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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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Schematic illustration depicts the evolution of neurodegeneration in autosomal dominant hereditary spastic paraplegia (SPG6-HSP). (A) Normal spinal motor neuron. At the early stages of the disease process, the tubulovesicular membranous structures with endosomal identity accumulated at the axonal and dendritic nerve endings, along the distal axons and in the neuronal cell bodies. This accumulation was likely caused by an impaired transport and/or impaired recycling of endosomes. (B–D) A rapidly evolving multifocal intraneuronal accumulation of these aggregates sequestered by a double limiting membrane for autophagy was observed within axons (B) and dendrites (C). Multifocal vacuolar degeneration then occurred in distal axons and dendritic extensions extending pari passu in a centripetal direction with concomitant cell body involvement (C, D).
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Figure 8: Schematic illustration depicts the evolution of neurodegeneration in autosomal dominant hereditary spastic paraplegia (SPG6-HSP). (A) Normal spinal motor neuron. At the early stages of the disease process, the tubulovesicular membranous structures with endosomal identity accumulated at the axonal and dendritic nerve endings, along the distal axons and in the neuronal cell bodies. This accumulation was likely caused by an impaired transport and/or impaired recycling of endosomes. (B–D) A rapidly evolving multifocal intraneuronal accumulation of these aggregates sequestered by a double limiting membrane for autophagy was observed within axons (B) and dendrites (C). Multifocal vacuolar degeneration then occurred in distal axons and dendritic extensions extending pari passu in a centripetal direction with concomitant cell body involvement (C, D).

Mentions: We hypothesize that accumulation of TV structures in Thy1.2-hNIPA1G106R Tg rats is caused by impaired trafficking of endosomes. Based on this hypothesis, the evolution of the neurodegeneration in Thy1.2-hNIPA1G106R rats is illustrated in Figure 8. The NIPA1G106R mutation leads to the accumulation of TV structures at the axonal and dendritic nerve endings, as well as in the neuronal cell bodies. This accumulation is likely caused by impaired transport and/or impaired recycling of endosomes. The adaxonal membranes originating from oligodendrocytes and Schwann cells will invaginate into axons, encircling and then sequestering these TV structures. Glial cells are known to actively participate in the removal of unwanted/accumulated or damaged organelles from axons for selective phagocytosis, a process suggestive of an early axonal disease, as previously proposed (28). However, this compensatory mechanism eventually fails to remove the burden of accumulated TV structures. Tubulovesicular structures that failed to be removed (and are unable to be transported) likely undergo an autodigestive process that results in the formation of vacuoles. Axons and dendrites distal to the location of vacuoles are degenerated, giving way to the formation of nascent axon/neurite tips, and the progression of pathology extends pari passu in a centripetal direction with concomitant cell body involvement. Even though we see neuronal cell body involvement in the spinal cord, the disease process clearly has the predominant feature of a length-dependent distal axonal disease. We also note that, in our model, axonal and dendritic sprouting/regeneration remains active, based on the presence of a prominent increase in the small myelinated fiber population in the peripheral nerves and marked neuritic proliferation in the spinal cord gray matter.


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)

Schematic illustration depicts the evolution of neurodegeneration in autosomal dominant hereditary spastic paraplegia (SPG6-HSP). (A) Normal spinal motor neuron. At the early stages of the disease process, the tubulovesicular membranous structures with endosomal identity accumulated at the axonal and dendritic nerve endings, along the distal axons and in the neuronal cell bodies. This accumulation was likely caused by an impaired transport and/or impaired recycling of endosomes. (B–D) A rapidly evolving multifocal intraneuronal accumulation of these aggregates sequestered by a double limiting membrane for autophagy was observed within axons (B) and dendrites (C). Multifocal vacuolar degeneration then occurred in distal axons and dendritic extensions extending pari passu in a centripetal direction with concomitant cell body involvement (C, D).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 8: Schematic illustration depicts the evolution of neurodegeneration in autosomal dominant hereditary spastic paraplegia (SPG6-HSP). (A) Normal spinal motor neuron. At the early stages of the disease process, the tubulovesicular membranous structures with endosomal identity accumulated at the axonal and dendritic nerve endings, along the distal axons and in the neuronal cell bodies. This accumulation was likely caused by an impaired transport and/or impaired recycling of endosomes. (B–D) A rapidly evolving multifocal intraneuronal accumulation of these aggregates sequestered by a double limiting membrane for autophagy was observed within axons (B) and dendrites (C). Multifocal vacuolar degeneration then occurred in distal axons and dendritic extensions extending pari passu in a centripetal direction with concomitant cell body involvement (C, D).
Mentions: We hypothesize that accumulation of TV structures in Thy1.2-hNIPA1G106R Tg rats is caused by impaired trafficking of endosomes. Based on this hypothesis, the evolution of the neurodegeneration in Thy1.2-hNIPA1G106R rats is illustrated in Figure 8. The NIPA1G106R mutation leads to the accumulation of TV structures at the axonal and dendritic nerve endings, as well as in the neuronal cell bodies. This accumulation is likely caused by impaired transport and/or impaired recycling of endosomes. The adaxonal membranes originating from oligodendrocytes and Schwann cells will invaginate into axons, encircling and then sequestering these TV structures. Glial cells are known to actively participate in the removal of unwanted/accumulated or damaged organelles from axons for selective phagocytosis, a process suggestive of an early axonal disease, as previously proposed (28). However, this compensatory mechanism eventually fails to remove the burden of accumulated TV structures. Tubulovesicular structures that failed to be removed (and are unable to be transported) likely undergo an autodigestive process that results in the formation of vacuoles. Axons and dendrites distal to the location of vacuoles are degenerated, giving way to the formation of nascent axon/neurite tips, and the progression of pathology extends pari passu in a centripetal direction with concomitant cell body involvement. Even though we see neuronal cell body involvement in the spinal cord, the disease process clearly has the predominant feature of a length-dependent distal axonal disease. We also note that, in our model, axonal and dendritic sprouting/regeneration remains active, based on the presence of a prominent increase in the small myelinated fiber population in the peripheral nerves and marked neuritic proliferation in the spinal cord gray matter.

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