Altered lysosome distribution is an early neuropathological event in neurological forms of Gaucher disease

Hila Zigdon; Anna Meshcheriakova; Tamar Farfel-Becker; Giora Volpert; Helena Sabanay; Anthony H Futerman

doi:10.1002/1873-3468.12591

Altered lysosome distribution is an early neuropathological event in neurological forms of Gaucher disease

FEBS Lett. 2017 Mar;591(5):774-783. doi: 10.1002/1873-3468.12591. Epub 2017 Feb 28.

Authors

Hila Zigdon¹, Anna Meshcheriakova¹, Tamar Farfel-Becker¹, Giora Volpert¹, Helena Sabanay², Anthony H Futerman¹

Affiliations

¹ Department of Biomolecular Sciences, Weizmann Institute of Science, Rehovot, Israel.
² Department of Chemical Research Support, Weizmann Institute of Science, Rehovot, Israel.

PMID: 28186340
DOI: 10.1002/1873-3468.12591

Abstract

In the lysosomal storage disorder Gaucher disease (GD), glucosylceramide (GlcCer) accumulates due to the defective activity of glucocerebrosidase. A subset of GD patients develops neuropathology. We now show mislocalization of Limp2-positive puncta and a large reduction in the number of Lamp1-positive puncta, which are associated with impaired tubulin. These changes occur at an early stage in animal models of GD, prior to development of overt symptoms and considerably earlier than neuronal loss. Altered lysosomal localization and cytoskeleton disruption precede the neuroinflammatory pathways, axonal dystrophy and neuronal loss previously characterized in neuronal forms of GD.

Keywords: Gaucher disease; glucosylceramide; lysosomes; neurons; neuropathology; paclitaxel.

Publication types

Letter
Research Support, Non-U.S. Gov't

MeSH terms

Actin Cytoskeleton / metabolism
Actin Cytoskeleton / ultrastructure
Animals
CD36 Antigens / genetics
CD36 Antigens / metabolism
Cell Death
Cerebral Cortex / metabolism
Cerebral Cortex / pathology
Disease Models, Animal
Gaucher Disease / genetics
Gaucher Disease / metabolism*
Gaucher Disease / pathology*
Gene Expression Profiling
Gene Expression Regulation
Glucosylceramidase / deficiency
Glucosylceramidase / genetics
Glucosylceramides / metabolism*
Humans
Lysosomal Membrane Proteins / genetics
Lysosomal Membrane Proteins / metabolism
Lysosomes / metabolism*
Lysosomes / ultrastructure
Mice
Mice, Inbred C57BL
Mice, Transgenic
Microtubules / metabolism
Microtubules / ultrastructure
Neurons / metabolism*
Neurons / ultrastructure
Primary Cell Culture
Time Factors
Tubulin / genetics
Tubulin / metabolism

Substances

CD36 Antigens
Glucosylceramides
Lamp1 protein, mouse
Lysosomal Membrane Proteins
Scarb2 protein, mouse
Tubulin
Glucosylceramidase