Brain Metabolite, N-Acetylaspartate Is a Potent Protein Aggregation Inhibitor.

Marina Warepam,Gurumayum Suraj Sharma,Kritika Kumari,Snigdha Krishna,Laishram Rajendrakumar Singh,Awdhesh Kumar Mishra,Mohd Sajjad Ahmad Khan,Hamidur Rahman

doi:10.3389/fncel.2021.617308

Abstract

Deposition of toxic protein inclusions is a common hallmark of many neurodegenerative disorders including Alzheimer's disease, Parkinson disease etc. N-acetylaspartate (NAA) is an important brain metabolite whose levels got altered under various neurodegenerative conditions. Indeed, NAA has been a widely accepted biological marker for various neurological disorders. We have also reported that NAA is a protein stabilizer. In the present communication, we investigated the role of NAA in modulating the aggregation propensity on two model proteins (carbonic anhydrase and catalase). We discovered that NAA suppresses protein aggregation and could solubilize preformed aggregates.

Highlights

The amino acid, N-acetylaspartate (NAA) is synthesized in the brain from aspartate and acetyl-coenzyme A by the enzyme L-aspartate N-acetyltransferase via acetylation of aspartate by acetyl coenzyme A
A high content of β-sheet and a single domain structure protein make it highly prone to aggregate at an unfolding temperature of 63◦C (Lavecchia and Zugaro, 1991; Sarraf et al, 2004)
To study the effect of NAA on the aggregation of CA, we monitored the kinetic processes of CA aggregation at 63◦C and pH 7.0 in the presence and absence of different concentrations of NAA by observing changes in the light scattering intensity at 500 nm

Summary

Introduction

The amino acid, N-acetylaspartate (NAA) is synthesized in the brain from aspartate and acetyl-coenzyme A by the enzyme L-aspartate N-acetyltransferase via acetylation of aspartate by acetyl coenzyme A. Almost all neurological disorders involving neuronal loss or dysfunction (e.g., including amyotrophic lateral sclerosis, alzheimers, multiple sclerosis, epilepsy, schizophrenia, NAA on Protein Aggregation cerebral ischemia, and glioblastoma) are associated with alterations in NAA levels (Paley et al, 1996; Danielsen and Ross, 1999; Kantarci and Jack, 2003; Kalra and Arnold, 2004; Briellmann et al, 2005; Abbott and Bustillo, 2006; Criste and Trapp, 2006). Altered level of NAA is associated with two inborn error of metabolism namely, Canavan disease (CD), in which there is a build-up of NAA (hyperacetylaspartia) and spongiform leukodystrophy (hypoacetylaspartia), caused due to the lack of aspartoacylase activity, where the enzyme that synthesizes NAA is apparently absent (Burlina et al, 1994; Boltshauser et al, 2004)

Methods

Results

Conclusion