Broader implications: biological and clinical significance of microtubule acetylation

Figures & data

Figure 1 Acetylation mechanisms.

Notes: (A) Schematic diagram of acetylation on lysine-40 of alpha-tubulin by MEC17. The acetyl group is provided by cofactor Ac-CoA. (B) Regulation of acetylation levels by MEC17, HDAC6, and SIRT2 activity and location of action. MEC17 acts in the lumen of the microtubule, while SIRT2 and HDAC6 deacetylate are thought to act on the periphery. It is unclear whether HDAC6 and SIRT2 work alone or synergistically.
Abbreviations: MEC17, alpha-tubulin-N-acetyltransferase 1; Ac-CoA, acetyl coenzyme A; HDAC6, histone deacetylase 6; SIRT2, sirtuin-2.

Figure 2 Overview of the importance of microtubule acetylation.

Notes: (A) Ac-tub expression pattern. Human epithelial cells (9/HTEo–) were immunostained with anti-Ac-tub antibodies (Santa Cruz Biotechnology, Dallas, TX, USA). (B) Transport. Microtubule acetylation increases binding affinity of microtubule motors to the microtubule, increasing both retrograde and anterograde organelle transport. (C) Inflammation. Upon lipopolysaccharide stimulation, MEC17 is inhibited along with IL-10, inducing inflammation. HDAC6 inhibition leads to IL-10 stimulation and to p38 inhibition, attenuating NF-κB upregulation and thus inflammation. (D) Signaling. Multiple signaling pathways are affected by microtubule acetylation. Here, we highlight eNOS, where Ac-tub is needed for basal eNOS phosphorylation and subcellular organization for optimal phosphorylation. (E) Gene therapy. Increased microtubule acetylation is known to increase plasmid movement, both distance and time. Ac-tub is shown in blue, while lack of PTM is shown in black.
Abbreviations: Ac-tub, acetylated alpha-tubulin; MEC17, alpha-tubulin-N-acetyltransferase 1; IL-10, interleukin-10; HDAC6, histone deacetylase 6; eNOS, endothelial nitric oxide synthase; PTM, posttranslational modification.

Table 1 Summary of potential microtubule acetylation therapeutic targets in neurodegenerative diseases

Disease	Target	Approach	Results	Reference
Alzheimer’s disease	HDAC6	4PBA	Rescue of cognitive defects, altering Αβ load, and reducing hyperphosphorylated tau	74
Parkinson’s disease	SIRT2	Genetic	Reversal of alpha-synuclein-induced neuronal toxicity and preventing cell death in Drosophila	81,82
Huntington’s disease	HDAC6	Genetic	No improvement in R6/2 mouse model	83
	SIRT2	Genetic	No improvement in Huntington’s disease transgenic mouse model	86
	SIRT2	AK-7	Improved motor function, increased survival, and reduced brain atrophy in R6/2 mouse model	87
Charcot–Marie–Tooth disease	HDAC6	Tubastatin A	Restored behavior (better steppage gait and less clawed hindpaws) and muscle mass	90
Rett syndrome	HDAC6	Tubastatin A	Restored microtubule acetylation and BDNF transport	92
	HDAC6	Genetic	Neuroprotective effects in MECP2-knockout mouse model	91
Amytrophic lateral sclerosis	HDAC6	Genetic	Increase of mutant SODI aggregation in HDAC6 knockout neurons	102
	HDAC6	Genetic	Delay of disease progression and increased survival in HDAC6- knockout mice with SOD1^G93A	101

Abbreviations: HDAC6, histone deacetylase 6; 4PBA, 4-phenylbutyric acid; SIRT2, sirtuin-2; BDNF, brain-derived neurotrophic factor; MECP2, methyl-CpG-binding protein 2; SOD1, superoxide dismutase 1.