Many lysosomal storage diseases (LSDs) cause childhood-onset neurodegeneration leading to profound psychomotor retardation and ophthalmological abnormalities. In general, LSDs are notoriously difficult to treat because although these diseases are monogenic in origin, they typically affect a host of cellular signaling cascades and cell biological processes. The pleiotropy associated with LSDs prevents the development of suitable therapeutic strategies that simultaneously target the multiple disease outcomes. Moreover, it is becoming increasingly clear that LSDs are also characterized by neurodevelopmental abnormalities such as diminished axonal development in the cortex and corpus callosum. Unfortunately, the mechanistic basis for these neuronal defects associated with LSDs remain poorly understood. The overarching goal of this proposal is to address these conceptual gaps using a Drosophila model of an LSD called mucolipidosis type IV (MLIV) that arises from loss of function mutations in a lysosomal Ca2+ channel called TRPML1. We previously established that the fly TRPML1 homolog, TRPML, is a late-endosomal/amphisomal Ca2+ channel that drives the fusion of these vesicles with lysosomes. Here, we will leverage the genetic tractability of the Drosophila to address the critical mechanistic questions regarding the neuropathology of LSDs.
In Aim 1, we will test the hypothesis that loss of TRPML results in alterations in the organization of cholesterol-enriched ordered membrane microdomains called lipid rafts. Because lipid rafts are critical for the functioning of a plethora of cellular signalig processes, alterations in the stability of these domains could provide a mechanistic explanation for the pleiotropy associated with lysosomal dysfunction.
In Aim 2, we will test the hypothesis that TRPML promotes synaptic growth by activating developmental c-Jun Kinase (JNK) signaling in neurons. Interestingly, diminished JNK activation results in hypoplasia and agenesis of axonal tracts of the cortex and corpus callosum. Therefore, decreased JNK activation following lysosomal dysfunction signaling may be the molecular explanation for why LSDs are characterized by axonal growth defects. If successful, these studies should provide us with mechanistic insight into some of the common neurological outcomes associated with lysosomal dysfunction and also aid in the establishment of concepts for therapeutically targeting the neurological sequelae of LSDs.

Public Health Relevance

Many lysosomal storage diseases (LSDs) cause childhood-onset neurodegeneration resulting in profound psychomotor retardation. However, the neurobiological basis of these diseases remains incompletely understood. As a consequence, no therapies exist for targeting the CNS dysfunction observed in LSDs. The goal of this project is to investigate novel aspects of LSD associated neuropathology in a Drosophila model of LSD called mucolipidosis type IV. At the conclusion of this study, we hope to have gained a more detailed understanding regarding the mechanisms underlying disease-associated neuronal dysfunction, and developed a conceptual framework for devising therapies.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Synapses, Cytoskeleton and Trafficking Study Section (SYN)
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Morris, Jill A
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University of Texas Health Science Center Houston
Schools of Medicine
United States
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