Induced pluripotent stem cell-based modeling of neurodegenerative diseases: a focus on autophagy

Johannes Jungverdorben, Andreas Till, Oliver Brüstle

The advent of cell reprogramming has enabled the generation of induced pluripotent stem cells (iPSCs) from patient skin fibroblasts or blood cells and their subsequent differentiation into tissue-specific cells, including neurons and glia. This approach can be used to recapitulate disease-specific phenotypes in classical cell culture paradigms and thus represents an invaluable asset for disease modeling and drug validation in the framework of personalized medicine. The autophagy pathway is a ubiquitous eukaryotic degradation and recycling system, which relies on lysosomal degradation of unwanted and potentially cytotoxic components. The relevance of autophagy in the pathogenesis of neurodegenerative diseases is underlined by the observation that disease-linked genetic variants of susceptibility factors frequently result in dysregulation of autophagic-lysosomal pathways. In particular, disrupted autophagy is implied in the accumulation of potentially neurotoxic products such as protein aggregates and their precursors and defective turnover of dysfunctional mitochondria. Here, we review the current state of iPSC-based assessment of autophagic dysfunction in the context of neurodegenerative disease modeling. The collected data show that iPSC technology is capable to reveal even subtle alterations in subcellular homeostatic processes, which form the molecular basis for disease manifestation.