Fellows' research: Biochemical basis of a rare human neurodegenerative disease, PHARC

16 Oct 2018

Fellows' research: Biochemical basis of a rare human neurodegenerative disease, PHARC


Dr. Siddhesh S. Kamat, Intermediate Fellow

Indian Institute of Science Education and Research (IISER), Pune

Our recently published research in Journal of Biological Chemistry, provides a biochemical explanation for why very long chain lipids (such as lysophosphatidylserine lipids) accumulate in the brains of ABHD12 knockout mice, which is a murine model of PHARC, a rare genetic neurodegenerative disease in humans.

In humans, polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract (PHARC) is an autosomally recessive genetic neurodegenerative disease, symptoms of which appear first in late childhood, and progressively worsen with age. This neurological disease is caused by deleterious (null) mutations to the Abhd12 gene, which encodes an integral membrane enzyme, ABHD12 that belongs to the metabolic serine hydrolase class of enzymes. This enzyme is currently annotated as a lipase i.e. it acts primarily on lipid substrates.

Recent studies have shown that ABHD12 knockout mice, the murine model of PHARC, show increased lysophosphatidylserine (lyso-PS) lipids in the brains of these mice, and especially very long chain lyso-PS lipids were considerably elevated. In order to explain these findings, our group used a combination of techniques ranging from organic synthesis, enzyme kinetics, LC-MS analysis, and high-resolution microscopy.

We first chemically synthesized a library of lipid substrates ranging from fatty acids C10 – C24 with different degrees of unsaturations. Next, using liquid chromatography in tandem with mass spectrometry (LC-MS), we performed rigorous enzyme kinetics studies for this lipid library against recombinant human, and endogenous mouse brain ABHD12, and found in both cases that there is a preference for very long chain lipids. Finally by high-resolution microscopy, we show that ABHD12 is localized to the membrane of the endoplasmic reticulum, a “hot” site for cellular very long chain lipid biosynthesis.

Projecting forward, we believe that the findings in this paper will certainly add new perspectives towards the biochemical understanding of PHARC, and enable researchers studying this human neurodegenerative disease with new tools in developing biomarkers for better diagnostics and downstream therapeutic intervention for this debilitating neurological condition.


Biochemical characterization of the PHARC associated serine hydrolase ABHD12 reveals its preference for very long chain lipidsAlaumy Joshi1, Minhaj Shaikh1, Shubham Singh1, Abinaya Rajendran, Amol Mhetre, Siddhesh S. Kamat*Journal of Biological Chemistry, September 2018.

1These authors contributed equally to this work.