Patient-derived iPS cells for investigating pathogenetic mechanisms of brain diseases that cause movement disorders

The general aim of the proposed project is to develop iPS cell-based platforms for elucidating disease mechanisms in monogenic neurological diseases. Specifically, the project focuses on monogenic neurological diseases affecting parts of the brain involved in motor function, and which thus cause movement disorders. By generating iPS cells from patients suffering from these diseases and differentiating these into the principal neuron types that are affected, one can investigate the molecular and cell physiological correlates of the diseases in ways that are not possible in the patients themselves. The project involves a close collaboration between basic research laboratories at IMB and clinical research groups at OUS, with collaborative ties to major international centers for clinical movement disorder research. The project thereby stimulates strongly translational research at a national and international level. It also contributes to laying the groundwork for establishing a general iPS cell-based approach relevant for elucidating brain disease mechanisms with a utility beyond the specific diseases to be focused on here.

Established iPS cells from 4 dystonia, 2 SCA-14 and 7 ALS patients, and neural progenitors from these iPS cell lines. Published article detailing case report and pathophenotypes in one dystonia patient with ACTB mutation. Assessed neuronal differentiation from neural progenitor cells of the ACTB mutation dystonia line; preliminary data suggest deficit. Established in vitro model of ALS using ALS patient-derived neurons and astrocytes. Designed microfluidic device to obtain an in vitro model wherein separate cell types can be manipulated and assayed selectively. This device will be usable to model many different neurological diseases in vitro. Started establishing in vitro differentiation protocols for microglia and skeletal muscle to obtain a 4-cell-type in vitro model of ALS. Published review article on stem cell-based disease models and therapies for ALS. Published review article on in vivo tracking of stem cells and stem cell-derived cells in patients with MRI.

The use of patient-derived induced pluripotent stem (iPS) cells represents a breakthrough in investigating the pathophysiology of genetic neurological diseases (Dimos et al 2008, Siller et al 2013). The general aim of this project is to use iPS cells to establish a platform to study underlying disease mechanisms associated with monogenic neurological diseases. The focus in this project is on hereditary movement disorders, specifically forms of spinocerebellar ataxia (SCA) and of dystonia that are linked to single gene mutations and that are represented in Norwegian and other European patient populations. These movement disorders severely affect quality of life, the underlying disease mechanisms are poorly understood, and their is currently no cure. By ge nerating iPS cells from patients suffering from these diseases and differentiating these into the principal neuron types that are affected, we will be able to investigate the molecular and cell physiological mechanisms of the disease in ways that are not possible in the patients themselves. The project involves a close collaboration between basic research laboratories (Oslo University Hospital/University of Oslo and major foreign universities) and clinical neurologists and neurogeneticists in Norway and a t major international centers for clinical movement disorder research. The project thereby stimulates strongly translational research at a national and international level. It also lays the groundwork for establishing a general iPS cell-based approach rel evant for elucidating brain disease mechanisms with a utility beyond the specific diseases focused on here.