Genetic risk factors for neurodegeneration

Studying the effect of genetic risk factors for neurodegenerative diseases using human iPSCs.


Recent genome-wide association studies (GWAS) have revealed a number of novel genetic risk factors associated with neurodegenerative diseases including Alzheimer’s disease (AD).

  • Now, it is time to address whether these single nucleotide polymorphisms (SNPs) or mutations associated with the diseases are sufficient to cause or exacerbate pathological phenotypes, and what are the underlying mechanisms.

Human neurodegenerative diseases are notoriously difficult to study because of the limited accessibility of complex human brain tissues.

  • Animal models, such as transgenic rodents, can recapitulate pathological phenotypes of neurodegenerative diseases including AD to an extent; however, the species gap between humans and other animal models makes it difficult to translate initial discoveries in model systems to application in humans, and may often underlie the failure of clinical trials for candidate drugs. Therefore, as well as studies using animal models, it is important to conduct experiments in the context of the human genome to comprehensively understand mechanisms of neurodegeneration.

Human induced pluripotent stem cell (iPSC)-derived brain cells in conjunction with recent innovative genome editing tools and protocols for generating different brain cell types have become powerful approaches for studying human neurodegenerative diseases.

  • Recent studies using iPSCs derived from individuals with AD, Frontotemporal dementia (FTD) or Down syndrome (DS) have shown that neurons or glial cells derived them display a number of readily observable disease phenotypes. Although further characterization is required, it suggests that human iPSC-derived neural cells represent in vitro human model of neurodegenerative diseases. In addition, three-dimensional (3D) human neural culture systems, cerebral organoids, have been developed to better recapitulate glia-neuron networks and the complexity of the human brain.
  • Comparing iPSC-derived brain cell types from patients with neurodegeneration and unaffected controls – who have different genetic backgrounds, comes with a caveat because factors aside from the disease-specific mutations could affect the results. To overcome this, genome editing techniques such as CRISPR/Cas9 have been tried to generate isogenic cell line in which only SNP or mutation sequence in the genome is different from their parental cell line.

Our group takes advantage of human iPSCs and the CRISPR/Cas9 tool to generate human cellular models for neurodegenerative disorders and to study the effects of a subset of these genetic risk factors. After generation of isogenic iPSCs harboring genetic risk factors, cells are differentiated into various brain cell types such as neurons and glial cells, or organoids. We use multiple molecular biological, electrophysiological and biochemical tools to determine their pathological phenotypes and to elucidate underlying mechanisms.


Mungenast et al., Mol Cell Neurosci (2015)