While these findings are provocative, further work is required to determine if this propagation of aggregates occurs in vivo or is relevant to TDP-43 protein aggregation, a proteotoxicity emerging as a cardinal feature of sporadic ALS (Mackenzie et al., 2010). While adoption of an alternative structure represents a key step in the pathogenic cascade for polyglutamine disease proteins, considerable work suggests that amyloid-like protein aggregates
in these disorders are BAY 73-4506 purchase not the toxic species, but rather coincident with the production of toxic conformers whose exact nature remains uncertain (Arrasate et al., 2004, Chia et al., 2010, Poirier et al., 2002 and Wacker et al., 2004). Nonetheless, production of protein aggregates always indicates that a process of polyglutamine proteotoxicity is underway;
hence, if dynamic interconversion between toxic conformers and aggregates is ongoing, then cell-to-cell PCI-32765 order transmission of altered polyglutamine species could promote propagation of pathology. In an in vitro investigation, a highly amyloidogenic polyglutamine species was added to the culture media of HEK293 cells stably expressing a nonpathogenic huntingtin protein fragment (Ren et al., 2009). Cellular uptake of the toxic polyglutamine species unexpectedly led to aggregation of the nonpathogenic huntingtin protein, which normally does not form aggregates. Furthermore, the aggregation of huntingtin-Q25 persisted through multiple rounds of cell division, but such aggregation could not be induced with unrelated amyloidogenic proteins, such as yeast Sup35 or Aβ. In an independent study, huntingtin protein aggregation was monitored with a fluorescent signal, and cell-to-cell transmission of huntingtin protein oligomers was documented (Herrera et al., 2011). Further studies will be required to validate the significance and relevance of such cell-to-cell spreading
in disease pathogenesis. If it is true that misfolded proteins can spread from one cell to another, then the obvious question that we must address is how this occurs. One approach to this issue is 17-DMAG (Alvespimycin) HCl to recognize that the process can operate in at least two different ways: (1) by extracellular release and uptake or (2) by delivery within membrane-bound structures (Figure 4). In this section, we will briefly review potential pathways by which misfolded proteins could achieve intercellular transit. Misfolded proteins that are aggregate-prone pose a continual challenge to degradative pathways, forcing neurons to heavily rely on autophagy for proteostasis. Hence, misfolded protein conformers are typically directed to membrane-bound structures, in particular autophagosomes that ultimately fuse with endosomes or lysosomes.