Activation of the heat shock response in familial amyloidotic polyneuropathy

The heat shock proteins (Hsps) have been implicated in a variety of neurodegenerative diseases in which the underlying pathology is protein aggregation. Here, we studied the heat shock response in familial amyloidotic polyneuropathy (FAP), a neurodegenerative disease caused by aggregation and extracellular tissue deposition of mutated transthyretin (TTR). We observed greater expression of Hsp27 and Hsp70 related to the presence of extracellular TTR aggregates in human FAP nerve, skin, and salivary gland biopsies than in normal controls. Transthyretin aggregates did not colocalize with Hsp, suggesting that extracellular TTR tissue deposits induce an intracellular stress response. Moreover, the heat shock transcription factor 1 was upregulated and localized to nuclei in affected tissues. Transgenic mice expressing the V30M mutant form of TTR similarly showed the presence of TTR deposits, induced activation of heat shock transcription factor 1, and increased synthesis of Hsp. Furthermore, the addition of toxic TTR aggregates to cultures of human and rodent neuroblastoma cell lines induced upregulation of Hsp70 and Hsp27. Taken together, these novel findings suggest new avenues for research on pathogenic mechanisms in FAP and identify the heat shock response as a potential pharmacologic treatment target for FAP.