title: Modeling Axonal Defects in Hereditary Spastic Paraplegia with Human Pluripotent Stem Cells.
abstract: BACKGROUND
  Cortical motor neurons, also known as upper motor neurons, are large projection neurons whose axons convey signals to lower motor neurons to control the muscle movements. Degeneration of cortical motor neuron axons is implicated in several debilitating disorders, including hereditary spastic paraplegia (HSP) and amyotrophic lateral sclerosis (ALS). Since the discovery of the first HSP gene,SPASTthat encodes spastin, over 70 distinct genetic loci associated with HSP have been identified. How the mutations of these functionally diverse genes result in axonal degeneration and why certain axons are affected in HSP remains largely unknown. The development of induced pluripotent stem cell (iPSC) technology has provided researchers an excellent resource to generate patient-specific human neurons to model human neuropathologic processes including axonal defects.
  
  
  METHODS
  In this article, we will frst review the pathology and pathways affected in the common forms of HSP subtypes by searching the PubMed database. We will then summurize the findings and insights gained from studies using iPSC-based models, and discuss the challenges and future directions.
  
  
  RESULTS
  HSPs, a heterogeneous group of genetic neurodegenerative disorders, are characterized by lower extremity weakness and spasticity that result from retrograde axonal degeneration of cortical motor neurons. Recently, iPSCs have been generated from several common forms of HSP including SPG4, SPG3A, and SPG11 patients. Neurons derived from HSP iPSCs exhibit disease-relevant axonal defects, such as impaired neurite outgrowth, increased axonal swellings, and reduced axonal transport.
  
  
  CONCLUSIONS
  These patient-derived neurons offer unique tools to study the pathogenic mechanisms and explore the treatments for rescuing axonal defects in HSP, as well as other diseases involving axonopathy.
authors.affiliation: Department of Neuroscience, University of Connecticut Health Center, Farmington, CT 06030.
authors.forename: Kyle R
authors.initials: KR
authors.lastname: Denton
authors.affiliation: Department of Biomedical Sciences, University of Illinois College of Medicine at Rockford, IL 61107; Department of Bioengineering, University of Illinois at Chicago, IL 60607.
authors.forename: Chongchong
authors.initials: C
authors.lastname: Xu
authors.affiliation: MD program, University of Illinois College of Medicine at Rockford, IL 61107.
authors.forename: Harsh
authors.initials: H
authors.lastname: Shah
authors.affiliation: Department of Biomedical Sciences, University of Illinois College of Medicine at Rockford, IL 61107; Department of Bioengineering, University of Illinois at Chicago, IL 60607.
authors.forename: Xue-Jun
authors.initials: XJ
authors.lastname: Li
keywords: HSP; atlastin-1; axonal degeneration; pluripotent stem cells; spastin