Originally Posted on Cell Press | 23 February 2012
Recent ﬁndings have suggested that tau pathology may spread in the brain by a prion-like mechanism. In this issue of Neuron, de Calignon et al. (2012) recreated an early stage of neuroﬁbrillary tangle pathology to show that tau protein aggregates initially generated in a circumscribed area spread throughout the brain and lead to neurodegeneration.
Neuroﬁbrillary tangles (NFTs) composed of a misfolded and aggregated form of tau are a hallmark event in the pathogenesis of Alzheimer’s disease (AD) and other neurodegenerative disorders, often called tauopathies, which include fronto-temporal dementia, Pick’s disease, and chronic traumatic encephalopathy, among others. In spite of compelling evidence indicating that NFTs play a major role in neurodegeneration, little is known about the mechanism and factors implicated in the initiation and spreading of this pathology in the brain.
Misfolding and aggregation is not a unique feature of tau; indeed, misfolded protein aggregates are implicated in more than 20 human diseases, collectively called protein misfolding disorders (PMDs). The PMD group comprises highly prevalent and insidious illnesses including AD, Parkinson’s disease, and type 2 diabetes, as well as rarer disorders, such as Huntington’s disease, systemic amyloidosis, amyotrophic lateral sclerosis, and transmissible spongiform encephalopathies (TSEs) (Chiti and Dobson, 2006; Moreno-Gonzalez and Soto, 2011).
Although the proteins implicated in each of these pathologies and the clinical manifestations of the diseases differ, the molecular mechanism of protein misfolding and the structural intermediates and endpoint of the protein aggregation are remarkably similar. Among PMDs, TSEs, also known as prion diseases, are the ones in which the causative role for the accumulation of misfolded protein aggregates are best established. This is because TSEs can be acquired by infection, and compelling evidence indicates that the misfolded prion protein is the main (if not the sole) component of the infectious agent (Soto, 2011).
TSEs are transmitted by the autocatalytic conversion of the natively folded prion protein seeded by the misfolded version of the protein. In this manner, misfolded prion aggregates spread throughout the body and can occasionally, through deﬁned routes, transmit between individuals to propagate the disease.
Until recently, the spreading and transmission of disease by propagation of protein misfolding was thought to be an oddity of the rogue prion protein. However, a series of recent and exciting studies has shown experimental evidence for prion-like mechanisms of pathological spreading of misfolded proteins associated to various diseases (Aguzzi and Rajendran, 2009; Brundin et al., 2010; Moreno-Gonzalez and Soto, 2011).