Current Projects

• Hereditary Spastic Paraplegia and the SPG6 Mutation

  Hereditary spastic paraplegia (HSP) refers to a diverse group of neurodegenerative disorders sharing a common clinical feature: progressive weakness and spasticity in the lower limbs. Incidence of HSP is around 1/10,000, with onset typically occurring between late childhood and early adulthood.
  
  The neuropathology of HSP involves axon degeneration of the corticospinal tract and fasciculus gracilis. Axon fiber degeneration occurs prominently at the distal ends of long fibers and is proposed to progress from distal to proximal areas in Wallerian-like process. Reduced cross-sectional areas in the spinal cord or atrophy of the corpus callosum have been observed in certain types of HSP.
  
  The HSPs are genetically heterogeneous, so far linked to 17 genes and 35 loci. There are autosomal dominant, autosomal recessive and X-linked varieties of HSP. The Kisanuki lab studies a severe form of autosomal dominant HSP caused by a mutation at the SPG6 locus (chromosome 15q) of the NIPA1 gene. NIPA1 mutations are predicted to cause HSP via a toxic gain-of-function mechanism, ostensibly through disruption of cellular transport—though the explicit function and biochemical pathways of NIPA1 are unknown.

• Investigation of SPG6-Hereditary Spastic Paraplegia

  The Kisanuki lab is pursuing a multifaceted approach to understanding and describing SPG6-HSP. Many experiments utilize transgenic rats with mutant NIPA1. Studies include:

  • Tracking the progression of motor deficits and behavioral phenotype
  • Examining histopathology of neural tissue and hindlimb muscle
  • Monitoring electrophysiological response in lower extremities
  • Characterizing NIPA1 expression and localization
  • Investigating impairment of axonal transport

  Future work will focus on treatment of HSP with viral gene therapy.