Membrane Biology and Neurodegeneration

The molecular bases for neurodegenerative diseases are beginning to be unraveled. Increasing evidence points to the contribution of  endosome and lysosome dysfunction in the development of many of these diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). We study endocytosis, focusing on how it regulates the metabolism of membrane lipids, in particular sphingolipids. We are testing the hypothesis that accumulation of sphingolipid intermediates leads to neurodegeneration in diseases such as ALS.

We also investigate progranulin, a lysosomal protein of unknown function. Haploinsufficiency of progranulin results in FTD with very high penetrance. Understanding the biology of progranulin and related pathways is key to understanding how FTD and potentially other neurodegenerative diseases develop. Our work on progranulin is supported by the Consortium for FTD Research, overseen by the Bluefield Project to Cure FTD.

Read more:

Petit CS.et al. (2020) Inhibition of sphingolipid synthesis improves outcomes and survival in GARP mutant wobbler mice, a model of motor neuron degeneration. Proc Natl Acad Sci U S A. pii: 201913956. 

Nguyen AD. et al. (2018) Murine knockin model for progranulin-deficient frontotemporal dementia with nonsense-mediated mRNA decay. Proc Natl Acad Sci U S A.115(12): E2849-E2858.

Fröhlich, F. et al. (2015) The GARP complex is required for cellular sphingolipid homeostasis. Elife 4:e08712.


Minami S.S. et al. (2014) Progranulin protects against amyloid β deposition and toxicity in Alzheimer’s disease mouse models. Nat. Med. 20(10):1157-1164.


Filiano, A.J. et al. (2013) Dissociation of frontotemporal dementia-related deficits and neuroinflammation in progranulin haploinsufficient mice. J. Neurosci. 33(12):5352-5361.


Martens, L.H. et al. (2012) Progranulin deficiency promotes neuroinflammation and neuronal loss following toxin-induced injury. J. Clin. Invest. 122(11): 3955-3959.

 

Neurodegeneration

Confocal images showing neurons (red) and activated microglia (green) in the nervous system of Grn–/– mice.
From J Clin Invest. 2012;122(11):3955-3959.