A ggregation-prone proteins associated with neurodegenerative disease, such as α-synuclein and β-amyloid, now appear to share key prion-like features with mammalian prion protein, such as the ability to recruit normal proteins to aggregates and to translocate between neurons. These features may shed light on the genesis of stereotyped lesion development patterns in conditions such as Alzheimer disease and Lewy body dementia. We discuss the qualifications of tau protein as a possible "prionoid" mediator of lesion spread based on recent characterizations of the secretion, uptake and transneuronal transfer of human tau isoforms in a variety of tauopathy models, and in human patients. In particular, we consider (1) the possibility that prionoid behavior of misprocessed tau in neurodegenerative disease may involve other aggregation-prone proteins, including PrP itself and (2) whether "prionlike" tau lesion propagation might include mechanisms other than protein-protein templating. Prions and TSEs as a General Model for Neurodegenerative DiseaseThe formation of abnormal protein aggregates provides a common element in the pathogenesis of the vast majority of neurodegenerative diseases in humans, including Alzheimer disease (AD), non-AD tauopathies, α-synucleinopathies such as Lewy body dementia, transmissible spongiform encephalopathies (TSEs), trinucleotide repeat diseases and amyotrophic lateral sclerosis. Since aggregate formation is generally considered (and has been modeled) as a cell-autonomous Is tau ready for admission to the prion club?Garth F. Hall* and Brian A. PatutoDepartment of Biological Sciences; University of Massachusetts Lowell; Lowell, MA USA process, investigations into the pathogenesis of most neurodegenerative diseases have until very recently focused on cytotoxicity mechanisms associated with aggregate formation. As a consequence, intercellular aspects of most neurodegenerative diseases have been relatively neglected until very recently, and remain poorly understood. An exception to this pattern has been the study of TSEs, in which the consequences of prion protein (PrP) misfolding were addressed at the organismal level years before meaningful studies of cellular mechanisms could be attempted. This is because the transmissability and bizarre epidemiology of these diseases made a basic understanding of the transmission mechanism prerequisite to any meaningful studies of TSE cytopathogenesis. However, during the 1980s and 1990s, PrP was progressively established as the necessary and sufficient agent for TSE transmission via the promulgation, systematic testing and validation of the "Prion Hypothesis." [1][2][3] Since then, the study of PrP biology and pathobiology at the molecular, cellular and organismal levels has led to a deepening appreciation of the subtlety with which specific misfolded conformers of PrP can reproduce and propagate disease-specific properties that define specific TSEs. Investigators have recently begun to use PrP propagation in TSEs as a model to address interneuronal aspect...