The Role Of Protein Misfolding in Neurodegenerative Diseases | Amprion

The Role of Protein Misfolding in Neurodegenerative Diseases

By March 30, 2018 No Comments

Originally Posted on Nature Reviews | 1 January 2003

Scientist Researching Protein Misfolding in in Neurodegenerative Diseases

Recent evidence indicates that diverse neurodegenerative brain diseases might have a common cause and pathological mechanism — the misfolding, aggregation and accumulation of proteins in the brain, resulting in neuronal apoptosis. Studies from different disciplines strongly support this protein misfolding in neurodegenerative disease hypothesis and indicate that a common therapy for these devastating disorders might be possible.

The aim of this article is to review the literature on the molecular mechanism of misfolded proteins and aggregation, its role in neurodegeneration and the potential targets for therapeutic intervention in neurodegenerative diseases. Many questions still need to be answered and future research in this field will result in exciting new discoveries that might impact other areas of biology.

To ensure that cells and organisms function properly, the correct activity of a network of thousands of proteins is essential. The function of a protein depends on its three-dimensional structure, which is determined by its amino-acid sequence. Chaperone Proteins supervise Protein Folding so that, in most cases, mistakes are avoided and malfunctioning proteins are removed. However, evidence is accumulating that protein misfolding and aggregation is the most likely cause of various neurological and systemic diseases. These Protein Conformational Disorders include the most common forms of neurodegenerative disease as well as some rare inherited disorders that involve deposition of protein aggregates in the brain.

Neurodegenerative diseases can affect abstract thinking, skilled movements, emotional feelings, cognition, memory and other abilities. This diverse group of diseases includes Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD) (and related polyglutamine disorders including several forms of spinocerebellar ataxia or SCA), transmissible spongiform encephalopathies (TSEs, which include several human and animal diseases) and amyotrophic lateral sclerosis (ALS).

Until recently, it was considered impossible to find a common molecular mecha-nism among this group of diseases. However, despite their obvious differences in clinical symptoms and dis-ease progression, these disorders do share some common features: most of them (except HD and SCA) have both sporadic and inherited origins, all of them appear later in life (usually after the fourth or fifth decade), and their pathology is characterized by neuronal loss and synaptic abnormalities.

The hallmark feature of conformational disorders is that a particular protein can fold into a stable alternative conformation, which in most cases results in its aggregation and accumulation in tissues as fibrillar deposits. These deposits have some similar morphological, structural and staining characteristics, but it is likely that different protein deposits might also have distinct biochemical or biological features, particularly depending on whether the aggregates accumulate intra- or extra-cellularly.

The name Amyloid was originally used to refer to the extracellular protein deposits found in AD and systemic amyloid disorders, but its use has recently been extended to include some intracellular aggregates. In this article I use the term amyloid-like deposits to refer to these aggregates, without meaning that they are absolutely equivalent. Amyloid is a generic term that refers to aggregates organized in a cross-β structure, with specific tinctorial properties (binding to Congo red and thioflavin S), higher resistance to proteolytic degradation and a fibrillar appearance under electron microscopy (straight, unbranched, 10 nm wide fibrils).

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