# Effects of Pathogenic Mutants of the Neuroprotective RNase 5-Angiogenin in Amyotrophic Lateral Sclerosis (ALS)

## TL;DR

This paper reviews how mutations in the angiogenin (ANG) gene contribute to ALS by impairing neuroprotection and angiogenesis, highlighting the need for further research into these mutations for better diagnosis and treatment.

## Contribution

The paper introduces the role of pathogenic ANG and RNase 4 mutations in ALS, emphasizing their impact on neuroprotection and the need for targeted therapeutic strategies.

## Key findings

- Pathogenic ANG mutants cause loss of function, impairing angiogenesis and motoneuron protection.
- ANG mutations often interact with other genetic variants to worsen ALS outcomes.
- Balanced ANG activity is crucial to avoid harmful effects while maintaining neuroprotection.

## Abstract

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease that affects the motoneurons. More than 40 genes are related with ALS, and amyloidogenic proteins like SOD1 and/or TDP-43 mutants are directly involved in the onset of ALS through the formation of polymorphic fibrillogenic aggregates. However, efficacious therapeutic approaches are still lacking. Notably, heterozygous missense mutations affecting the gene coding for RNase 5, an enzyme also called angiogenin (ANG), were found to favor ALS onset. This is also true for the less-studied but angiogenic RNase 4. This review reports the substrate targets and illustrates the neuroprotective role of native ANG in the neo-vascularization of motoneurons. Then, it discusses the molecular determinants of many pathogenic ANG mutants, which almost always cause loss of function related to ALS, resulting in failures in angiogenesis and motoneuron protection. In addition, ANG mutations are sometimes combined with variants of other factors, thereby potentiating ALS effects. However, the activity of the native ANG enzyme should be finely balanced, and not excessive, to avoid possible harmful effects. Considering the interplay of these angiogenic RNases in many cellular processes, this review aims to stimulate further investigations to better elucidate the consequences of mutations in ANG and/or RNase 4 genes, in order to achieve early diagnosis and, possibly, successful therapies against ALS.