The Diagnostic Potential of Amyloidogenic Proteins

Abstract

Neurodegenerative disorders are a highly prevalent class of diseases, whose pathological mechanisms start before the appearance of any clear symptoms. This fact has prompted scientists to search for biomarkers that could aid early treatment. These currently incurable pathologies share the presence of aberrant aggregates called amyloids in the nervous system, which are composed of specific proteins. In this review, we discuss how these proteins, their conformations and modifications could be exploited as biomarkers for diagnostic purposes. We focus on proteins that are associated with the most prevalent neurodegenerative disorders, including Alzheimer’s and Parkinson’s diseases, amyotrophic lateral sclerosis, and frontotemporal dementia. We also describe current challenges in detection, the most recent techniques with diagnostic potentials and possible future developments in diagnosis.

A new paradigm for diagnosis of neurodegenerative diseases: peripheral exosomes of brain origin

“…A common feature of neurodegenerative diseases is the misfolding, aggregation and accumulation of pathological amyloids inside or outside of the brain cells [ 1 ]. Accordingly, the detection of these pathological proteins in body fluids and accessible tissues may be an ideal candidate for early diagnosis of these diseases [ 2 , 3 ]. However, due to the significant differences in their concentrations among various tissues and biofluids, the detection of these protein aggregates, in most cases by standard assays, is only possible in the affected brain [ 3 ].…”

A Chemical Mutagenesis Approach to Insert Post-Translational Modifications in Aggregation-Prone Proteins

“…1 Alzheimer's disease (AD), the most common form of dementia, is distinguished by disease hallmarks including amyloid-β (Aβ) plaques and tau-containing neurofibrillary tangles. 2,3 Aβ is an aggregationprone peptide produced from aberrant cleavage of the amyloid precursor protein (APP), an integral membrane protein abundant at the synapses, by the sequential proteolytic cleavage of the β-and -secretases. 4 Genetic mutations of APP and of the secretase genes promoting this proteolytic pathway and are linked to familial AD.…”

“…8 PTMs including truncation, serine phosphorylation, lysine acetylation, methionine oxidation and polyglutamylation are found in Aβ aggregates, with reported effects such as increasing or reducing the rate of aggregation and plaque formation. 2,8 However, detailed biomolecular and mechanistic studies of each PTM is hindered by the lack of site-specific tools to introduce them. To date, PTMs in Aβ have been generated by solid-state peptide synthesis, [9][10][11] enzymatic reaction, 12,13 and non-site specific chemical modification.…”

A Chemical Mutagenesis Approach to Insert Post-translational Modifications in Aggregation-Prone Proteins

“…Genetic mutations of APP and of the secretase genes promoting this proteolytic pathway are linked to familial AD. − Furthermore, most cases of AD are sporadic, and post-translational modifications (PTMs) can be induced by environmental factors such as inflammation . PTMs, including truncation, serine phosphorylation, lysine acetylation, methionine oxidation, and polyglutamylation, are found in Aβ aggregates, with reported effects such as increasing or reducing the rate of aggregation and plaque formation. , However, detailed biomolecular and mechanistic studies of each PTM are hindered by the lack of site-specific tools to introduce them. To date, PTMs in Aβ have been generated by solid-state peptide synthesis, − enzymatic reaction, , and non-site-specific chemical modification .…”