# A Focus on the Link Between Metal Dyshomeostasis, Norepinephrine, and Protein Aggregation

## TL;DR

This review explores how imbalances in metals, norepinephrine, and protein aggregation may contribute to neurodegenerative diseases like Alzheimer's and Parkinson's.

## Contribution

The paper provides a comprehensive overview of the interplay between norepinephrine, metal dyshomeostasis, and protein aggregation in neurodegeneration.

## Key findings

- Norepinephrine and reactive oxygen species contribute to neuromelanin formation and protein aggregation.
- Metal-mediated oxidation of catecholamines disrupts protein stability and oligomerization.
- Oxidative by-products modify neuroproteins, potentially leading to neurodegenerative processes.

## Abstract

Neurodegenerative disorders are one of the main public health problems worldwide and, for this reason, they have attracted the attention of several researchers who aim to better understand the molecular processes linked to the etiology of these disorders, including Alzheimer’s and Parkinson’s diseases. In this review, we describe both the beneficial and toxic effect of norepinephrine (NE) and its connected ROS/metal-mediated pathways, which end in neuromelanin (NM) formation and protein aggregation. In particular, we emphasize the importance of stabilizing the delicate homeostatic balance that regulates (i) the metal/ROS-promoted oxidation of catecholamines, as NE, and (ii) the generation of oxidative by-products capable of covalently and non-covalently modifying neuroproteins, thus altering their stability and their oligomerization; these processes may end in (iii) the incorporation of protein conjugates into vesicles, which then evolve into neuromelanin (NM) organelles. In general, we aim to provide an up-to-date overview of the challenges and controversies emerging from the current literature to delineate a direction for future research.