The Haruhisa Inoue lab reports iPS cells can model Alexander disease and Perry syndrome.

When iPS cells were discovered, there was immediate hope that they could become an ethically uncontroversial substitute for embryonic stem cell-based regenerative medicines. While this opinion still holds, many doctors like CiRA professor and neurologist Haruhisa Inoue have realized iPS cells can also be used to study disease mechanisms. "Before iPS cells, all our living models for neurogenerative diseases were based on immortalized cell lines or animals like mice," he said. By reprogramming patient blood or skin cells to iPS cells and then differentiating them into neurons, one can watch a disease like Alzheimer's disease develop in real time in human cells.

In its most recent publications, the Inoue lab has reported that patient iPS cells can be used to model two lesser known neurodegenerative diseases, Alexander disease and Perry syndrome. Inoue thinks Alexander disease is challenging to study. "Alexander disease causes a wide variety of clinical symptoms, including delayed development, seizure, or spasticity," he said, convincing him patient iPS cells could make an insightful model. Similar to the amyloid plaques associated with Alzheimer's disease, Alexander disease is associated with aggregates known as Rosenthal fibers within astrocytes. Perry syndrome, on the other hand, is extremely rare, with less than 100 cases reported, and is associated with a loss of neurons in the substantia nigra, the same region that is inflicted by Parkinson's disease. "Patients normally die within five years of diagnosis due to respiratory failure," Inoue said.

Alexander disease is the result of mutations in glial fibrillary protein (GFAP) that are believed to cause Rosenthal fibers found in patient astrocytes. Consistently, the researchers found that astrocytes derived from patient iPS cells formed Rosenthal fibers, but those derived from healthy iPS cells did not. Interestingly, patient astrocytes also expressed more of a molecules associated with cell-cell interactions and inflammation compared with healthy cells. Changes in these molecules could explain the multiple of clinical symptoms and provide a drug target for the disease. "Our next step is to look for drug compounds that can change the expression," Inoue said.

The cause of Perry syndrome is mutations in another gene. "DCTN1 [gene] produces dynactin," explained Inoue. Several different types of DCTN1 mutations have been found in Perry syndrome, and all could affect the function of dynactin, which is a protein critical for cell structure and mobility. Like Alexander disease, protein aggregates of dynactin are associated with Perry syndrome, a feature confirmed in a new patient iPS cell model by the Inoue lab. Perry syndrome is also associated with the aggregation of another protein, TDP-43, but TDP-43 aggregates were not seen in the iPS cell model. Inoue suspects, therefore, that TDP-43 could be a late marker of Perry syndrome and that the aggregation of dynactin would make a better drug target for preventing early stages of the disease.

Paper Details

Alexander disease

Journal: Acta Neuropathologica Communications

Title: Modeling Alexander disease with patient iPSCs reveals cellular molecular pathology of astrocytes

Authors: Takayuki Kondo ¹, Misato Funayama ¹, Michiyo Miyake ¹, Kayoko Tsukita ¹, Takumi Era ², Hitoshi Osaka ³, Takashi Ayaki ⁴, Ryosuke Takahashi ⁴, and Haruhisa Inoue ¹

Author Affiliations:

1. Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan
2. Department of Cell Modulation, Institute of Molecular Embyrology and Genetics, Kumamoto University, Kumamoto, Japan
3. Department of Pediatrics, Jichi Medical School, Tochigi, Japan
4. Department of Neurology, Graduate School of Medicine, Kyoto University, Kyoto, Japan

• doi: 10.1186/s40478-016-0337-0

Perry syndrome

Journal: Parkinsonism & Related Disorders

Title: Cytoplasmic aggregates of dynactin in iPSC-derived tyrosine hydroxylase-positive neurons from a patient with Perry syndrome

Authors: Takayasu Mishima ^1,2, Taizo Ishikawa ^1,3, Keiko Imamura ¹, Takayuki Kondo ¹, Yasushi Koshiba ^1,4, Ryosuke Takahashi ⁴, Jun Takahashi ¹, Akihiro Watanabe ⁵, Naoki Fujii ¹, Yoshio Tsuboi ², and Haruhisa Inoue ¹

Author Affiliations:

1. Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, Japan
2. Department of Neurology, School of Medicine, Fukuoka University, Fukuoka, Japan
3. Sumitomo Dainippon Pharma, Osaka, Japan
4. Department of Neurology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
5. Department of Neurology, National Omuta Hospital, Fukuoka Japan

• doi:10.1016/j.parkreldis.2016.06.007