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Publications of the Week

Cell Type-Specific Lipid Storage Changes in Parkinson’s Disease Patient Brains Are Recapitulated by Experimental Glycolipid Disturbance

By November 5, 2020November 9th, 2020No Comments

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This week we profile a recent publication in PNAS from Dr. Oeystein Brekk (pictured, left) at the Neuroregeneration
Institute at McLean Hospital co-led by Dr. Penny Hallett (right) and Dr. Ole Isacson (center).

Can you provide a brief overview of your lab’s current research focus?

Currently, we are working on the physiological roles of cellular lipids in the central nervous system, and how deregulation of these lipid species may promote processes that ultimately lead to neurodegeneration. For example, cellular lipids are implicated in mobilization of several immune responses, and an underlying deficit in handling of such lipids could impact both the severity and duration of a neuroinflammatory cascade in response to an outside pathogen, be it bacterial or viral. Such a prolonged immune responses could ultimately lead to neurodegenerative events typically associated with diseases such as Parkinson’s disease.

What is the significance of the findings in this publication?

This study identified a unique lipid signature in human post-mortem Parkinson’s disease brain, wherein lipids accumulated in the dopaminergic neurons most vulnerable in the disease, and in adjacent immune cells (microglia). Concurrently, lipid content was dramatically reduced in neighboring astrocytes – a specialized class of glia that among other functions are involved in neutralizing potentially harmful lipid substrates that accumulate in neurons. We could replicate this lipid signature in an animal model targeting a single lipid metabolic enzyme (GBA1), mutations in which constitute the largest genetic risk factor for developing Parkinson’s disease. Taken together, we believe these lipid changes constitute an important adaptation in the Parkinsonian brain that can be utilized to expand existing models and therapeutic strategies for this disease.

What are the next steps for this research?

The lipid signature we observed in human Parkinson’s disease patient brain involved three distinct cell types, with great diversity in their expression of lipid synthesizing, metabolic, and lipid transport proteins. If there are critical steps in this multi-faceted process that are perturbed, such mechanisms could be targeted with the hopes of restoring balance between the lipid compartments to that of a healthy subject brain.

This work was funded by:

·       NIH/National Institute of Neurological Disorders and Stroke (R01 NS092667, to P.J.H.)
·       NIH/ National Institute on Aging (R01 AG060195, to O.I.)
·       the US Department of Defense (W81XWH2010368, to O.I.; W81XWH2010371, to P.J.H.)
·       the Consolidated Anti-Aging Foundation (O.I.)
·       the Orchard Foundation (O.I.)
·       the Harold and Ronna Cooper Postdoctoral Fellowship for Parkinson’s Disease Research (O.R.B.).

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