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, SPAST that 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. CONCLUSION 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.

The Neglected Genes of ALS: Cytoskeletal Dynamics Impact Synaptic Degeneration in ALS

“…However, SPAST mutations leading to an HSP phenotype display a dying-back axonopathy of the affected neurons, especially the corticospinal MNs. Moreover, such axon abnormalities have been identified in iPSC-derived neurons (Denton et al, 2014(Denton et al, , 2016, which are known to be a powerful tool to study human neurons in vitro.…”

Comparative Transcriptional Profiling of Motor Neuron Disorder-Associated Genes in Various Human Cell Culture Models

“…The potential of iPSC to generate a patient-specific cell model that represents the cell type affected by the disease of interest with the same genetic background opened new possibilities to study MND in a human neuronal cell culture model (reviewed in Denton et al, 2016). For example, analysis of SPAST-deficient neurons generated from SPG4 patients revealed pathophysiological axonal defects like axonal swellings, a hallmark of HSP disease pathology, in human iPSC-derived neurons (Havlicek et al, 2013;Denton et al, 2014).…”

Motor Evoked Potentials in Hereditary Spastic Paraplegia—A Systematic Review

“…Recent research using stem cell models to study HSP disease pathogenesis, including SPG4 (HSP- SPAST ), SPG3A (HSP- atlastin-1 ), and SPG11 (HSP- spatacsin ) (5–7), have revealed several potential treatment options targeting the underlying disease mechanisms (8). There is a paucity of clinical trials for HSP drug treatment options, the most recent trials targeting SPG5 (HSP- CYP7B1 ) showed improvement of biological markers but no discernible clinical improvement (1, 9, 10).…”