Biology:ABHD12

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example


alpha/beta-Hydrolase domain containing 12 (ABHD12) is a serine hydrolase encoded by the ABHD12 gene that participates in the breakdown of the endocannabinoid neurotransmitter 2-arachidonylglycerol (2-AG) in the central nervous system.[1] It is responsible for about 9% of brain 2-AG hydrolysis.[1] Together, ABHD12 along with two other enzymes, monoacylglycerol lipase (MAGL) and ABHD6, control 99% of 2-AG hydrolysis in the brain.[1] ABHD12 also serves as a lysophospholipase and metabolizes lysophosphatidylserine (LPS).[2]

Protein structure

ABHD12 is a ≈45 kDa integrated membrane glycoprotein, with an active site proposed to face into the extracellular space.[3]

Currently, the crystal structure of ABHD12 is not known.

Function

ABHD12 is a lysophosphatidylserine (lysoPS) lipase responsible for regulation of immune and neurological processes, and shown to act on the endocannabinoid arachidonoylglycerol (AG) as a monoacylglycerol lipase.[4][5] Endocannabinoids are associated with a range of physiological processes. ABHD12 acts on 2-AG, and accounts for approximately 9% of 2-AG hydrolysis in the brain.[1] Along with MAGL and ABHD6, ABHD12 is responsible for 99% of 2-AG hydrolysis in the brain,[3] and has also been shown to act on the 1(3)-AG isomer.[5] Based on the extracellular face of the ABHD12 active site and its ability to act on multiple isomeric substrates, ABHD12 has been suggested to act as a guard to the extracellular 2-AG-CB2R signalling pathway in microglia, and peripheral 2-AG signalling, however this has not been confirmed.[5][1]

ABHD12 transcription is abundant in the brain, specifically microglia, but has also been identified in peripheral cell types like macrophages and osteoclasts.[6] Murine models have shown ABHD12 plays a role in regulation of lysophosphatidylserine pathways in the brain.[7]

Clinical significance

Mutations that compromise the catalytic activity of ABHD12 have been causally linked to the rare neurodegenerative disease PHARC (polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, cataracts)[6] and a small proportion of retinitis pigmentosa.[8][9]

History

Identification of ABHD12 was first reported in genetic profiling of autosomal recessive retinitis pigmentosa in 1995.[8] In 2010, mutations in ABHD12 were reported as a causal link for the neurodegenerative disease PHARC .[6]

Mutations

Mutations in ABHD12 are associated with the rare neurodegenerative disorder PHARC, as well as retinitis pigmentosa. Null mutations have been shown to lead to development of PHARC, while other mutations can result in a range of phenotypes, from non-syndromic retinal degeneration to PHARC.[10]

Currently, PHARC has been identified in at least 27 individuals, with 15 identified loss of function variants of ABHD12,[11] comprising four nonsense, four missense, four frameshift and one splicing mutation.[6][10][11][12][13][14][15] ABHD12 missense mutations have been identified in individuals with retinitis pigmentosa, and a growing range of phenotypes associated with ABHD12 mutations from PHARC to non-syndromic retinal degeneration are being discovered.[10][14]

In vitro, enzymatic activity of ABHD12 can be eliminated by site mutation the residues Serine-246, Aspartate-333, or Histidine-372, which form a catalytic triad in the hydrolase domain.[5]

Inhibitors

Inhibitors of ABHD12 have been identified.[2] Orlistat (tetrahydrolipstatin; THL) and methyl arachidonyl fluorophosphonate (MAFP), so-called "universal lipase/serine hydrolase inhibitors" that are extremely non-selective enzyme inhibitors, were found to inhibit ABHD12.[2] Selective reversible inhibitors have also been identified, including betulinic acid, maslinic acid, oleanolic acid, and ursolic acid.[2]

Models

The α/β hydrolase domain including lipase motif and catalytic triad is conserved between murine and human ABHD12.[7]

Based on the observation of ABHD12 mutation in PHARC affected subjects, PHARC cell lines have been considered as human models of ABHD12 knockout.[6]

Mouse knockout (ABHD12 -/-) models demonstrate cerebellar microgliosis, motor and auditory impairment, alongside elevated neuroinflammation with progression associated with age. These characteristics are considered PHARC-like phenotypes as a murine model for human PHARC, however the mouse knockout model doesn't demonstrate ocular or myelination defects, or early onset typical of PHARC.[7] The ABHD -/- murine model shows increased long-chain lysoPS accumulation in the brain suggesting lysoPS signalling contributes to PHARC-like pathology.[7]

A zebrafish knockdown (+/-) model has been developed which demonstrates ophthalmic defects including microphthalmia, lack of lens clarity, and disrupted retina architecture.[11]

Interactions

Elevated lysoPS accumulation in ABHD12 knockout mice suggests lysoPS as an in vivo substrate of ABHD12.[7] Elevated lysoPS production in ABHD12 null cells from PHARC subjects can be reversed using an inhibitor of ABHD16A.[16]

In vitro studies demonstrate enzymatic hydrolysis of monoacylglycerol long lipid chains by ABHD12. ABHD12 can use both 1(3)-AG and 2-AG as substrates at comparable enzymatic rates.[5]

ABHD12 has been shown to be associated with AMPA type glutamate receptors in the brains of rats.[17]

See also

References

  1. ↑ 1.0 1.1 1.2 1.3 1.4 "The serine hydrolases MAGL, ABHD6 and ABHD12 as guardians of 2-arachidonoylglycerol signalling through cannabinoid receptors". Acta Physiologica 204 (2): 267–76. February 2012. doi:10.1111/j.1748-1716.2011.02280.x. PMID 21418147. 
  2. ↑ 2.0 2.1 2.2 2.3 "Discovery of triterpenoids as reversible inhibitors of α/β-hydrolase domain containing 12 (ABHD12)". PLOS ONE 9 (5): e98286. 2014. doi:10.1371/journal.pone.0098286. PMID 24879289. Bibcode: 2014PLoSO...998286P. 
  3. ↑ 3.0 3.1 "A comprehensive profile of brain enzymes that hydrolyze the endocannabinoid 2-arachidonoylglycerol". Chemistry & Biology 14 (12): 1347–56. December 2007. doi:10.1016/j.chembiol.2007.11.006. PMID 18096503. 
  4. ↑ "The serine hydrolase ABHD6 controls the accumulation and efficacy of 2-AG at cannabinoid receptors". Nature Neuroscience 13 (8): 951–7. August 2010. doi:10.1038/nn.2601. PMID 20657592. 
  5. ↑ 5.0 5.1 5.2 5.3 5.4 "Biochemical and pharmacological characterization of human α/β-hydrolase domain containing 6 (ABHD6) and 12 (ABHD12)". Journal of Lipid Research 53 (11): 2413–24. November 2012. doi:10.1194/jlr.M030411. PMID 22969151. 
  6. ↑ 6.0 6.1 6.2 6.3 6.4 "Mutations in ABHD12 cause the neurodegenerative disease PHARC: An inborn error of endocannabinoid metabolism". American Journal of Human Genetics 87 (3): 410–7. September 2010. doi:10.1016/j.ajhg.2010.08.002. PMID 20797687. 
  7. ↑ 7.0 7.1 7.2 7.3 7.4 "ABHD12 controls brain lysophosphatidylserine pathways that are deregulated in a murine model of the neurodegenerative disease PHARC". Proceedings of the National Academy of Sciences of the United States of America 110 (4): 1500–5. January 2013. doi:10.1073/pnas.1217121110. PMID 23297193. Bibcode: 2013PNAS..110.1500B. 
  8. ↑ 8.0 8.1 "Retinitis pigmentosa in Spain". Clinical Genetics 48 (3): 120–122. 1995. doi:10.1111/j.1399-0004.1995.tb04069.x. 
  9. ↑ "Genetic characterization and disease mechanism of retinitis pigmentosa; current scenario". 3 Biotech 7 (4): 251. August 2017. doi:10.1007/s13205-017-0878-3. PMID 28721681. 
  10. ↑ 10.0 10.1 10.2 "Exome sequencing extends the phenotypic spectrum for ABHD12 mutations: from syndromic to nonsyndromic retinal degeneration". Ophthalmology 121 (8): 1620–7. August 2014. doi:10.1016/j.ophtha.2014.02.008. PMID 24697911. 
  11. ↑ 11.0 11.1 11.2 "Functional validation of ABHD12 mutations in the neurodegenerative disease PHARC". Neurobiology of Disease 98: 36–51. February 2017. doi:10.1016/j.nbd.2016.11.008. PMID 27890673. 
  12. ↑ "Targeted next-generation sequencing identifies a homozygous nonsense mutation in ABHD12, the gene underlying PHARC, in a family clinically diagnosed with Usher syndrome type 3" (in En). Orphanet Journal of Rare Diseases 7 (1): 59. September 2012. doi:10.1186/1750-1172-7-59. PMID 22938382. 
  13. ↑ "Two novel mutations in ABHD12: expansion of the mutation spectrum in PHARC and assessment of their functional effects". Human Mutation 34 (12): 1672–8. December 2013. doi:10.1002/humu.22437. PMID 24027063. 
  14. ↑ 14.0 14.1 "Novel ABHD12 mutations in PHARC patients: the differential diagnosis of deaf-blindness". The Annals of Otology, Rhinology, and Laryngology 124 (1_suppl): 77S–83S. May 2015. doi:10.1177/0003489415574513. PMID 25743180. 
  15. ↑ "Phenotypical features of two patients diagnosed with PHARC syndrome and carriers of a new homozygous mutation in the ABHD12 gene". Journal of the Neurological Sciences 387: 134–138. April 2018. doi:10.1016/j.jns.2018.02.021. PMID 29571850. 
  16. ↑ "Immunomodulatory lysophosphatidylserines are regulated by ABHD16A and ABHD12 interplay". Nature Chemical Biology 11 (2): 164–71. February 2015. doi:10.1038/nchembio.1721. PMID 25580854. 
  17. ↑ "High-resolution proteomics unravel architecture and molecular diversity of native AMPA receptor complexes". Neuron 74 (4): 621–33. May 2012. doi:10.1016/j.neuron.2012.03.034. PMID 22632720. 



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