Patricia Dickson, PhD, Centennial Professor of Pediatrics
Jonathan D. Cooper, PhD, Professor of Pediatrics
Marco Sardiello, PhD, Associate Professor of Pediatrics

Collaborative Pilot Award:

Monitoring Lysosomal Content and Signaling in Lysosomal Storage Disorders

Collaborative Award: Monitoring Lysosomal Content and Signaling in Lysosomal Storage Disorders

Project: Progress in the understanding and treatment of neuronopathic lysosomal storage disorders (LSDs) is severely hindered by an incomplete understanding of their pathogenesis. In the last decade, multidisciplinary scientific advances have radically transformed our understanding of the lysosome from a mere collection of degradative enzymes to a dynamic signaling hub that participates in—and regulates—cell metabolism as a whole.

The study of the lysosome as a fully integrated organelle in LSDs, however, has not followed organically. Little or no insight has been gained on changes (accumulation or deficiency) in metabolites beyond the primary storage material, their role in the regulation of lysosomal homeostasis, and the subsequent perturbations in the function of the lysosome as a signaling hub. We propose to leverage a novel multiomics approach to characterize how changes in the lysosomal proteome and metabolome influence the epigenomic and transcriptomic profile of iPSC. These will derived from individuals with CLN2 disease, Krabbe disease, and MPS IIIB, representative neuronopathic LSDs that have markedly different cellular pathologies and in which contrasting types of storage material accumulate.

Andrew Yoo, PhD, Associate Professor Department of Developmental Biology

Individual Pilot Award:

 Identification of transcript signatures of neurodegeneration in directly reprogrammed neurons of late-onset Alzheimer’s Disease

Project: The ability to generate human neurons by directly converting fibroblasts of adult individuals offers experimental benefits to model late-onset disorders. Most notably, direct neuronal conversion, via microRNA induction, propagates epigenetic age stored in the starting fibroblasts to reprogrammed neurons, thereby mimicking the age of fibroblast donors. Using this approach, we have demonstrated that directly reprogrammed neurons derived from adult-onset Huntington disease (HD) and tauopathy patients recapitulated hallmarks of neurodegenerative phenotypes.

While studying the transcriptome of HD patient-derived neurons, we came across an interesting observation that in HD neurons that eventually undergo cell death, we detected several unannotated novel transcripts specifically expressed in degenerating neurons of symptomatic HD patients. Importantly, the same signal was not as pronounced in neurons that do not degeneration from pre-symptomatic stages. Rescuing symptomatic neurons from neurodegeneration lowered the amount of the transcript signal, indicating that directly converted neurons allow the identification of neuron-specific signals correlated to the degenerative state of patient neurons.

We would like to expand on this preliminary result and test the feasibility of AD-associated transcript signals as novel markers that can predict neurodegeneration of LOAD.