There have been several notable associations between ALS pathophysiology and dysfunction in elements directly downstream of HSF1 activation in response to stress, including accumulation of misfolded and aggregated proteins such as mutant FUS, SOD1 and OPTN38–41, perturbed HSP-mediated autophagic clearance of TDP-4342,43, and reduced expression of HSP40 and HSP70 in sporadic ALS spinal cord tissue26. Here, HSPA4 is linked to amyotrophic lateral sclerosis.