Pathogenesis of autosomal dominant hereditary spastic paraplegia (SPG6) revealed by a rat model.

Fumihiro Watanabe, William D. Arnold, Robert E Hammer, Odelia Ghodsizadeh, Harmeet Moti, Mackenzie Schumer, Ahmed Hashmi, Anthony Hernandez, Amita Sneh, Zarife Sahenk, Yaz Y. Kisanuki

Research output: Contribution to journalArticlepeer-review

15 Scopus citations


Hereditary spastic paraplegias (HSPs) are characterized by progressive spasticity and weakness in the lower extremities that result from length-dependent central to peripheral axonal degeneration. Mutations in the non-imprinted Prader-Willi/Angelman syndrome locus 1 (NIPA1) transmembrane protein cause an autosomal dominant form of HSP (SPG6). Here, we report that transgenic (Tg) rats expressing a human NIPA1/SPG6 mutation in neurons (Thy1.2-hNIPA1) show marked early onset behavioral and electrophysiologic abnormalities. Detailed morphologic analyses reveal unique histopathologic findings, including the accumulation of tubulovesicular organelles with endosomal features that start at axonal and dendritic terminals, followed by multifocal vacuolar degeneration in both the CNS and peripheral nerves. In addition, the NIPA1 mutation in the spinal cord from older Tg rats results in an increase in bone morphogenetic protein type II receptor expression, suggesting that its degradation is impaired. This Thy1.2-hNIPA1 Tg rat model may serve as a valuable tool for understanding endosomal trafficking in the pathogenesis of a subgroup of HSP with an abnormal interaction with bone morphogenetic protein type II receptor, as well as for developing potential therapeutic strategies for diseases with axonal degeneration and similar pathogenetic mechanisms.

Original languageEnglish (US)
Pages (from-to)1016-1028
Number of pages13
JournalJournal of neuropathology and experimental neurology
Issue number11
StatePublished - Nov 2013

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Neurology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience


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