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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS079618-02
Application #
8551775
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Morris, Jill A
Project Start
2012-09-30
Project End
2017-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
2
Fiscal Year
2013
Total Cost
$332,051
Indirect Cost
$120,957
Name
Baylor College of Medicine
Department
Genetics
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Pal, Rituraj; Palmieri, Michela; Loehr, James A et al. (2014) Src-dependent impairment of autophagy by oxidative stress in a mouse model of Duchenne muscular dystrophy. Nat Commun 5:4425