Abstract
Background: Niemann-Pick disease type C (NPC) is a rare autosomal-recessive lysosomal storage disease that is also associated with progressive neurodegeneration. NPC shares many pathological features with Alzheimer's disease, including neurofibrillary tangles, axonal spheroids, β-amyloid deposition, and dystrophic neurites. Here, we examined if these pathological features could be detected in induced pluripotent stem cell (iPSC)-derived neurons from NPC patients. Methods: Brain tissues from 8 NPC patients and 5 controls were analyzed for histopathological and biochemical markers of pathology. To model disease in culture, iPSCs from NPC patients and controls were differentiated into cortical neurons. Results: We found hyperphosphorylated tau, altered processing of amyloid precursor protein, and increased Aβ42 in NPC postmortem brains and in iPSC-derived cortical neurons from NPC patients. Conclusion: Our findings demonstrated that the main pathogenic phenotypes typically found in NPC brains were also observed in patient-derived neurons, providing a useful model for further mechanistic and therapeutic studies of NPC.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1022-1027 |
| Number of pages | 6 |
| Journal | Movement Disorders |
| Volume | 36 |
| Issue number | 4 |
| DOIs | |
| State | Published - Apr 2021 |
Funding
We are grateful to Niccolo E. Mencacci for helpful comments, Callen L. Spencer for staining of brain tissue sections, Northwestern Stem Cell Core Facility for generation of iPSC lines, NICHD Brain and Tissue Bank for Developmental Disorders at the University of Maryland, Baltimore for brain tissues. This work was supported by NINDS grants R01 NS076054 and R37 NS096241 (to D.K.), NIA grant AG 13854 (to E.H.B.), and in part by Lysosomal Therapeutics, Inc. (to J.M.M.). This work was supported by NINDS grants R01 NS076054 and R37 NS096241 (to D.K.), NIA grant AG 13854 (to E.H.B.), and in part by Lysosomal Therapeutics, Inc. (to J.M.M.). Funding agencies: We are grateful to Niccolo E. Mencacci for helpful comments, Callen L. Spencer for staining of brain tissue sections, Northwestern Stem Cell Core Facility for generation of iPSC lines, NICHD Brain and Tissue Bank for Developmental Disorders at the University of Maryland, Baltimore for brain tissues. This work was supported by NINDS grants R01 NS076054 and R37 NS096241 (to D.K.), NIA grant AG 13854 (to E.H.B.), and in part by Lysosomal Therapeutics, Inc. (to J.M.M.).
Keywords
- Niemann-Pick disease; iPSC; disease modeling; brain pathology
ASJC Scopus subject areas
- Clinical Neurology
- Neurology
