Neuronal ceroid lipofuscinoses (NCLs) are among the most devastating inherited disorders of childhood and the most common cause of neurodegeneration in children in the U.S. There is currently no cure for these disorders, and treatments remain largely supportive. NCLs are characterized by the progressive intralysosomal accumulation of ceroid lipopigment; this accumulation is thought to result from defects in lysosomal metabolism or trafficking, but could itself contribute to pathogenesis. We hypothesize that enhancing clearance processes will counteract disease progression in NCLs, even if the primary defect remains uncorrected. To test this hypothesis, we will boost lysosomal function by using genetic (Tfeb) and chemical (trehalose) enhancers of clearance processes in two mouse models of NCLs.
In Aim 1 we will generate and characterize transgenic mice that conditionally express either a normal or constitutively active form of the transcription factor EB (TFEB), a master modulator of lysosomal and autophagic pathways. We will also perform molecular genetic analyses that will enable us to map the TFEB targetome, a crucial step in understanding its activities in health and disease.
In Aim 2 we will cross these transgenics with Cln3 ex7/8 and Cln8mnd mice, two well-characterized models of NCLs, to investigate the effects of genetic TFEB enhancement on disease course. Importantly, we use models of NCL caused by mutations in two distinct genes in order to rigorously test whether TFEB- mediated clearance can indeed mitigate disease regardless of the underlying defect.
In Aim 3 we will study the metabolism of trehalose, a putative inducer of autophagic pathways, which our data indicate activates TFEB; we will test the effect of trehalose on disease course in the two NCL models. Results from this project will show whether genetically or chemically induced lysosomal enhancement is able to counteract disease progression in NCLs and impact health and life span of affected animals. Positive results from this study will be the foundation for the development of a therapy for these devastating disorders. In addition, any knowledge gained from studies on NCLs could, in principle, be applicable to other neurodegenerative disorders caused by defects in lysosome-mediated cellular clearance.

Public Health Relevance

Neuronal ceroid lipofuscinoses (NCLs) are among the most devastating inherited disorders of childhood and the most common cause of neurodegeneration in children in the U.S. The proposed work will assess the potential of genetic and chemical enhancers of cellular clearance to counteract disease progression in NCLs, providing new therapeutic avenues for the treatment of these disorders.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Morris, Jill A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Baylor College of Medicine
Schools of Medicine
United States
Zip Code
di Ronza, Alberto; Bajaj, Lakshya; Sharma, Jaiprakash et al. (2018) CLN8 is an endoplasmic reticulum cargo receptor that regulates lysosome biogenesis. Nat Cell Biol 20:1370-1377
Lotfi, Parisa; Tse, Dennis Y; Di Ronza, Alberto et al. (2018) Trehalose reduces retinal degeneration, neuroinflammation and storage burden caused by a lysosomal hydrolase deficiency. Autophagy 14:1419-1434
Bajaj, Lakshya; Lotfi, Parisa; Pal, Rituraj et al. (2018) Lysosome biogenesis in health and disease. J Neurochem :
Pal, Rituraj; Palmieri, Michela; Chaudhury, Arindam et al. (2018) Src regulates amino acid-mediated mTORC1 activation by disrupting GATOR1-Rag GTPase interaction. Nat Commun 9:4351
Chang, Kevin T; Guo, Junyan; di Ronza, Alberto et al. (2018) Aminode: Identification of Evolutionary Constraints in the Human Proteome. Sci Rep 8:1357
Palmieri, Michela; Pal, Rituraj; Sardiello, Marco (2017) AKT modulates the autophagy-lysosome pathway via TFEB. Cell Cycle 16:1237-1238
Palmieri, Michela; Pal, Rituraj; Nelvagal, Hemanth R et al. (2017) mTORC1-independent TFEB activation via Akt inhibition promotes cellular clearance in neurodegenerative storage diseases. Nat Commun 8:14338
Pal, Rituraj; Bondar, Vitaliy V; Adamski, Carolyn J et al. (2017) Inhibition of ERK1/2 Restores GSK3? Activity and Protein Synthesis Levels in a Model of Tuberous Sclerosis. Sci Rep 7:4174
Pal, Rituraj; Bajaj, Lakshya; Sharma, Jaiprakash et al. (2016) NADPH oxidase promotes Parkinsonian phenotypes by impairing autophagic flux in an mTORC1-independent fashion in a cellular model of Parkinson's disease. Sci Rep 6:22866
Sardiello, Marco (2016) Transcription factor EB: from master coordinator of lysosomal pathways to candidate therapeutic target in degenerative storage diseases. Ann N Y Acad Sci 1371:3-14

Showing the most recent 10 out of 15 publications