Propagating sticky matters: An update on 'prion-Like' templated misfolding in neurodegenerative disorders

摘要

Having led the way for decades, research on prions-the infamous agents at the core of devastating infectious neurological diseases-has recently successfully spread to new territories. During the last decade, major neurodegenerative conditions including Alzheimer's disease (AD), Parkinson's disease (PD), Hunting-ton's disease, amyotrophic lateral sclerosis (ALS) as well as fron-totemporal lobar degeneration (FTLD) have been causally linked to diverse biologically unrelated proteins such as beta-amyloid, tau, alpha-synuclein, huntingtin, SOD1, as well as TDP-43, which-when misfolded-form P-sheet-rich, relatively protease-resistant oligomers with a high propensity to build up amyloid-like aggregates. Through a process termed "templated misfolding," to describe the conversion of native soluble proteins via misfolding into insoluble aggregates, seeds of aggregated proteins are thought to self-perpetuate into large aggregates ("seed-nucleation") either within neighboring neurons or glial cells, or the extracellular milieu. Sharing remarkable similarities with the "classical" conversion of cellular prion protein (PrP~c) into scrapie prion protein (PrP~sc), aggregated proteins finally kill their host or neighbor cells by mechanisms that remain subject of currently ongoing research [for review, see (2)].