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Department Of AnesthesiologyResearchMarta Lipinski, PhDProjectsNeurodegeneration and Aging

Neurodegeneration and Aging

Defects in autophagy are known to play a causative role in neurodegenerative diseases including Parkinson’s disease (PD) and Alzheimer's disease (AD). It is also attenuated during normal brain aging. However, why autophagy is disrupted is not fully understood. We are using in vivo and in vitro models, including human induced pluripotent stem cells (iPSCs), transgenic mouse models and omics analyses to examine the mechanisms affecting autophagy and lysosomal function during brain aging and in neurodegenerative disease.

Parkinson's Disease

Mechanisms of the PARK10 gene USP24 in regulation of autophagy

USP24 is a gene located in the PARK10 locus associated with late on-set Parkinson's disease. We identified USP24 as a novel regulator of autophagy and are using cell-based models including human iPS cells differentiated into dopaminergic neurons to investigate its function and mechanisms. Our data demonstrate that USP24 negatively regulates autophagy flux by decreasing protein stability of the ULK1 kinase, an important upstream regulator of autophagy. We are also investigating whether USP24 interacts with other genes implicated in PD and whether its inactivation may be a potential future target for treatment of PD and other neurodegenerative conditions.

Figure 1. Knock-down of USP24 in human iPSCs differentiated into dopaminergic neurons leads to increase in neurite length over time. A) Human iPSCs were differentiated into dopaminergic neurons (TH+) transduced with control non-targeting lentiviral shRNA or shRNA against USP24. Cells were aged in culture for 6 weeks following transduction. Dopaminergic neurons are marked with TH and all neurons with Tuj1. B) While there were no differences between young control and USP24 knock-down neurons (1 week after transduction) the neurite length in neurons transduced with shRNA against USP24 increased over time (up to 6 weeks). C) Quantification of total neuronal (Tuj1+) and dopaminergic (TH+) neurite length per neuron at 6 weeks after transduction.

Multi-omics for study of lipid-protein interactions during brain aging

Interactions between proteins, lipids and metabolites, give rise to higher cellular, tissue and organismal phenotypes and functions. These interactions are affected not only by the overall tissue abundance of individual components but also by their distribution between specific cell types and localization to intracellular compartments such as lysosomes or mitochondria. Together with collaborators, Dr. Maureen Kane at UMSOP and Dr. Michael Cummings at UMCP, we are developing an analytical multi-omics pipeline to identify cell-type and organelle-specific functional relationships between lipids, proteins and metabolites, and their effects on organellar, cellular and organismal function during brain aging.

Collaborators:

  • Ricardo Feldman, PhD (UMB-SOM, Microbiology & Immunology)
  • Ola Awad, PhD (UMB-SOM, Microbiology & Immunology)
  • Xianmin Zeng, PhD (Buck Institute, Novato, CA)
  • Maureen Kane, PhD (University of Maryland School of Pharmacy)
  • Jace Jones, PhD (University of Maryland School of Pharmacy)
  • Michael Cummings, PhD (University of Maryland College Park)
  • Michael Whalen, PhD (Harvard School of Medicine)

References:

  • Morel Y, Hegdekar N, Sarkar C, Lipinski MM, Kane MA and Jones JW. Structure-Specific, Accurate Quantitation of Plasmalogen Glycerophosphoethanolamine. Analytica Chimica Acta. 2021; Nov 22; 1186:339088. PMID: 34756256
  • Thayer JA, Awad O, Hegdekar N, Sarkar C, Tesfay H, Burt C, Zeng X, Feldman RA and Lipinski MM. The PARK10 gene USP24 is a negative regulator of autophagy and ULK1 protein stability. Autophagy. 2020; 16(1):140-152. PMID: 30957634
  • Lipinski MM, Hoffman G, Ng A, Zhou W, Py BF, Hsu E, Liu X, Eisenberg J, Liu J, Blenis J, Xavier RJ, A and Yuan, J. Genome-wide siRNA screen reveals multiple MTORC1 independent signaling pathways regulating autophagy under normal nutritional conditions. Developmental Cell. 2010; 18(6):1041-52. PMID: 20627085.