TY - JOUR
T1 - Neuronal accumulation of glucosylceramide in a mouse model of neuronopathic gaucher disease leads to neurodegeneration
AU - Farfel-Becker, Tamar
AU - Vitner, Einat B.
AU - Kelly, Samuel L.
AU - Bame, Jessica R.
AU - Duan, Jingjing
AU - Shinder, Vera
AU - Merrill, Alfred H., Jr.
AU - Dobrenis, Kostantin
AU - Futerman, Anthony H.
N1 - NIH/NICHD Center for Research on Intellectual and Developmental Disabilities [P30HD071593]; Children's Gaucher Research FundThe electron microscopy analyses conducted in the Cell and Molecular Neuroimaging Core facility at the Albert Einstein College of Medicine of Yeshiva University was supported by an NIH/NICHD Center grant (#P30HD071593) for Research on Intellectual and Developmental Disabilities. This work was generously supported by the Children's Gaucher Research Fund.
PY - 2014/2
Y1 - 2014/2
N2 - Gaucher disease has recently received wide attention due to the unexpected discovery that it is a genetic risk factor forParkinson's disease.Gaucher disease is causedby the defective activity of the lysosomal enzyme, glucocerebrosidase (GCase; GBA1), resulting in intracellular accumulation of the glycosphingolipids, glucosylceramide and psychosine. The rare neuronopathic forms of GD (nGD) are characterized by profound neurological impairment and neuronal cell death. We have previously described the progression of neuropathological changes in amouse model of nGD.We now examine the relationship between glycosphingolipid accumulation and initiation of pathology at two pre-symptomatic stages of the disease in four different brain areas which display differential degrees of susceptibility to GCase deficiency. Liquid chromatography electrospray ionization tandem mass spectrometry demonstrated glucosylceramide and psychosine accumulation in nGD brains prior to the appearance of neuroinflammation, although only glucosylceramide accumulation correlated with neuroinflammation and neuron loss. Levels of other sphingolipids, including the pro-apoptotic lipid, ceramide, were mostly unaltered. Transmission electron microscopy revealed that glucosylceramide accumulation occurs in neurons, mostly in the form of membrane-delimited pseudo-tubules located near the nucleus. Highly disrupted glucosylceramide-storing cells, which are likely degenerating neurons containing massive inclusions, numerous autophagosomes and unique ultrastructural features, were also observed. Together, our results indicate that a certain level of neuronal glucosylceramide storage is required to trigger neuropathological changes in affected brain areas, while other brain areas containing similar glucosylceramide levels are unaltered, presumably because of intrinsic differences in neuronal properties, or in the neuronal environment, between various brain regions.
AB - Gaucher disease has recently received wide attention due to the unexpected discovery that it is a genetic risk factor forParkinson's disease.Gaucher disease is causedby the defective activity of the lysosomal enzyme, glucocerebrosidase (GCase; GBA1), resulting in intracellular accumulation of the glycosphingolipids, glucosylceramide and psychosine. The rare neuronopathic forms of GD (nGD) are characterized by profound neurological impairment and neuronal cell death. We have previously described the progression of neuropathological changes in amouse model of nGD.We now examine the relationship between glycosphingolipid accumulation and initiation of pathology at two pre-symptomatic stages of the disease in four different brain areas which display differential degrees of susceptibility to GCase deficiency. Liquid chromatography electrospray ionization tandem mass spectrometry demonstrated glucosylceramide and psychosine accumulation in nGD brains prior to the appearance of neuroinflammation, although only glucosylceramide accumulation correlated with neuroinflammation and neuron loss. Levels of other sphingolipids, including the pro-apoptotic lipid, ceramide, were mostly unaltered. Transmission electron microscopy revealed that glucosylceramide accumulation occurs in neurons, mostly in the form of membrane-delimited pseudo-tubules located near the nucleus. Highly disrupted glucosylceramide-storing cells, which are likely degenerating neurons containing massive inclusions, numerous autophagosomes and unique ultrastructural features, were also observed. Together, our results indicate that a certain level of neuronal glucosylceramide storage is required to trigger neuropathological changes in affected brain areas, while other brain areas containing similar glucosylceramide levels are unaltered, presumably because of intrinsic differences in neuronal properties, or in the neuronal environment, between various brain regions.
UR - http://www.scopus.com/inward/record.url?scp=84893009529&partnerID=8YFLogxK
U2 - https://doi.org/10.1093/hmg/ddt468
DO - https://doi.org/10.1093/hmg/ddt468
M3 - مقالة
SN - 0964-6906
VL - 23
SP - 843
EP - 854
JO - Human Molecular Genetics
JF - Human Molecular Genetics
IS - 4
M1 - ddt468
ER -