Originally Posted on Neurological Review | February 2008
A key molecular pathway implicated in diverse neurodegenerative brain diseases is the misfolding, aggregation, and accumulation of proteins in the brain. Compelling evidence strongly supports the hypothesis that accumulation of misfolded proteins leads to synaptic dysfunction, neuronal apoptosis, brain damage, and disease. However, the mechanism by which protein misfolding and aggregation trigger neurodegeneration and the identity of the neurotoxic structure is still unclear.
The aim of this article is to review the literature around the molecular mechanism and role of misfolded protein aggregates in neurodegeneration and the potential for the misfolding process to lead to a transmissible form of disease by a prion-based model of propagation.
Neurodegenerative diseases are some of the most debilitating disorders, affecting thinking, skilled movements, feelings, cognition, and memory. This diverse group of diseases includes common disorders such as Alzheimer disease (AD) and Parkinson disease (PD) and rarer disorders such as Huntington disease, spinocerebellar ataxia, transmissible spongiform encephalopathies, and amyotrophic lateral sclero-sis. Despite the important differences in clinical manifestation, neurodegenerative disorders share some common features such as their appearance late in life, the extensive neuronal loss and synaptic abnormalities, and the presence of cerebral deposits of misfolded protein aggregates.
These deposits are a typical disease signature, and although the main protein component is different in each disease, they have similar morphological, structural, and staining characteristics. Amyloid is the name originally given to extracellular protein deposits found in AD and systemic amyloid disorders, but it is nowadays used to refer in general to dis-ease-associated protein aggregates. In this article, we use the term amyloid-like deposits to refer to these aggregates without necessarily meaning that they are structurally equivalent.
In each neurodegenerative disease, the distribution and composition of protein aggregates are different. In AD, there are 2 types of protein deposits. Amyloid plaques are deposited extracellularly in the brain parenchyma and around the cerebral vessel walls, and their main component is a 40- to 42-residue peptide termed β-amyloid protein. Neurofibrillary tangles are located in the cytoplasm of degenerating neurons and are composed of aggregates of hyperphosphorylated tau protein.
In patients with PD, Lewy bodies are observed in the cytoplasm of neurons of the substantia nigra in the brain. The major constituents of these aggregates are fragments of a protein named α-synuclein. In patients with Huntington disease, intranuclear deposits of a poly-glutamine-rich version of huntingtin protein are a typical feature of the brain. Patients with amyotrophic lateral sclerosis have aggregates mainly composed of superoxide dismutase in cell bodies and axons of motor neurons. Finally, the brains of humans and animals with diverse forms of transmissible spongiform encephalopathy are characterized by accumulation of protease-resistant aggregates of the prion protein (PrP).
Compelling evidence coming from biochemical, genetic, and neuropathological studies supports the involvement of protein misfolding and aggregation in the pathology of neurodegenerative diseases. For example, the presence of abnormal aggregates usually occurs in the brain regions mostly damaged by the disease. Mutations in the gene encoding for the misfolded protein produce inherited forms of the disease, which usually have an earlier onset and more severe phenotype than the sporadic forms. Transgenic animals expressing the human mutant gene for the misfolded protein develop some of the typical neuropathological and clinical characteristics of the human disease. Finally, misfolded protein aggregates produced in vitro are neurotoxic, inducing apoptosis.