ORIGINAL ARTICLE Pathogenesis of Autosomal Dominant Hereditary Spastic Paraplegia (SPG6) Revealed by a Rat Model

Hereditary spastic paraplegias (HSPs) are characterized by progres-sive spasticity and weakness in the lower extremities that result from length-dependent central to peripheral axonal degeneration. Muta-tions 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-hNIPA1G106R) show marked early onset behavioral and electrophysiologic abnor-malities. 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 NIPA1G106R 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-hNIPA1G106R Tg rat model may serve as a valuable tool for understanding endosomal trafficking in the patho-genesis of a subgroup of HSP with an abnormal interaction with bone morphogenetic protein type II receptor, as well as for developing po-tential therapeutic strategies for diseases with axonal degeneration and similar pathogenetic mechanisms