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.
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.
|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|
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