# Differential Roles of Angiotensin A and Alamandine in Parkinson's Disease: A Therapeutic Perspective on Nonclassical RAS Pathways

## TL;DR

This review explores how nonclassical RAS pathways, including angiotensin A and alamandine, may help treat Parkinson's disease by protecting brain cells.

## Contribution

The paper highlights the novel therapeutic potential of nonclassical RAS components in Parkinson's disease.

## Key findings

- The classical RAS pathway contributes to neurodegeneration in Parkinson's disease.
- Nonclassical RAS pathways, such as Ang1–7 and alamandine, offer neuroprotection.
- Dysregulation of nonclassical RAS pathways is linked to Parkinson's progression.

## Abstract

Background: Parkinson's disease (PD) is a neurodegenerative disease characterized by progressive neurodegeneration of dopaminergic neurons (DNs) in the substantia nigra (SN). PD neuropathology is mainly related to inflammation, mitochondrial dysfunction, oxidative stress, and endoplasmic reticulum (ER) stress. The underlying causes for the progression of PD are linked to the uncontrolled activation of different signaling pathways, such as the renin–angiotensin system (RAS), which is highly expressed in the nigrostriatal pathway. RAS has two main pathways: the classical pathway, which includes angiotensin I (AngI), AngII, angiotensin‐converting enzyme (ACE), Ang type 1 receptor (AT1R), and Ang type 2 receptor (AT2R), that has a neuro‐detrimental effect on PD neuropathology, and the nonclassical pathway, which includes angiotensin‐converting enzyme 2 (ACE2)/Angiotensin 1–7 (Ang1–7), that has a neuroprotective effect against different neurological disorders, including PD. The nonclassical pathway is activated to overcome the harmful impact of the classical pathway on the brain, thereby converting AngII to angiotensin A (Ang‐A) via mononuclear leukocyte‐derived aspartate decarboxylase (MILDAD). Ang‐A is further converted to the neuroprotective alamandine, which acts on the mass‐related G‐protein coupled receptor member D (MrgD). In PD, overactivation of the classical pathway is associated with neurodegeneration of the DNs in the SN. However, the nonclassical pathway, mainly Ang1–7/alamandine, is deregulated in PD. The objective of the review: This review aims to explore and discuss the potential role of the nonclassical RAS pathway in the pathogenesis and progression of PD and its implications for future therapeutic strategies.

The role of the Classical and Non‐Classical RAS pathway in Parkinson's disease: Pathogenesis and Therapeutic strategies. PD, Parkinson's disease; DNs, Dopaminergic neurons; SN, Substantia Nigra; α‐syn, alpha‐synuclein; RAS, renin‐angiotensin system; Ang II, Angiotensin II; AT1R, Angiotensin II type 1 Receptor; ACE2, angiotensin‐converting enzyme 2; Ang 1‐7, Angiotensin 1‐7; Ang A, Angiotensin A.