SummaryPrions are proteins that access self-templating amyloid forms, which confer phenotypic changes that can spread from individual to individual within or between species. These infectious phenotypes can be beneficial, as with yeast prions, or deleterious, as with mammalian prions that transmit spongiform encephalopathies. However, the ability to form self-templating amyloid is not unique to prion proteins. Diverse polypeptides that tend to populate intrinsically unfolded states also form self-templating amyloid conformers that are associated with devastating neurodegenerative disorders. Moreover, two RNA-binding proteins, FUS and TDP-43, which form cytoplasmic aggregates in amyotrophic lateral sclerosis, harbor a 'prion domain' similar to those found in several yeast prion proteins. Can these proteins and the neurodegenerative diseases to which they are linked become 'infectious' too? Here, we highlight advances that define the transmissibility of amyloid forms connected with Alzheimer's disease, Parkinson's disease and Huntington's disease. Collectively, these findings suggest that amyloid conformers can spread from cell to cell within the brains of afflicted individuals, thereby spreading the specific neurodegenerative phenotypes distinctive to the protein being converted to amyloid. Importantly, this transmissibility mandates a re-evaluation of emerging neuronal graft and stem-cell therapies. In this Commentary, we suggest how these treatments might be optimized to overcome the transmissible conformers that confer neurodegeneration.Key words: Amyloid, Infectivity, Prion, Stem cell, Therapy, Transmissibility Journal of Cell Science1192 to familial forms of GSS (Hsiao et al., 1989), FFI (Medori et al., 1992) and CJD (Goldgaber et al., 1989). Moreover, in mice, an FFI-linked mutation in PrP can induce neurodegenerative disease and spontaneous generation of infectious material . At the other extreme, missense mutations in PrP can confer resistance to prion disease (Mead et al., 2009). Importantly, PrPknockout mice resist infection by exogenous TSE-inducing prions (Bueler et al., 1993). This resistance arises because the infectious form of PrP must recruit and convert endogenous PrP to transmit disease. Indeed, if PrP-expressing neurons are grafted into PrPknockout mice, then only the grafts become infected upon prion exposure, whereas surrounding tissue is unperturbed (Brandner et al., 1996). This experimental observation might prove to be pivotal for devising strategies to mitigate the transmissibility of other human neurodegenerative disease proteins.The cascade of amyloid seeding incited by prions, however, is not always problematic and is certainly not restricted to mammals. In yeast, several proteins form prions that confer specific heritable phenotypes, which are either benign or advantageous under diverse environmental conditions (Alberti et al., 2009;Shorter and Lindquist, 2005;True and Lindquist, 2000;Tyedmers et al., 2008). These specific heritable phenotypes can be induced de novo by the infecti...

Aggregation of ␣-synuclein (␣-syn), a process that generates oligomeric intermediates, is a common pathological feature of several neurodegenerative disorders. Despite the potential importance of the oligomeric ␣-syn intermediates in neuron function, their biochemical properties and pathobiological functions in vivo remain vastly unknown. Here we used two-dimensional analytical separation and an array of biochemical and cell-based assays to characterize ␣-syn oligomers that are present in the nervous system of A53T ␣-syn transgenic mice. The most prominent species identified were 53 Å detergent-soluble oligomers, which preceded neurological symptom onset, and were found at equivalent amounts in regions containing ␣-syn inclusions as well as histologically unaffected regions. These oligomers were resistant to SDS, heat, and urea but were sensitive to proteinase-K digestion. Although the oligomers shared similar basic biochemical properties, those obtained from inclusion-bearing regions were prominently reactive to antibodies that recognize oxidized ␣-syn oligomers, significantly accelerated aggregation of ␣-syn in vitro, and caused primary cortical neuron degeneration. In contrast, oligomers obtained from non-inclusion-bearing regions were not toxic and delayed the in vitro formation of ␣-syn fibrils. These data indicate that specific conformations of ␣-syn oligomers are present in distinct brain regions of A53T ␣-syn transgenic mice. The contribution of these oligomers to the development of neuron dysfunction appears to be independent of their absolute quantities and basic biochemical properties but is dictated by the composition and conformation of the intermediates as well as unrecognized brainregion-specific intrinsic factors.

Hsp104, a hexameric AAA+ ATPase found in yeast, transduces energy from cycles of ATP binding and hydrolysis to resolve disordered protein aggregates and cross-β amyloid conformers. These disaggregation activities are often co-ordinated by the Hsp70 chaperone system and confer considerable selective advantages. First, renaturation of aggregated conformers by Hsp104 is critical for yeast survival after various environmental stresses. Second, amyloid remodeling by Hsp104 enables yeast to exploit multifarious prions as a reservoir of beneficial and heritable phenotypic variation. Curiously, although highly conserved in plants, fungi and bacteria, Hsp104 orthologues are absent from metazoa. Indeed, metazoan proteostasis seems devoid of a system that couples protein disaggregation to renaturation. Here, we review recent endeavors to enhance metazoan proteostasis by applying Hsp104 to the specific protein-misfolding events that underpin two deadly neurodegenerative amyloidoses. Hsp104 potently inhibits Aβ42 amyloidogenesis, which is connected with Alzheimer's disease, but appears unable to disaggregate preformed Aβ42 fibers. By contrast, Hsp104 inhibits and reverses the formation of α-synuclein oligomers and fibers, which are connected to Parkinson's disease. Importantly, Hsp104 antagonizes the degeneration of dopaminergic neurons induced by α-synuclein misfolding in the rat substantia nigra. These studies raise hopes for developing Hsp104 as a therapeutic agent.