alpha-synuclein contributes to neuroinflammation and neuronal cell death after cerebral ischemia.
- MicroRNAs and the Pep-1-SOD1 complex may protect neural cells and aid recovery.
- PINK1, PLKs, and hyperglycemia worsen neuronal injury linked to alpha-synuclein.

## Abstract

Cerebral ischemia is defined by insufficient blood supply to the brain and is a leading cause of mortality and neurological disability worldwide. Alpha-synuclein (α-Syn) is a protein associated with several neurodegenerative disorders, including Parkinson’s disease, and has also been linked to the pathophysiology of cerebral ischemia. This narrative review provides a detailed overview of the current understanding of α-Syn in cerebral ischemia. We examine its impact on neuroinflammation, synaptic dysfunction, oxidative stress, and neuronal cell death, as well as its potential protective roles. Additionally, we explore therapeutic strategies targeting α-Syn, including pharmacological agents, gene knockdown models, and RNA-based therapies. We also discuss α-Syn expression changes in animal and human studies and its potential as a diagnostic biomarker. By clarifying the complex interplay between α-Syn and cerebral ischemia, this review aims to deepen our understanding of ischemic brain injury mechanisms and support the development of novel treatment approaches.

Regulation of α-Syn and its effects after cerebral ischemia. Various modulators regulate α-Syn after cerebral ischemia in both protective and detrimental ways. The left (green) panel highlights the protective roles of microRNAs and the Pep-1-SOD1 complex, which, by acting through multiple pathways, produce positive effects on neural cells and promote recovery following cerebral ischemia. The right (pink) panel shows the roles of PTEN-induced putative kinase 1 (PINK1), polo-like kinases (PLKs), and hyperglycemia, which, through specific known and unknown cellular and molecular pathways, exacerbate neuronal injury and delay brain recovery. Together, these modulators impact α-Syn pathology after cerebral ischemia; however, there are additional known and yet-to-be-identified modulators that are not represented in this figure. Created in BioRender. Davoody, S. (2025) https://BioRender.com/wyem7eq.