Heritable Neurodegenerative and Autoimmune Disorders

Child Health And Human Development

Investigators

Linked publications, trials & patents

Abstract

The Section on Developmental Genetics conducts both laboratory and clinical investigations to understand the molecular mechanisms of complex genetic disorders of inflammation, autoimmunity and neurodegeneration in order to develop novel and rational therapeutic approaches. Towards these goals, the laboratory research of this Section is focused on understanding the regulation and physiological functions of primarily two genes: (1) uteroglobin (UG), also known as Clara cell 10 kDa protein (CC10), and (2) palmitoyl-protein thioesterase-1 (PPT1), the mutations of which are the genetic basis of infantile neuronal ceroid lipofuscinosis (INCL), a devastating neurodegenerative storage disease of childhood. Investigations in both areas have led to ongoing clinical trials. Recently, using PPT1-knockout mice, which recapitulates virtually all clinical and pathological features INCL, we uncovered, for the first time that this enzyme deficiency leads to abnormal accumulation of s-acylated proteins in the endoplasmic reticulum (ER) causing ER stress. ER stress mediates activation of cysteine proteinase in the ER, caspase-12, which leads to caspase-3 activation and apoptosis. This is an extremely important and significant discovery not only because it provides insight into a complex mechanism of neurodegeneration in INCL but also identifies several potential targets for the development of rational therapeutic approaches for this uniformly fatal disease.