Decreased estradiol release from astrocytes contributes to the neurodegeneration in a mouse model of Niemann-Pick disease type C.
Niemann-Pick disease type C (NPC) is a deadly neurodegenerative disease often caused by mutation in a gene called NPC1, which results in the accumulation of unesterified cholesterol and glycosphingolipids in the endosomal-lysosomal system. Most studies on the mechanisms of neurodegeneration in NPC have focused on neurons. However, the possibility also exists that NPC1 affects neuronal functions indirectly by acting on other cells that are intimately interacting with neurons. In this study, using a heterotypic neuron-glia coculture system, we found that wild-type neurons cultured on a layer of NPC1-/- astrocytes showed decreased neurite growth compared with those cultured on wild-type astrocytes. RT-PCR and immunohistochemical assessments showed significantly lower expression of neurosteroid enzymes and StAR (steroidogenic acute regulatory protein) in NPC1-/- astrocyte cultures than in wild-type cultures. Furthermore, a reduced level of estradiol was measured from both astrocyte culture medium and whole brains from NPC1-/- mice. Administration of 17beta-estradiol to neonatal NPC1-/- mice significantly delayed the onset of neurological symptoms, increased Purkinje cell survival, and extended the animals' life span. Our findings suggest that astrocyte dysfunction contributes to the neurodegeneration of NPC and estradiol treatment may be useful in ameliorating progression of the disease.
Chen
Gang
G
Institute of Neuroscience and Key Laboratory of Neurobiology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
Li
Hai-Min
HM
Chen
Yi-Ren
YR
Gu
Xiao-Song
XS
Duan
Shumin
S
D000818:Animals; D001057:Apolipoproteins E / Q000378:metabolism; D001253:Astrocytes / Q000378:metabolism* / Q000648:ultrastructure; D001522:Behavior, Animal / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D018920:Coculture Techniques; D004396:Coloring Agents; D018450:Disease Progression; D004958:Estradiol / Q000378:metabolism* / Q000502:physiology; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins; D008107:Liver Diseases / Q000150:complications / Q000188:drug therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009410:Nerve Degeneration / Q000473:pathology*; D018377:Neurotransmitter Agents / Q000378:metabolism; D000077296:Niemann-Pick C1 Protein; D052556:Niemann-Pick Disease, Type C / Q000473:pathology*; D004856:Postural Balance / Q000502:physiology; D011506:Proteins / Q000235:genetics; D011689:Purkinje Cells / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction
D001057:Apolipoproteins E; D004396:Coloring Agents; D047908:Intracellular Signaling Peptides and Proteins; D018377:Neurotransmitter Agents; D000077296:Niemann-Pick C1 Protein; C106831:Npc1 protein, mouse; D011506:Proteins; D004958:Estradiol; D002784:Cholesterol