Session Information
Date: Wednesday, June 22, 2016
Session Title: Ataxia
Session Time: 12:00pm-1:30pm
Location: Exhibit Hall located in Hall B, Level 2
Objective: Here we set out to study the cellular pathology of ITPR1-deletions underlying SCA15 in a human model of iPSC-derived cortical neurons.
Background: Spinocerebellar Ataxia 15 (SCA15-) patients present with pure progressive cerebellar ataxia and possible pyramidal, extrapyramidal and cortical features (1, 2). Heterozygous deletions up to 350 kb in the inositol-1,4,5-triphosphate-receptor type 1-gene (ITPR1) resulting in haploinsufficiency of the ligand-gated calcium-channel on the membrane of the endoplasmatic reticulum (ER) are the underlying genetic cause (3). ITPR1 is highly expressed in the cerebellum and cortex with an assumed role in calcium homeostasis & neurotransmitter exocytosis (4).
Methods: Fibroblasts were collected from 3 SCA15-patients via a skin biopsy, expanded and banked at low passage number. Reprogramming was performed via episomal gene delivery (5), iPSC-colonies picked and expanded. Two clones per patient were validated and carried further to conduct neural differentiation (12 days dual SMAD inhibition (6), default neural inductive conditions for 80-100 days (7)).
Results: Patient-derived iPSCs were confirmed as pluripotent via ICC and qPCR for marker pluripotency genes, karyotypically normal apart from the heterozygous ITPR1-deletion and 5 out of 6 were integration-free. Neural differentiation yields a high proportion of cortical neurons in patient and control lines. Preliminary Ca-imaging trial data in fibroblasts, iPS-cells and neurons shows disturbance of store-operated calcium entry in patient-neurons only.
Conclusions: Here we have generated the first human neuronal model to study spinocerebellar ataxia 15. Future Work: To follow up the encouraging preliminary results we currently use ICC, live-imaging, cytotoxicity assays and electrophysiology to investigate the interplay between ER-calcium-stores, mitochondria and cytosol impacting on cell-integrity and transmitter exocytosis to conclude on the pathomechanism leading to neurodegeneration in SCA15 further. A phenotypic rescue will be investigated via treatment with different calcium-stabilisators (e.g. dantrolene).
At Ataxia UK but with less updated data.
To cite this abstract in AMA style:
S. Wiethoff, C. Arber, S. Wray, Y. Zhi, R. Patani, H. Henry. Modelling spinocerebellar ataxia 15 with iPS cell derived neurons [abstract]. Mov Disord. 2016; 31 (suppl 2). https://www.mdsabstracts.org/abstract/modelling-spinocerebellar-ataxia-15-with-ips-cell-derived-neurons/. Accessed June 14, 2025.« Back to 2016 International Congress
MDS Abstracts - https://www.mdsabstracts.org/abstract/modelling-spinocerebellar-ataxia-15-with-ips-cell-derived-neurons/