# Non-canonical cell death in neurodegeneration: emerging mechanisms and therapeutic Frontiers

## TL;DR

This review explores non-canonical cell death pathways in neurodegenerative diseases and their potential for developing new therapies.

## Contribution

The paper highlights emerging non-canonical cell death mechanisms and their therapeutic implications in neurodegeneration.

## Key findings

- Non-canonical cell death pathways like ferroptosis and necroptosis are linked to neuroinflammation and oxidative stress in neurodegenerative diseases.
- Pharmacological agents such as ferrostatin-1 and PARP-inhibitors show neuroprotective effects in experimental models.
- Challenges in translating these findings to clinical treatments include blood-brain barrier issues and overlapping mechanisms.

## Abstract

Neurodegenerative diseases, specifically Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), and Amyotrophic Lateral Sclerosis (ALS) are defined by progressively increased neuronal loss that lacks curative therapies. Increasing evidence supports that non-canonical regulated cell death pathways including ferroptosis, necroptosis, pyroptosis, and parthanatos, are implicated in pathological mechanisms of neuroinflammation, and oxidative stress, and mitochondrial dysfunction, likely impacting neurodegenerative pathologies. In this review, we summarize the existing literature on the molecular pathways and potential pathogenic implications of these cell death pathways in neurodegenerative diseases, highlighting their upstream triggers, regulatory proteins, and downstream effectors. We also briefly describe representative pharmacological agents, including ferrostatin-1, necrostatin-1, MCC950 and PARP-inhibitors, that have shown neuroprotective effects in experimental studies. Experimental studies provide valuable information, but translation to clinical treatments presents barriers including overlapping regulated cell death mechanisms, constraints of bloodbrain barrier penetrance and concern for safety. Future development may come through concepts such as biomarker-based patient stratification strategies, multivalent interventions, and improved translational models. Identifying these new regulated cell death pathways may eventually provide new avenues to slow the progression of neurodegeneration and develop more targeted therapies.