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Anil B. Mukherjee, M.D., Ph.D.

Senior Investigator

Section on Developmental Genetics


Building 10, Room 9D42
10 Center Drive
Bethesda, MD 20892


Research Topics

Heritable Neurodegenerative, Inflammatory, and Autoimmune Disorders

The Section on Developmental Genetics conducts laboratory and clinical investigations into neurodegenerative, inflammatory, and autoimmune disorders. Our research currently focuses on understanding the molecular mechanisms of pathogenesis of a group of hereditary childhood neurodegenerative lysosomal storage disorders called neuronal ceroid lipofuscinosis (NCL), commonly known as Batten disease. Mutations in eight genes cause various types of NCLs. Currently, there are no effective treatments for any of the NCLs. The infantile NCL or INCL is an autosomal recessive disease caused by mutations in the CLN1 gene, which encodes a lysosomal enzyme, palmitoyl-protein thioesterase-1 (PPT1). PPT1 catalyzes the cleavage of thioester linkage in palmitoylated (S-acylated) proteins (constituent of ceroid), facilitating their degradation in lysosomes. Thus, PPT1 deficiency causes accumulation of ceroid in lysosomes, leading to INCL pathogenesis. Children afflicted with INCL are normal at birth but, by 11 to 18 months of age, exhibit signs of psychomotor retardation. By 2 years of age, they are completely blind due to retinal degeneration and, by the age 4, manifest no brain activity and remain in a vegetative state for 6 to 8 years before eventual death. These grim outcomes underscore the urgent need for the development of rational and effective therapeutic strategies not only for INCL but also for all NCLs.

The aim of our clinical studies is to apply the knowledge gained from our laboratory investigations to develop novel therapeutic strategies for Batten disease. The results of our earlier investigations led to a bench-to-bedside clinical trial that is currently under way. Using CNL1-knockout (PPT1-KO) mice, which recapitulate virtually all clinical and pathological features of INCL, we discovered that PPT1 deficiency causes endoplasmic reticulum (ER) and oxidative stress, which at least in part causes neuronal death by apoptosis. We also delineated a mechanism by which PPT1 deficiency disrupts the recycling of the synaptic vesicle (SV) proteins, which are essential for regenerating fresh SVs to replenish the SV pool size at the nerve terminals in order to maintain uninterrupted neurotransmission. During the past year, we demonstrated that ER and oxidative stresses mediate neuronal apoptosis and neuroinflammation. Further, we showed that omega-3 and omega-6 fatty acids suppress ER and oxidative-stress in cultured neurons and neuronal progenitor cells from PPT1-KO mice, suggesting that these fatty acids may have therapeutic potential. We also discovered that nucleophilic small molecules with antioxidant properties ameliorate the neurological abnormalities in PPT1-KO mice and extend their lifespan. These and other related studies (uteroglobin, IgA nephropathy, etc.) provide insight into the complex mechanisms of heritable disorders of neurodegeneration, inflammation, and autoimmune diseases and identify several potential therapeutic targets. Our ongoing laboratory and clinical investigations have advanced our knowledge of these diseases. We plan to apply new findings from our laboratory to develop novel therapeutic approaches not only for INCL but also for other related diseases.


Anil B. Mukherjee, M.D., Ph.D., is a Senior Investigator and Head of the Section on Developmental Genetics, PDEGEN, NICHD. This section conducts both laboratory and clinical investigations in order to understand the molecular mechanism(s) of heritable neurodegenerative and autoimmune-disorders that affect children. Current research focuses primarily on infantile neuronal ceroid lipofuscinosis (INCL), a devastating neurodegenerative storage disease caused by mutations in the palmitoyl-protein thioesterase-1 (PPT1) gene. The laboratory research of Dr. Mukherjee and his colleagues uncovered that PPT1-deficiency leads endoplasmic reticulum and oxidative stress, which mediate neuronal death by apoptosis. A few years ago, researchers in this section screened a number of small molecules that functionally mimic PPT1. On the basis of the results of their laboratory investigations, the section was given a “bench-to-bedside award” to conduct a clinical trial to determine if a combined regimen of Cystagon™ (cysteamine bitartrate) and Mucomyst® (N-acetylcysteine) is beneficial for patients with INCL. These studies are currently ongoing. Laboratory investigations to identify non-toxic compounds to suppress nonsense mutations in the PPT1 gene, which account for 31% of children with INCL in the US, are currently being pursued. For in vivo testing of these compounds a mouse model carrying the most common PPT1 nonsense mutations is being generated. Dr. Mukherjee received his Ph.D. from the University of Utah in Salt Lake City and underwent postdoctoral training in Human Genetics at Columbia University College of Physicians and Surgeons in New York. He then served as an Assistant Professor of Pediatrics and Human Genetics at the State University of New York at Buffalo for four years, following which he became a medical student at the same university and received his M.D. degree. He obtained postgraduate training in Internal Medicine and after that joined the Biochemical and Developmental Genetics Section of the NICHD as a Clinical Associate. Subsequently, he joined the US Public Health Service as a Medical Officer and was tenured to the position he currently holds. He was elected Fellow of the Medical Sciences Section of the American Association for the Advancement of Science for his scientific achievements. He is also a member of the American Society of Biochemistry and Molecular Biology and the American Human Genetics Society. Dr. Mukherjee has received numerous honors and awards, including a USPHS Commendation Medal and a Lifetime Achievement Award from his Medical School Alumni Association.

Selected Publications

  1. Sarkar C, Chandra G, Peng S, Zhang Z, Liu A, Mukherjee AB. Neuroprotection and lifespan extension in Ppt1(-/-) mice by NtBuHA: therapeutic implications for INCL. Nat Neurosci. 2013;16(11):1608-17.
  2. Bouchelion A, Zhang Z, Li Y, Qian H, Mukherjee AB. Mice homozygous for c.451C>T mutation in Cln1 gene recapitulate INCL phenotype. Ann Clin Transl Neurol. 2014;1(12):1006-23.
  3. Kim SJ, Zhang Z, Sarkar C, Tsai PC, Lee YC, Dye L, Mukherjee AB. Palmitoyl protein thioesterase-1 deficiency impairs synaptic vesicle recycling at nerve terminals, contributing to neuropathology in humans and mice. J Clin Invest. 2008;118(9):3075-86.
  4. Levin SW, Baker EH, Zein WM, Zhang Z, Quezado ZM, Miao N, Gropman A, Griffin KJ, Bianconi S, Chandra G, Khan OI, Caruso RC, Liu A, Mukherjee AB. Oral cysteamine bitartrate and N-acetylcysteine for patients with infantile neuronal ceroid lipofuscinosis: a pilot study. Lancet Neurol. 2014;13(8):777-87.
This page was last updated on October 18th, 2011