HDAC6 is a target for protection and regeneration following injury in the nervous system.
Central nervous system (CNS) trauma can result in tissue disruption, neuronal and axonal degeneration, and neurological dysfunction. The limited spontaneous CNS repair in adulthood and aging is often insufficient to overcome disability. Several investigations have demonstrated that targeting HDAC activity can protect neurons and glia and improve outcomes in CNS injury and disease models. However, the enthusiasm for pan-HDAC inhibition in treating neurological conditions is tempered by their toxicity toward a host of CNS cell types -a biological extension of their anticancer properties. Identification of the HDAC isoform, or isoforms, that specifically mediate the beneficial effects of pan-HDAC inhibition could overcome this concern. Here, we show that pan-HDAC inhibition not only promotes neuronal protection against oxidative stress, a common mediator of injury in many neurological conditions, but also promotes neurite growth on myelin-associated glycoprotein and chondroitin sulfate proteoglycan substrates. Real-time PCR revealed a robust and selective increase in HDAC6 expression due to injury in neurons. Accordingly, we have used pharmacological and genetic approaches to demonstrate that inhibition of HDAC6 can promote survival and regeneration of neurons. Consistent with a cytoplasmic localization, the biological effects of HDAC6 inhibition appear transcription-independent. Notably, we find that selective inhibition of HDAC6 avoids cell death associated with pan-HDAC inhibition. Together, these findings define HDAC6 as a potential nontoxic therapeutic target for ameliorating CNS injury characterized by oxidative stress-induced neurodegeneration and insufficient axonal regeneration.
Rivieccio
Mark A
MA
Burke Medical Research Institute, 785 Mamaroneck Avenue, White Plains, NY 10605, USA.
Brochier
Camille
C
Willis
Dianna E
DE
Walker
Breset A
BA
D'Annibale
Melissa A
MA
McLaughlin
Kathryn
K
Siddiq
Ambreena
A
Kozikowski
Alan P
AP
Jaffrey
Samie R
SR
Twiss
Jeffery L
JL
Ratan
Rajiv R
RR
Langley
Brett
B
D000818:Animals; D017209:Apoptosis; D002490:Central Nervous System / Q000201:enzymology / Q000293:injuries* / Q000502:physiology*; D002540:Cerebral Cortex / Q000201:enzymology / Q000502:physiology; D005727:Ganglia, Spinal / Q000201:enzymology / Q000502:physiology; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D008297:Male; D009416:Nerve Regeneration; D016501:Neurites / Q000201:enzymology / Q000502:physiology*; D019636:Neurodegenerative Diseases / Q000201:enzymology; D009474:Neurons / Q000201:enzymology / Q000502:physiology*; D018384:Oxidative Stress; D034622:RNA Interference; D051381:Rats; D017207:Rats, Sprague-Dawley
C545556:HDAC6 protein, rat; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases