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

Watanabe F, Arnold WD, Hammer RE, Ghodsizadeh O, Moti H, Schumer M, Hashmi A, Hernandez A, Sneh A, Sahenk Z, Kisanuki YY - J. Neuropathol. Exp. Neurol. (2013)

Bottom Line: 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.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.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.

View Article: PubMed Central - PubMed

Affiliation: From the Department of Neurology, The Ohio State University, Columbus, Ohio (FW, WDA, OG, HM, MS, AH, AH, ZS, YYK); The Department of Biochemistry, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas (REH); Department of Pediatrics and Pathology, The Ohio State University/Nationwide Children's Hospital (ZS); and Center for Gene Therapy, The Research Institute, Nationwide Children's Hospital (ZS), Columbus, Ohio.

ABSTRACT
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.

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Thy1.2-hNIPA1G106R transgenic (Tg) rat peripheral nerve. (A) One-micrometer-thick toluidine blue–stained plastic sections from the proximal sciatic nerve of a Tg rat showing large myelinated fiber loss. Arrows point to clusters of thinly myelinated regenerating axonal sprouts; a fiber undergoing Wallerian degeneration is marked with an arrowhead. (B) Fiber loss was more prominent distally in the tibial nerve from a Tg rat. (C) Wild-type (WT) proximal sciatic nerve. Scale bar = 10 μm. (D) At the ultrastructural level, there were empty stacks of Schwann cell processes (arrows), some engulfing collagen, because of unmyelinated axon loss in the Tg nerve. Scale bar = 2 μm. (E, F) Myelinated fiber size distribution histograms of sciatic (E) and tibial (F) nerves from WT and Tg rats at 40 weeks of age. The composite histograms were derived from 3 rats in each group. Loss of large myelinated fibers (i.e. myelinated fibers with axon diameter >5 μm) in the Tg was more prominent distally in the tibial branch (F) compared with the proximal sciatic nerve (E). The prominent increase in the small myelinated fiber population seen at both levels reflects ongoing regeneration.
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Figure 6: Thy1.2-hNIPA1G106R transgenic (Tg) rat peripheral nerve. (A) One-micrometer-thick toluidine blue–stained plastic sections from the proximal sciatic nerve of a Tg rat showing large myelinated fiber loss. Arrows point to clusters of thinly myelinated regenerating axonal sprouts; a fiber undergoing Wallerian degeneration is marked with an arrowhead. (B) Fiber loss was more prominent distally in the tibial nerve from a Tg rat. (C) Wild-type (WT) proximal sciatic nerve. Scale bar = 10 μm. (D) At the ultrastructural level, there were empty stacks of Schwann cell processes (arrows), some engulfing collagen, because of unmyelinated axon loss in the Tg nerve. Scale bar = 2 μm. (E, F) Myelinated fiber size distribution histograms of sciatic (E) and tibial (F) nerves from WT and Tg rats at 40 weeks of age. The composite histograms were derived from 3 rats in each group. Loss of large myelinated fibers (i.e. myelinated fibers with axon diameter >5 μm) in the Tg was more prominent distally in the tibial branch (F) compared with the proximal sciatic nerve (E). The prominent increase in the small myelinated fiber population seen at both levels reflects ongoing regeneration.

Mentions: Multifocal vacuolar degeneration along the axons occurred at subsequent ages. By light microscopy, scattered axons from the sciatic and tibial nerves showed large vacuoles, displacing the axonal contents to the periphery before myelin collapse. Granulovacuolar disintegration of the axonal contents was present at the ultrastructural level (not shown). Acute Wallerian degenerative changes and myelin ovoids as the final stage were also noted in numerous fibers. Myelinated and unmyelinated fiber loss with a nonrandom preservation of some fibers increased with age in both proximal and distal sciatic nerves (Fig. 6A–D). Thinly myelinated small regenerating fibers in clusters were also common.


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

Watanabe F, Arnold WD, Hammer RE, Ghodsizadeh O, Moti H, Schumer M, Hashmi A, Hernandez A, Sneh A, Sahenk Z, Kisanuki YY - J. Neuropathol. Exp. Neurol. (2013)

Thy1.2-hNIPA1G106R transgenic (Tg) rat peripheral nerve. (A) One-micrometer-thick toluidine blue–stained plastic sections from the proximal sciatic nerve of a Tg rat showing large myelinated fiber loss. Arrows point to clusters of thinly myelinated regenerating axonal sprouts; a fiber undergoing Wallerian degeneration is marked with an arrowhead. (B) Fiber loss was more prominent distally in the tibial nerve from a Tg rat. (C) Wild-type (WT) proximal sciatic nerve. Scale bar = 10 μm. (D) At the ultrastructural level, there were empty stacks of Schwann cell processes (arrows), some engulfing collagen, because of unmyelinated axon loss in the Tg nerve. Scale bar = 2 μm. (E, F) Myelinated fiber size distribution histograms of sciatic (E) and tibial (F) nerves from WT and Tg rats at 40 weeks of age. The composite histograms were derived from 3 rats in each group. Loss of large myelinated fibers (i.e. myelinated fibers with axon diameter >5 μm) in the Tg was more prominent distally in the tibial branch (F) compared with the proximal sciatic nerve (E). The prominent increase in the small myelinated fiber population seen at both levels reflects ongoing regeneration.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3814936&req=5

Figure 6: Thy1.2-hNIPA1G106R transgenic (Tg) rat peripheral nerve. (A) One-micrometer-thick toluidine blue–stained plastic sections from the proximal sciatic nerve of a Tg rat showing large myelinated fiber loss. Arrows point to clusters of thinly myelinated regenerating axonal sprouts; a fiber undergoing Wallerian degeneration is marked with an arrowhead. (B) Fiber loss was more prominent distally in the tibial nerve from a Tg rat. (C) Wild-type (WT) proximal sciatic nerve. Scale bar = 10 μm. (D) At the ultrastructural level, there were empty stacks of Schwann cell processes (arrows), some engulfing collagen, because of unmyelinated axon loss in the Tg nerve. Scale bar = 2 μm. (E, F) Myelinated fiber size distribution histograms of sciatic (E) and tibial (F) nerves from WT and Tg rats at 40 weeks of age. The composite histograms were derived from 3 rats in each group. Loss of large myelinated fibers (i.e. myelinated fibers with axon diameter >5 μm) in the Tg was more prominent distally in the tibial branch (F) compared with the proximal sciatic nerve (E). The prominent increase in the small myelinated fiber population seen at both levels reflects ongoing regeneration.
Mentions: Multifocal vacuolar degeneration along the axons occurred at subsequent ages. By light microscopy, scattered axons from the sciatic and tibial nerves showed large vacuoles, displacing the axonal contents to the periphery before myelin collapse. Granulovacuolar disintegration of the axonal contents was present at the ultrastructural level (not shown). Acute Wallerian degenerative changes and myelin ovoids as the final stage were also noted in numerous fibers. Myelinated and unmyelinated fiber loss with a nonrandom preservation of some fibers increased with age in both proximal and distal sciatic nerves (Fig. 6A–D). Thinly myelinated small regenerating fibers in clusters were also common.

Bottom Line: 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.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.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.

View Article: PubMed Central - PubMed

Affiliation: From the Department of Neurology, The Ohio State University, Columbus, Ohio (FW, WDA, OG, HM, MS, AH, AH, ZS, YYK); The Department of Biochemistry, The University of Texas Southwestern Medical Center at Dallas, Dallas, Texas (REH); Department of Pediatrics and Pathology, The Ohio State University/Nationwide Children's Hospital (ZS); and Center for Gene Therapy, The Research Institute, Nationwide Children's Hospital (ZS), Columbus, Ohio.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus