About

We are interested in identifying novel pathways that enable cellular and organismal adaptation to metabolic stress and changes in environmental conditions. We also study how these pathways go awry in human diseases such as cancer, neurodegeneration, and metabolic syndrome in order to engineer new therapeutic modalities. To address these questions, our lab uses a multidisciplinary approach to study the biochemical functions of the lysosome in vitro and in vivo. Lysosomes are membrane-bound compartments that degrade macromolecules and clear damaged organelles to enable cellular adaptation to various metabolic states. Lysosomal function is critical for organismal homeostasis—mutations in genes encoding lysosomal proteins cause severe human disorders known as lysosomal storage diseases, and lysosome dysfunction is implicated in age-associated diseases including cancer, neurodegeneration and metabolic syndrome.

Research topics

• Biology
• Cell biology
• Genetics
• Biochemistry
• Immunology
• Molecular biology

Selected publications

• Translational lipidomics reveals BMP and its precursor LPG as biomarkers for CLN5 Batten disease

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-03-21

  articleOpen accessSenior authorCorresponding

  Abstract CLN5 Batten disease, caused by biallelic mutations in CLN5 , is a rare, early-onset neurodegenerative lysosomal storage disorder that has no cure and lacks validated biomarkers, hindering accurate diagnosis and assessment of therapeutic response. We recently identified CLN5 as the synthase of bis(monoacylglycero)phosphate (BMP), an endolysosomal phospholipid crucial for lysosome function and lipid catabolism. This suggested BMP and its precursor lysophosphatidylglycerol (LPG) as clinically relevant biomarkers. It also prompted in vivo confirmation of CLN5 as the biologically relevant lysosomal BMP synthase. Here we show that murine and ovine disease models lacking CLN5 show significant and universal depletion of BMP and elevation of LPG across tissues and brain regions, consistent with the biochemical function of CLN5. Additionally, lysosomal lysates from murine models of CLN5 Batten disease lack the ability to synthesize BMP from its precursor LPG, establishing CLN5 as the main BMP synthase in vivo . Of importance, CLN5 patient-derived fibroblasts show BMP depletion and LPG elevation. Translating these results towards clinical utility, we demonstrate BMP and LPG to be accessible biomarkers for CLN5 Batten disease in both plasma and dried blood spots, enabling early diagnosis and patient screening.

  PublisherOA PDFDOI

• Rare biallelic loss-of-function variants in the <i>LRRK2</i> kinase cause interstitial lung disease

  medRxiv · 2026-05-19

  articleOpen access

  Summary We report that biallelic LRRK2 loss-of-function (LoF) causes a Mendelian form of interstitial lung disease characterized by alveolar epithelial cell dysfunction and lung fibrosis in two brothers with a homozygous nonsense variant. Integrated clinical, imaging, histopathological, and biomarker analyses showed absent LRRK2 protein, reduced Rab10 phosphorylation, impaired alveolar type 2 cell function, and disrupted surfactant homeostasis. Consistent with a recessive genetic disorder, heterozygous LoF carriers have not been reported to have a lung phenotype. Additional biallelic LRRK2 LoF cases were identified in ILD cohorts, linking LRRK2 LoF to lung disease, in contrast to heterozygous activating missense variants that cause Parkinson’s disease (PD).

  PublisherDOI

• Mucin-binding protein shuttles enable delivery of brain-targeted therapeutics

  bioRxiv (Cold Spring Harbor Laboratory) · 2026-03-25

  articleOpen access

  The blood-brain barrier (BBB) poses a major obstacle to the delivery of therapeutics into the central nervous system (CNS) due to its highly restrictive permeability. Here, we introduce glycan-targeted delivery vehicles, or GlycoShuttles, that traverse the BBB by harnessing the cerebrovascular glycocalyx, a carbohydrate-rich layer lining the BBB lumen. We discover that mucin-domain glycoproteins within this structure serve as novel entry portals for brain delivery and engineer mucin-binding protein shuttles that enable efficient transport of diverse molecular cargo across the BBB into multiple key brain cell types. This modular platform facilitates enhanced brain delivery of a variety of payloads, including antibodies and lysosomal proteins, and demonstrates therapeutic efficacy in mouse models of dementia. Our findings establish mucin-targeted GlycoShuttles as a versatile platform for noninvasive brain delivery of therapeutics, opening new avenues for the treatment of CNS diseases.

  PublisherOA PDFDOI

• Hepatic lipid remodeling in cold exposure uncovers direct regulation of bis(monoacylglycero)phosphate lipids by phospholipase A2 group XV

  Cell Metabolism · 2025-05-14 · 12 citations

  articleOpen access

  Cold exposure is a selective environmental stress that elicits a rapid metabolic shift to maintain energy homeostasis. In response to cold exposure, the liver rewires the metabolic state, shifting from glucose to lipid catabolism. By probing the liver lipids in cold exposure, we observed that the lysosomal bis(monoacylglycero)phosphate (BMP) lipids were rapidly increased during cold exposure. BMP lipid changes occurred independently of lysosomal abundance but were dependent on the lysosomal transcriptional regulator transcription factor EB (TFEB). Knockdown of Tfeb in hepatocytes decreased BMP lipid levels and led to cold intolerance in mice. We assessed TFEB-binding sites of lysosomal genes and determined that the phospholipase a2 group XV (PLA2G15) regulates BMP lipid catabolism. Decreasing Pla2g15 levels in mice increased BMP lipids, ablated the cold-induced rise in BMP lipids, and improved cold tolerance. Mutation of the catalytic site of PLA2G15 ablated the BMP lipid breakdown. Together, our studies uncover TFEB regulation of BMP lipids through PLA2G15 catabolism. • Liver bis(monoacylglycerol)phosphate (BMP) lipids are increased with cold exposure • BMP lipids regulate liver lysosomal function and metabolic adaptation to cold • Phospholipase A2 group XV (PLA2G15) regulates BMP lipids in cold exposure • PLA2G15 loss increases BMP lipids, lysosomal lipid processing, and energy expenditure Davidson et al. demonstrated that liver lysosomes orchestrate the metabolic adaptation to cold by rewiring lipid processing. They show that phospholipase A2 group XV (PLA2G15) breaks down bis(monoacylglycerol)phosphate (BMP) lipids to shift lysosomal function and metabolism in response to direct transcription factor EB regulation.

  PublisherDOI

• Lysosomal Immunoprecipitation (LysoIP) from Cells and Tissues for Metabolomic and Proteomic Analyses

  Methods in molecular biology · 2025-10-13 · 1 citations

  book-chapterSenior author
  PublisherDOI

• Abstract 3034 Neurodegeneration: Intra-Lysosomal Lipid Metabolism in the Driver's Seat

  Journal of Biological Chemistry · 2025-05-01

  articleOpen access1st authorCorresponding

  Although only 1-3% of the volume of a cell, lysosomes have emerged as critical metabolic and signaling hubs.These membrane-bound compartments degrade macromolecules and clear damaged organelles to enable cellular adaptation to various metabolic states.Lysosomal function is critical for organismal homeostasis-mutations in genes encoding lysosomal proteins cause severe human disorders known as lysosomal storage diseases and lysosomal dysfunction is implicated in age-associated diseases including cancer, metabolic syndrome and neurodegeneration.However, the biochemical basis of the lysosomal dysfunction and how it leads to human diseases remain to be discovered.In my talk, I will present our research focused on elucidating the role of the lysosome in neurodegeneration through decoding lysosomal gene function.This work led to the discovery of novel lipid synthesis, degradation, and transport pathways whose loss causes neurodegenerative diseases, thus providing a foundation for potential therapeutic interventions.

  PublisherOA PDFDOI

• Cellular and organismal function of choline metabolism

  Nature Metabolism · 2025-01-08 · 51 citations

  reviewOpen access
  PublisherOA PDFDOI

• Defined human tri-lineage brain microtissues

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-08-07

  preprintOpen access

  SUMMARY Microglia are the immune cells of the central nervous system and are thought to be key players in both physiological and disease conditions. Several microglial features are poorly conserved between mice and human, such as the function of the neurodegeneration-associated immune receptor Trem2. Induced pluripotent stem cell (iPSC)-derived microglia offer a powerful opportunity to generate and study human microglia. However, human iPSC-derived microglia often exhibit activated phenotypes in vitro , and assessing their impact on other brain cell types remains challenging due to limitations in current co-culture systems. Here, we developed fully defined brain microtissues, composed of human iPSC-derived neurons, astrocytes, and microglia, co-cultured in 2D or 3D formats. Our microtissues are stable and self-sufficient over time, requiring no exogenous cytokines or growth factors. All three cell types exhibit morphologies characteristic of their in vivo environment and show functional properties. Co-cultured microglia develop more homeostatic phenotypes compared to microglia exposed to exogenous cytokines. Hence, these tri-cultures provide a unique approach to investigate cell-cell interactions between brain cell types. We found that astrocytes and not neurons are sufficient for microglial survival and maturation, and that astrocyte-derived M-CSF is essential for microglial survival. Single-cell and single-nucleus RNA sequencing analyses nominated a network of reciprocal communication between cell types. Brain microtissues faithfully recapitulated pathogenic α-synuclein seeding and aggregation, suggesting their usefulness as human cell models to study not only normal but also pathological cell biological processes.

  PublisherOA PDFDOI

• Robust analytical methods for bis(monoacylglycero)phosphate profiling in health and disease

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-02-17

  preprintOpen accessSenior authorCorresponding

  Abstract Bis(monoacylglycero)phosphate (BMP), a distinct anionic phospholipid predominantly found in late endosomes and lysosomes, plays a pivotal role in supporting lysosomal functions and maintaining metabolic homeostasis. Its impaired function is associated with an array of disorders, notably neurodegenerative diseases. However, the identification and quantitation of BMP remains difficult due to its structural similarity to isomer phosphatidylglycerol (PG), thus necessitating robust analytical methods for accurate and reliable BMP profiling. In this study, we present comprehensive liquid chromatography – tandem mass spectrometry (MS2) methodologies for the precise and systematic analysis of BMP species in biological samples. We detail LC/MS methods for both an untargeted Orbitrap mass spectrometer and a targeted triple quadrupole (QQQ) mass spectrometer. We utilize differences in polarity and structure to annotate BMPs and PGs based on retention time and positive mode MS2 fragmentation patterns, respectively. Further, we propose a new approach for overcoming common challenges in BMP profiling by leveraging the newly discovered biochemical function of CLN5 as the BMP synthase. Since genetic ablation of CLN5 leads to specific depletion of BMPs but not PGs, we use lipid extracts from CLN5 knockout (KO) and wild-type (WT) cells as biological standards to confidently annotate BMPs as targets with significantly low BMP Identification Index (BMPII), defined as BMPII = CLN5 KO / WT. We additionally propose the BMP enrichment score (BMPES) as a secondary validation metric, defined as lysosomal abundance of BMP / whole-cell abundance. Altogether, this approach constitutes a robust method for BMP profiling and annotation, furthering research into health and disease.

  PublisherDOI

• PLA2G15 is a BMP hydrolase and its targeting ameliorates lysosomal disease

  Nature · 2025-05-07 · 21 citations

  articleOpen accessSenior author

  Lysosomes catabolize lipids and other biological molecules, maintaining cellular and organismal homeostasis. Bis(monoacylglycero)phosphate (BMP), a major lipid constituent of intralysosomal vesicles, stimulates lipid-degrading enzymes and is altered in various human conditions, including neurodegenerative diseases1,2. Although lysosomal BMP synthase was recently discovered3, the enzymes mediating BMP turnover remain elusive. Here we show that lysosomal phospholipase PLA2G15 is a physiological BMP hydrolase. We further demonstrate that the resistance of BMP to lysosomal hydrolysis arises from its unique sn2, sn2′ esterification position and stereochemistry, as neither feature alone confers resistance. Purified PLA2G15 catabolizes most BMP species derived from cell and tissue lysosomes. Furthermore, PLA2G15 efficiently hydrolyses synthesized BMP stereoisomers with primary esters, challenging the long-held thought that BMP stereochemistry alone ensures resistance to acid phospholipases. Conversely, BMP with secondary esters and S,S stereoconfiguration is stable in vitro and requires acyl migration for hydrolysis in lysosomes. Consistent with our biochemical data, PLA2G15-deficient cells and tissues accumulate several BMP species, a phenotype reversible by supplementing wild-type PLA2G15 but not its inactive mutant. Targeting PLA2G15 reduces the cholesterol accumulation in fibroblasts of patients with Niemann–Pick disease type C1 and significantly ameliorates disease pathologies in Niemann–Pick disease type C1-deficient mice, leading to an extended lifespan. Our findings established the rules governing BMP stability in lysosomes and identified PLA2G15 as a lysosomal BMP hydrolase and a potential target for therapeutic intervention in neurodegenerative diseases. Lysosomal phospholipase PLA2G15 was identified as a physiological BMP hydrolase whose activity depends on unique esterification and stereochemistry of BMP and offers a potential therapeutic target for Niemann–Pick disease type C1 and other neurodegenerative conditions.

  PublisherOA PDFDOI

Frequent coauthors

• David M. Sabatini

  Czech Academy of Sciences, Institute of Organic Chemistry and Biochemistry

  321 shared

• Walter W. Chen

  Southwestern Medical Center

  129 shared

• Gregory A. Wyant

  Harvard University

  115 shared

• Sze Ham Chan

  University of Virginia

  73 shared

• Nouf N. Laqtom

  Stanford University

  59 shared

• Elizaveta Freinkman

  Immunai (United States)

  58 shared

• Caroline A. Lewis

  Guardant (United States)

  53 shared

• Kıvanç Birsoy

  Rockefeller University

  42 shared

Labs

• Abu-Remaileh LabPI

Education

• Postdoc

  Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology

  2019

• Ph.D. in Human Genetics and Molecular Biology, Human Genetics

  Hebrew University of Jerusalem Faculty of Medicine

  2014

• M.Sc., in Human Genetics and Molecular Biology, Human Genetics

  Hebrew University of Jerusalem Faculty of Medicine

  2008

• Bachelor of Science, Biotechnology and Genetic Engineering

  Jordan University of Science and Technology

  2006