Table 1.

Mechanistic role of HDAC family, in various neurological disorders and their localization in brain.

Class	Sub Class	Modulat-or	Sub Cellular Localization	Pathophysiological Role/Disease			Drug Target		References
							Specific Drugs	Examples
				Gene/ Protein Upregulated		Gene/ Protein Downregulated
Class I	HDAC1 (Neurotoxic/ protective)	HDAC3 (-ve modulator) AD	Hippocampus, cortex	Parkinsonism			Sodium butyrate, Phenyl butyrate	Butyric acid, Valproic acid Tubastatin A Lacosamide	[27, 150-154]
				NF-kB, p21ras P21rac Glutamate	BDNF GDNF HSP70 Alpha- synuclein Bcl2 Gelsolin
				Alzheimer’s Disease
				HSP90 Alpha-synuclein Beta-catenin Tau protein H4k8 acetylation Acetylation (H3k9, H3k14, H4k5,&H4k12)		gluR1, PSD95 Neprilysin Tubulin acetylation
							Specific Drugs	Examples
				Gene/ Protein Upregulated		Gene/ Protein Downregulated
-	-	-	-	Huntington’s Disease			-	-	-
				Glial fibrillary acidic protein
	HDAC2 (Neuro-toxic/protective –NR)	-	Nucleus	Parkinsonism-			Butyric acid Valproic acid	-	[151, 154]
				NF-kB, p21ras P21rac Glutamate P53 E2F1 GATA4		BDNF GDNF HSP70
	HDAC3 (Neuro-toxic) HDAC 8(Neuro-toxic/protective- (NR)	-	Nucleus/ cytoplasm Nucleus	Alzheimer’s-			Valproic acid RGFP963 EGCG VorinostatTSA RGFP966 Phenyl butyrate ACY-738 or tubastatin, Sodium phenylbutyrate, MC1568		[152, 154-158] [17, 154, 159-161]
				Aβ peptide GSK3β Tau phosphorylation Tau acetylation β secretase cleavage of APP amyloid β(1-42) accumulation		BDNF PSD95 GluR1 HSP acetylation
				Huntington’s –
				Implicate aberrant transcriptional patterns Helps fuel CAG repeats expression Negative regulation of gene expression Histone methylation caspases Site- specific acetylation of mutant huntigtin Histone acetylation Huntington’s – Negative regulation of gene expression Histone methylation caspases Site- specific acetylation of mutant huntigtin Histone acetylation Amyotrophic lateral sclerosis
				Mir206/FGFBP1-mediated muscle reinnervation	α- tubulin acetylation histone skeletal muscle electrical potentials myogenic genes expression
							Specific Drugs	Examples
				Gene/ Protein Upregulated		Gene/ Protein Downregulated
Class II (a)	HDAC 4 (Neuro-protective) S	-	Nucleus/cytoplasm	Amyotrophic lateral sclerosis-			ACY-738 or tubastatin, Sodium phenylbutyrate, MC1568	Valproic acid Trichostatin A BML-210	[154, 161, 162]
				Mir206/FGFBP1-mediated muscle reinnervation	Histone acetylation α- tubulin acetylation myogeneic genes expression
	HDAC5 (Neuro-toxic/protective)	-	Nucleus/cytoplasm	Alzheimer’s-			Valproic acid EGCG	Trichostatin A BML-210	[14, 27, 152, 154]
				plays a role in the consolidation of contextual and tone dependent fear memories Alpha-synuclein Beta-catenin Tau protein	PSD95 Neprilysin Tubulin acetylation
-	-	-	-	Parkinsonism-			Phenyl butyrate	Valproic acid
				Essential for spatiotemporal control of ERG (early response gene) programme during memory encoding Histone H3 lysine 9 Acetylation
	HDAC7 (neuroprotective)	-	Nucleus/cytoplasm	Parkinsonism			Valproate, RGFP109	TSA, Vorinostat, sodium phenyl butyrate	[163]
				Decrease beta catenin activity in chondrocytes interact with Bcl6 Decrease BDNF and GDNF expression
	HDAC9 (Neuro-toxic/protective-NR)	-	Nucleus/cytoplasm	Amyotrophic lateral sclerosis			MC1568 ACY-738	Valproic acid Trichostatin A BML-210	[154, 159-161]
				FGFBP1-mediated muscle reinnervation	Skeletal muscle electrical potentials, myogenic genes
Class II(b)	HDAC6 (Neuro-protective /toxic)	-	Cytoplasm	Huntington’s Disease			Vorinostat	TSA Phenylbutyrate RGFP966	[154, 157]
				Accumulation of misfolded protein Glial fibrillary	Decrease tubulin acetylation Histone acetylation
	-	-	-	Alzheimer’s Disease			Tubastatin A MPT0G211	4-Phenylbutyrate Tubacin EGCG	[152, 154]
				HDAC6-HSP90 binding Tau hyperphosphorylation	Tubulin acetylation
							Specific Drugs	Examples
				Gene/ Protein Upregulated		Gene/ Protein Downregulated
-	-	-	-	Parkinsonism			Valproate	TSA, Vorinostat, sodium phenyl butyrate	[27, 154]
				Deacetylation of Prxl and Prxl2 (peroxiredoxin) Oxidative cell injury	BDNF& GDNF expression
	HDAC10 (Neuro-Toxic/protective-NR)	-	Cytoplasm	Alzheimer’s Disease			Valproic acid EGCG	Trichostatin A BML-210	[154]
				plays a role in the consolidation of contextual and tone dependant fear memories	Tubulin acetylation
Class III (sirtuins)	Sirt 1	-	Nucleus	Alzheimer’s Disease			Crebinostat Salisistate	Valproate RGFP963 EGCG	[154]
				Fear learning& memory in wild type mice on treatment, Granulin expression Synepsin1 expression	mi-RNA mi-134 expression CREB& BDNF expression
	Sirt 2	-	Cortex, striatum, hippocampus, spinal cord	Parkinsonism			AGK-2	Trichostatin A BML-210	[154, 164, 165]
				Regulate microtubule function, cell cycle, oxidative stress, Autophagy, overexp- ession increases α synuclein aggregation	Glutamate transporter 1 and glutamate/ aspartate transporter
-	-	-	-	Huntington’s Disease			Vorinostat	Trichostatin A BML-210	[154, 157]
				Increase accumulation of polyglutamine in the N terminus of neuron	Histone acetylation
	-	-	-	Alzheimer’s Disease			-	Vorinostat, sodium phenyl butyrate Trichostatin A	[166]
				Abnormally overexpressed and deacetylates tubulin which results microtubule stabilization
	Sirt 3	-	Mitochondria/Cytoplasm	Alzheimer’s Disease			-		[167]
				Dysregulation of sirt 3 linked to mitochondrial dysfunction, Over expression restored the expression of ND2 and ND4 and increase mitochondrial oxygen consumption by repressing mito p53 activity, Shows strong deacetylaseactivity
				Gene/ Protein Upregulated		Gene/ Protein Downregulated
-	-	-	-	Parkinsonism-			-	-	[168, 169]
				Sirt 3 acts indirectly on PINK1 and the sirt3-FOXO3 pathway activates mitophagy via PINK1 parkin pathway Decrease level of superoxide (SOD-2) and glutathione peroxidase expression in MPTP induce SIRT KO mice in vivo, Clinically not reported
	Sirt 4	-	Mitochondria	Alzheimer’s Disease			-	Vorinostat Quicinostat s	[111, 169]
				Specific role of Sirt 4 is not well reported but shows various physiological role in various tissues. Recent study shows Sirt 4 is up-regulated in brain on treatment with kainic acid decrease the level of glutamate leads to neuro-degeneration.
	Sirt 5	-	Mitochondria	Parkinsonism			-	Valproic acid	[169]
				Expression of sirt5 seen in MPTP induced nigrostriatal degeneration in SIRT5 KO mice.
	Sirt 6	-	Mitochondria	Alzheimer’s Disease			-	Vorinostat Quicinostat s	[169, 170]
				Recent study shows that sirt 6 increase the stability of tau protein while decrease level of sirt6 increase the hyperphosrylated tau levels
	Sirt7	-	Nucleus/Nucleolus	Specific role of sirt7 in neurodegenerative diseases and brain not well reported			-		[30, 118]
-	Sirt8	-	Nucleolus	Expression of Sirt8 is not well reported in neurodegenerative disorders.			-	-	[170]
Class IV	HDAC11 (Neurotoxic/protective-NR)	-	Nucleus (cornu Ammonis1)/spinal cord	Schizophrenia			-	-	[171]
				EGF FGF Interleukin-10	BDNF GDNF Nerotrophin-3(NT-3)