Additional Information
 

Mechanistic Rationale

HDAC6 inhibitor treatment will prevent tau aggregation and stop or slow the progression of AD

Healthy neurons

Dysfunctional neurons

Neurons contain

microtubules, which

perform important

transport functions

Acetylated tau proteins provide structure to microtubules and support axonal transport.

HDAC6 deacetylates tau, which becomes unbound from microtubules. Free tau becomes phosphorylated.

Eventually, tau becomes hyper-phosphorylated, which leads to neurofibrillary tangles(NFTs).

Tangles accumulate

within neurons,

microtubules fail to

function and eventually neurons die.

HDAC6 inhibitor treatment will preserve axonal transport and stop or slow the progression of AD and ALS

Neurons contain microtubules, which perform important transport functions.

Acetylated tau and tubulin proteins provide structure to microtubules and support axonal transport

HDAC6 deacetylates tau and tubulin, which makes microtubules less resilient and axonal transport is disrupted.

 

Supporting Literature

Extensive data from multiple research groups support Eikonizo’s approach for using HDAC6 inhibitors as a disease-modifying therapeutic for neurodegeneration in AD and ALS

HDAC6 deacetylates tau and tubulin, engaging key mechanisms relevant in neurodegeneration

     Tau

  1. Carlomagno Y, Chung D eun C, Yue M, Castanedes-Casey M, Madden BJ, Dunmore J, et al. An Acetylation–phosphorylation switch that regulates tau aggregation propensity and function. J Biol Chem. 2017;292(37):15277–86. PMID:28760828.

  2. Tseng JH, Xie L, Song S, Xie Y, Allen L, Ajit D, et al. The Deacetylase HDAC6 Mediates Endogenous Neuritic Tau Pathology. Cell Rep. 2017; PMID:28854366.

  3. Cook C, Carlomagno Y, Gendron TF, Dunmore J, Scheffel K, Stetler C, et al. Acetylation of the KXGS motifs in tau is a critical determinant in modulation of tau aggregation and clearance. Hum Mol Genet. 2014;23(1):104–16. PMID:23962722.

     Tubulin

  1. Hubbert C, Guardiola A, Shao R, Kawaguchi Y, Ito A, Nixon A, et al. HDAC6 is a microtubule-associated deacetylase. Nature. 2002 May 23;417(6887):455–8. PMID:12024216.

  2. Dompierre JP, Godin JD, Charrin BC, Cordelières FP, King SJ, Humbert S, et al. Histone deacetylase 6 inhibition compensates for the transport deficit in Huntington’s disease by increasing tubulin acetylation. J Neurosci. 2007 Mar 28;27(13):3571–83. PMID:17392473.

Multiple HDAC6 inhibitor (HDAC6i) tool compounds have desired mechanistic effects in disease models

  1. Tseng JH, Xie L, Song S, Xie Y, Allen L, Ajit D, et al. The Deacetylase HDAC6 Mediates Endogenous Neuritic Tau Pathology. Cell Rep. 2017; PMID:28854366.

  2. D’Ydewalle C, Krishnan J, Chiheb DM, Van Damme P, Irobi J, Kozikowski AP, et al. HDAC6 inhibitors reverse axonal loss in a mouse model of mutant HSPB1-induced Charcot-Marie-Tooth disease. Nat Med. 2011;17(8):968–74. PMID:21785432.

  3. Selenica ML, Benner L, Housley SB, Manchec B, Lee DC, Nash KR, et al. Histone deacetylase 6 inhibition improves memory and reduces total tau levels in a mouse model of tau deposition. Alzheimer’s Res Ther. 2014; PMID:24576665.

  4. Fan SJ, Huang FI, Liou JP, Yang CR. The novel histone de acetylase 6 inhibitor, MPT0G211, ameliorates tau phosphorylation and cognitive deficits in an Alzheimer’s disease model article. Cell Death Dis. 2018;9(6). PMID:29844403.

  5. Zhang L, Liu C, Wu J, Tao J-J, Sui X-L, Yao Z-G, et al. Tubastatin A/ACY-1215 improves cognition in Alzheimer’s disease transgenic mice. J Alzheimers Dis. 2014 Jul 25;41(4):1193–205. PMID:24844691.

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