Depending on the stress, histone deacetylase inhibitors act as heat shock protein co-inducers in motor neurons and potentiate arimoclomol, exerting neuroprotection through multiple mechanisms in ALS models

Abstract

Upregulation of heat shock proteins (HSPs) is an approach to treatment of neurodegenerative disorders with impaired proteostasis. Many neurons, including motor neurons affected in amyotrophic lateral sclerosis (ALS), are relatively resistant to stress-induced upregulation of HSPs. This study demonstrated that histone deacetylase (HDAC) inhibitors enable the heat shock response in cultured spinal motor neurons, in a stress-dependent manner, and can improve the efficacy of HSP-inducing drugs in murine spinal cord cultures subjected to thermal or proteotoxic stress. The effect of particular HDAC inhibitors differed with the stress paradigm. The HDAC6 (class IIb) inhibitor, tubastatin A, acted as a co-inducer of Hsp70 (HSPA1A) expression with heat shock, but not with proteotoxic stress induced by expression of mutant SOD1 linked to familial ALS. Certain HDAC class I inhibitors (the pan inhibitor, SAHA, or the HDAC1/3 inhibitor, RGFP109) were HSP co-inducers comparable to the hydroxyamine arimoclomol in response to proteotoxic stress, but not thermal stress. Regardless, stress-induced Hsp70 expression could be enhanced by combining an HDAC inhibitor with either arimoclomol or with an HSP90 inhibitor that constitutively induced HSPs. HDAC inhibition failed to induce Hsp70 in motor neurons expressing ALS-linked mutant FUS, in which the heat shock response was suppressed; yet SAHA, RGFP109, and arimoclomol did reduce loss of nuclear FUS, a disease hallmark, and HDAC inhibition rescued the DNA repair response in iPSC-derived motor neurons carrying the FUS P525L mutation, pointing to multiple mechanisms of neuroprotection by both HDAC inhibiting drugs and arimoclomol.

Histone Deacetylases Inhibitors in Neurodegenerative Diseases, Neuroprotection and Neuronal Differentiation

“…HDAC inhibition also rescued the DNA repair response in iPSC-derived motor neurons carrying the ALS associated FUS P525L mutation. These observations suggest multiple mechanisms of neuroprotection by both HDAC inhibiting drugs and arimoclomol in ALS (Kuta et al, 2020).…”

Amyotrophic Lateral Sclerosis: Proteins, Proteostasis, Prions, and Promises

“…In iPSC-derived spinal motor neurons, arimoclomol was able to retain FUS in the nucleus, and restore the DNA-damage response in cells expressing ALS-mutant FUS R521H (Kuta et al, 2020 ).…”

Opportunities for histone deacetylase inhibition in amyotrophic lateral sclerosis

“…Additionally, they were able to increase nuclear FUS and elevate DNA repair mechanisms in the FUS R521H motor neurons. In summary, these results strongly suggest that these effects are due to multiple mechanisms of neuroprotection by both HDAC‐inhibiting drugs and arimoclomol (Kuta et al, 2020).…”

“…Vorinostat and NXD30001 co‐treatment increased HSP70 expression upon HSP90 inhibition (Cha et al, 2014). In the study of Kuta et al (2020), it was discovered that HDAC inhibition could enhance co‐induction of HSP70 by the HSP inducer arimoclomol in different stress scenarios. HDAC inhibition could preserve DNA repair and promote nuclear retention of mutant FUS through non‐HSP‐mediated mechanisms.…”