Chapter 8 - Modeling hereditary spastic paraplegias using induced pluripotent stem cells

Abstract

Hereditary spastic paraplegias (HSPs), a heterogeneous group of neurological disorders, are caused by axonal degeneration involving the long corticospinal tract which leads to the progressive spasticity and weakness of lower limbs. Over 80 different gene loci associated with HSP have been identified. Studying various HSP proteins reveals several common cellular themes in these debilitating diseases including vesicular trafficking, organelle shaping and morphogenesis, lipid/cholesterol metabolism, and endolysosomal and autophagic dysfunction. Though animal and cell models have been developed to study HSP, it remains a challenge to obtain patient-specific cortical neurons that are specifically affected and impaired in HSP. Recently, the discovery of induced pluripotent stem cells (iPSCs) provides a promising tool in neurological disease modeling due to their ability of self-renewal and capability of differentiation into various cell types. HSP patient iPSC-derived cortical projection neurons offer a unique source for HSP modeling to understand the molecular and cellular mechanisms, reveal neuronal pathological phenotypes, and test potential drugs. Here, we will introduce HSP and different common cellular themes, summarize in vitro HSP models using human pluripotent stem cells, and discuss the current challenges and future directions of HSP iPSC modeling.