Laboratory of Lipids & Neurological Diseases

Laboratory of Lipids
& Neurological
Diseases

We investigate how the central nervous system acquires, metabolizes, and traffics lipids; and how impaired lipid metabolism drives neurodegenerative diseases like FTD, ALS, and Parkinson's Disease.

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Baylor College of Medicine Texas Children's Hospital Houston, TX
00 / Overview

Research program

An interdisciplinary program decoding brain lipid biology to combat neurodegenerative diseases.

Lab overview infographic: Decoding Brain Lipid Biology to Combat Neurodegenerative Diseases — showing LC-MS/MS lipidomics, metabolic tracing, chemical proteomics, organic synthesis, genetics, molecular biology, iPSC-derived models, murine models, and biochemistry radiating from a central brain visualization. Mission: to understand how lipids shape brain function and drive disease, and to translate discoveries into therapeutic strategies.
01 / About

Scope of work

The brain is one of the most lipid-rich organs in the human body — yet how lipids are acquired, distributed, and metabolized in the central nervous system remains poorly understood. Our lab works at the interface of chemistry, biochemistry, and neuroscience to fill this knowledge gap.

We integrate LC‑MS/MS lipidomics, metabolic tracing, chemical proteomics, organic synthesis, genetics, biochemistry, and iPSC‑derived cellular and murine models to investigate how deregulated lipid metabolism drives neurodegeneration.

~60%
Brain dry weight is lipid
5
Active research questions
14+
Peer‑reviewed publications
∞
Curiosity for the field
Principal Investigator
Shubham Singh, Ph.D.
Assistant Professor of Pediatrics & Neurology
Institution
Baylor College of Medicine
Texas Children's Hospital
02 / Focus

Research

Brain is one of the most lipid-rich organs in the human body, yet the mechanisms through which lipids are acquired, distributed, and metabolized in the central nervous system remain elusive. We are investigating the fundamental principles of lipid metabolism in brain, and elucidating mechanisms through which deregulated lipids arise and contribute to neurodegenerative diseases like frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), and Parkinson’s disease. A few broad questions that were are interested to answer in long-run,

Brain anatomical diagram showing neurodegenerative diseases and their associated lipid-metabolism risk genes — Alzheimer's (APOE4, INPP5D, PLCG2, ABCA1, ABCA2, ABCA5), Parkinson's (GBA, PSAP, PLA2G6), FTD (GRN), ALS (PLA2G6, SPTLC1), Huntington's, and PHARC/Spastic Paraplegia (ABHD12).
Alzheimer's disease
APOE4 · INPP5D · PLCG2
ABCA1 · ABCA2 · ABCA5
Parkinson's disease
GBA · PSAP · PLA2G6
Frontotemporal dementia
GRN
Amyotrophic lateral sclerosis
PLA2G6 · SPTLC1
Huntington's disease
Lipid dysregulation in striatum
PHARC & spastic paraplegia
ABHD12
03 / Research

Key questions

In long-run, we aim to address following questions:

01

What proportion of brain lipids are acquired from the diet versus synthesized locally within the brain?

Brain is one of the most lipid-rich organs in the body, yet it remains unclear how much of its lipid content is derived from the diet versus synthesized locally within the central nervous system. Because the blood-brain barrier restricts movement of many circulating lipids, neural cells must tightly regulate lipid uptake and endogenous synthesis to maintain membrane integrity, myelination, and cellular signaling. Also, it remains unclear how excessive lipids that cannot be degraded like cholesterol are flushed out of brain. We seek to understand how the brain balances these distinct sources of lipids and how disruption of these pathways contributes to neurological disease.

Blood‑brain barrier Cholesterol efflux ApoE pathways Glymphatic clearance
Schematic showing lipid transport into the brain: dietary lipids from gut, lipoprotein particles in blood, blood-brain barrier transport, local synthesis in neurons/astrocytes/oligodendrocytes/microglia, efflux via ApoE-dependent lipoproteins, and glymphatic CSF clearance.
02

How does the brain balance glucose utilization between energy production and glycosphingolipid synthesis?

Glucose is the primary energy source for the brain — but it's also a critical building block for the synthesis of complex lipids, including glycosphingolipids that are essential for neuronal membranes, myelin formation, and cellular signaling. How the brain allocates glucose between these competing demands remains poorly understood.

Metabolic tracing Glycosphingolipids Mitochondria Myelin
Diagram showing brain glucose utilization branching into ATP production via mitochondria and glycosphingolipid synthesis with building-block annotations (fatty acid, sphingosine, galactose, glucose, N-acetylgalactosamine, sialic acid).
03

How do neurons and glia coordinate lipid metabolism?

Neurons and glial cells have distinct but highly interconnected metabolic roles in the brain. Because neurons possess limited capacity for lipid storage and synthesis, they rely heavily on glial cells including astrocytes, oligodendrocytes for lipid synthesis and microglia for lipid recycling. We seek to understand how these cell types coordinate lipid synthesis, trafficking, utilization, and clearance to maintain neuronal function and myelin integrity. Disruption of this metabolic partnership may contribute to lipid accumulation, neuroinflammation, and neurodegeneration.

Astrocytes Oligodendrocytes Microglia
04

How does genetic variation in lipid metabolism predispose to neurodegeneration?

Genetic studies have identified numerous neurodegenerative disease risk genes that function in lipid metabolism, trafficking, and lysosomal homeostasis. Mutations in genes involved in cholesterol metabolism, sphingolipid degradation, and lipid transport can disrupt neuronal lipid balance, leading to lipid accumulation, neuroinflammation, and cellular dysfunction. We seek to understand how genetic variation alters lipid metabolic pathways in the nervous system and why these defects selectively predispose neurons to degeneration. Defining these mechanisms may uncover new biomarkers and therapeutic targets for neurodegenerative disease.

APOE · ABCA GBA · GRN ABHD12 · SPTLC1 Lysosomal homeostasis
Brain anatomical figure overlaid with neurodegeneration risk genes mapped to disease regions — Alzheimer's, Parkinson's, FTD, ALS, Huntington's, and PHARC/Spastic Paraplegia.
05

How do lipid disturbances arise in sporadic neurodegeneration, and can they predict disease risk?

Most neurodegenerative diseases occur sporadically, without a clear inherited genetic cause, yet many exhibit profound disturbances in lipid metabolism. Aging, diet, metabolic stress, inflammation, and environmental factors may progressively disrupt lipid homeostasis in the brain, leading to toxic lipid accumulation, impaired lysosomal function, and neuronal vulnerability. We seek to understand how these lipid alterations emerge during early disease progression and whether specific lipid signatures in the brain or circulation can serve as biomarkers to predict neurodegeneration risk before the onset of clinical symptoms.

Plasma lipidomics Biomarkers Aging Lipid droplets
Sporadic neurodegeneration: factors including aging, environmental exposures, metabolic stress, inflammation and lifestyle leading to brain lipid accumulation. Comparison of healthy control brain and neurodegenerated brain showing accumulation of lipid droplets and sphingolipids; with research questions about mechanism and biomarker potential.
04 / Approach

An interdisciplinary toolkit

We combine quantitative mass spectrometry, chemical biology, cellular and murine models.

01

LC‑MS/MS lipidomics

Quantitative profiling of thousands of lipid species across tissues, fluids, and cellular compartments.

02

Metabolic tracing

Isotope-labeled precursors track the synthesis, breakdown, and inter-organelle flow of brain lipids.

03

Chemical proteomics

Bifunctional lipid probes map lipid-binding and lipid-modifying enzymes.

04

Organic synthesis

Custom lipid probes, and analogs designed and synthesized in-house.

05

Genetics & molecular biology

CRISPR, knockouts, and disease-variant models to interrogate gene–lipid–phenotype.

06

iPSC‑derived models

Patient-derived iPSCs differentiated into neurons, astrocytes, and microglia for human disease modeling.

07

Murine models

Genetically engineered mouse models for in-vivo metabolic flux and disease modelling.

08

Biochemistry

Enzymology and structural biochemistry of lipid hydrolases, transferases, and transport proteins.

05 / People

The team

We are interdisciplinary group integrating chemical biology, mass spectrometry and in vivo disease modelling to address fundamental questions in lipid metabolism and neurological diseases

The Laboratory of Lipids and Neurological Diseases team at the Texas Children's Hospital Feigin Tower — Shubham Singh (PI), Hanna Norwood, Femil J. Shajan, Jyotsna Shukla, and Srividhya Raja.
The lab at Feigin Tower, Texas Children's Hospital · Houston
Shubham Singh, Principal Investigator — wearing a white lab coat with Baylor College of Medicine and Texas Children's Hospital badges
Shubham Singh
Principal Investigator · Asst. Prof. of Pediatrics/Neurology

Jyotsna Shukla, Postdoctoral Fellow
Jyotsna Shukla
Postdoctoral Fellow

Ph.D. in immunology (National Institute of Immunology); postdoctoral training at IISER-Pune. Investigates how deregulated lipids drive neuroinflammation and neurodegeneration.

Femil J. Shajan, Postdoctoral Fellow
Femil J. Shajan
Postdoctoral Fellow

Ph.D. in Chemical Biology (Temple University). Studies mechanisms of lipid transport in the central nervous system and how defects in these pathways contribute to neurodegeneration.

Srividhya Raja, Research Assistant
Srividhya Raja
Research Assistant · M.S.

Research volunteer in the lab, training in molecular biology and mass spectrometry–based omics approaches.

Your name here.
Postdoc · Grad Student · Intern

We're actively recruiting curious scientists across all career stages. See open positions →

Alumni

Name Role in lab Current Position
Hanna Norwood Research Technician II M.D. at McGovern Medical School (UTHealth), Houston
Venkata Pullabhotla Intern Undergraduate at Rice University, Houston
06 / Publications

Selected publications

2025
Alzheimer's & Dementia · PMID 40922380

Plasma lipidome dysregulation in frontotemporal dementia reveals shared, genotype-specific, and severity-linked alterations.

Ambaw Y., Ljubenkov P.A., Singh S., Hamed A., Sebastian B., Boxer A.L., Walther T.C.*, Farese R.V.*

View ↗
2025
bioRxiv · Manuscript in preparation

LipidCruncher: an open-source web application for processing, visualizing, analyzing lipidomics data.

Hamed A., Ambaw Y., Singh S., Weng Z.L., Farese R.V.*, Walther T.C.*

App ↗
2024
Cell · 187(24), 6820–6834

PLD3 and PLD4 synthesize S,S-BMP, a key phospholipid enabling lipid degradation in lysosomes.

Singh S., U.D., Ambaw Y., Joshua L.S., Farese R.V.*, Walther T.C.*

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2024
Nat. Cell Biology · In revision

Senescence impedes ferroptosis through SASP-mediated GCH1 upregulation.

Peng N., Singh S., Zhao Z., Kim J., Mo Y., Farese R.V., Walther T.C., Jiang X.*

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2023
Nature Communications · 13, 5924

Deficiency of frontotemporal dementia gene GRN results in gangliosidosis.

Sebastian B., Swarup S., Ambaw Y., Richards R.C., Fischer A.W., Singh S., Aggarwal G., …, Harper J.W., Walther T.C.*, Farese R.V.*

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2023
Microbiology Spectrum · 11(1), e02597-22

Respiratory quinone switch from menaquinone to polyketide quinone during the development cycle in Streptomyces sp. MNU77.

Mehdiratta K., Nain S., Sharma M., Singh S., Srivastva S., Dhamale B.D., Mohanty D., Kamat S.S., Natarajan V.T., Sharma R., Gokhale R.S.*

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2022
eLife · 11, e77665

DIP2 is a unique regulator of diacylglycerol lipid homeostasis in eukaryotes.

Mondal S., Kinatukara P., Singh S., Sailasree P., Patil G.S., Shambhavi S., Madduri K.M., Kamat S.S., Kumar S., Sankaranarayanan R.*

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2022
PNAS · 119(8), e2110293119

Kupyaphores are zinc homeostatic metallophores required for colonization of Mycobacterium tuberculosis.

Mehdiratta K., Singh S., Sharma S., Bhosale R., et al., Mohanty D., Reddy D.S., Natarajan V.T., Kamat S.S.*, Gokhale R.S.*

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2021
Eur. J. Neuroscience · 54(10), 7442–7457

Loss of enzymatic activity of the PHARC-associated lipase ABHD12 results in increased phagocytosis that causes neuroinflammation.

Singh S., Kamat S.S.*

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2021
Chemical Science · 12, 12939–12949

Leveraging an enzyme/artificial substrate system to enhance cellular persulfides and mitigate neuroinflammation.

Bora P., Manna S., Nair M., Sathe R., Singh S., Adury V.S.S., Gupta K., Mukherjee A., Saini D.K., Kamat S.S., Hazra A.B.*, Chakrapani H.*

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2020
Biochemistry · 59(24), 2299–2311

Mapping the neuroanatomy of ABHD16A–ABHD12 and lysophosphatidylserine provides new insights into the pathophysiology of PHARC.

Singh S.*, Joshi A., Kamat S.S.* (*Co-corresponding author)

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2020
Cell Chemical Biology · 2021 Jan 21; S2451-9456(21)00008

Fatty acid chain length drives lysophosphatidylserine-dependent immunological outputs.

Khandewal N.#, Sheikh M.#, Mhetre A.#, Singh S.#, Sajeevan T., Joshi A., Balaji N.K., Chakrapani H., Kamat S.S.* (#Equal contribution)

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2020
Transgenic Research · 29, 553–562

Pre-natal growth retardation rate and fast mass accumulation in mice lacking Dip2A is dependent on dietary lipid nutrients.

Kinatukara P., Sailasree P., Patil G.S., Shambhavi S., Singh S., Mhetre A., Madduri K.M., Kamat S.S., Kumar S., Sankaranarayanan R.*

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2019
Nature Chemical Biology · 15, 169–178

A chemical genetic screen identifies ABHD12 as an oxidized phosphatidylserine lipase.

Kelkar D.S.#, Ravikumar G.#, Mehendale N.#, Singh S.#, Joshi A., Sharma A.K., Mhetre A., Rajendran A., Chakrapani H., Kamat S.S. (#Equal contribution)

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2018
J. Biological Chemistry · 293(44), 16953–16963

Biochemical characterization of the PHARC-associated serine hydrolase ABHD12 reveals its preference for very long chain lipids.

Joshi A.#, Shaikh M.#, Singh S.#, Rajendran A., Mhetre A., Kamat S.S.* (#Equal contribution)

View ↗
2018
ACS Chemical Biology · 13(8), 2280–2287

Lipidomics suggests a new role for ceramide synthase in phagocytosis.

Pathak D.#, Mehendale N.#, Singh S., Mallik R., Kamat S.S.* (#Equal contribution)

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Showing 16 publications. Full list including reviews and methods papers on Google Scholar.

Full list on Google Scholar
07 / Open positions

Join us

We're actively recruiting postdocs, graduate students, and research interns. Curiosity, scientific rigor, and a willingness to learn across disciplines matter more to us than a particular technical expertise.

Send a cover letter, CV, and contact information for three references to:

shubham.singh@bcm.edu
Postdoctoral Fellow
Open
Graduate Student
Open
Graduate Student
Open
Research Intern
Open
Research Volunteer
Rolling
08 / Contact

Find us

We're on the 10th floor of Feigin Tower on the Texas Medical Center in Houston.

Address
1102 Bates Avenue
Feigin Tower, 10th floor
Houston, TX 77030