Pelletier S, Gingras S, Howell S, Vogel P, Ihle JN.
An early onset progressive motor neuron disorder in Scyl1-deficient mice is associated with mislocalization of TDP-43.
J Neurosci. 2012 Nov 21;32(47):16560-73.
PubMed.
Pelletier and colleagues demonstrate that mice deficient in Scyl1 may be a new model for early onset progressive motor neuron disease with some features reminiscent of amyotrophic lateral sclerosis (ALS). The study confirms previous work by Schmidt et al., which had shown that the underlying gene defect of the mouse mutant "muscle deficient" is a loss-of-function mutation in Scyl1. SCYL1 is a ubiquitously expressed protein with a number of suggested cellular “housekeeping” functions, including COP1-mediated retrograde protein trafficking and the cytoplasmic shuttling of transfer RNA (Chafe and Mangroo, 2010). Remarkably, mice with constitutive deletion of the gene are viable and display a motor neuron-centric phenotype. In contrast, homozygous deletion of several other housekeeping genes associated with ALS and other motor neuron diseases typically results in embryonic lethality. Pelletier et al. speculate that other members of the SCYL family may be able to compensate for the loss of SCYL1.
Intriguingly, spinal cord motor neurons of Scyl1-/- mice display cytoplasmic inclusions of TAR DNA-binding protein 43 (TDP-43) and ubiquilin 2, two proteins linked to ALS. Cytoplasmic TDP-43 inclusions are a pathological hallmark of most ALS cases, frontotemporal lobar degeneration with ubiquitin aggregates, and some other neurodegenerative diseases (Neumann et al., 2006; Deng et al, 2011). Similarly, ubiquilin 2 builds up in cytoplasmic inclusions found in many ALS cases (Deng et al, 2011). The presence of this type of neuropathology in Scyl1-deficient mice is striking, and provides further evidence that the mislocalization of TDP-43 and ubiquilin 2 may be a central event in motor neuron degeneration. However, it is still unclear whether neurodegeneration is triggered by a loss of function of these proteins after aggregation, gain of a toxic property, or a combination of the two. Researchers have developed a number of transgenic rodent models that express wild-type or mutant human TDP-43 and display a range of motor deficits (reviewed in Tsao et al., 2012). Many of these models exhibit intranuclear TDP-43 aggregates as well as diffuse cytoplasmic ubiquitin staining, while cytoplasmic TDP-43 inclusions are much rarer. This observation suggests that the formation of cytoplasmic TDP-43 inclusions per se is not essential for the development of disease, and that sequestration into nuclear inclusions may also result in loss of function leading to increased neuronal vulnerability. In addition, TDP-43 may adopt new toxic properties once mislocalized. Two more questions are whether SCYL1 regulates the homeostasis of TDP-43 and ubiquilin 2 directly and what the molecular mechanisms thereof may be.
Although so far there are no reports of Scyl1 mutations in human disease, a more complete understanding of SCYL1’s role in maintaining motor neuron viability in mice will likely provide important insights into the mechanisms of motor neuron disease. Without a doubt, this new mouse model provides a valuable tool for investigating the molecular basis of motor neuron degeneration.
References:
Chafe SC, Mangroo D.
Scyl1 facilitates nuclear tRNA export in mammalian cells by acting at the nuclear pore complex.
Mol Biol Cell. 2010 Jul 15;21(14):2483-99.
PubMed.
Deng HX, Chen W, Hong ST, Boycott KM, Gorrie GH, Siddique N, Yang Y, Fecto F, Shi Y, Zhai H, Jiang H, Hirano M, Rampersaud E, Jansen GH, Donkervoort S, Bigio EH, Brooks BR, Ajroud K, Sufit RL, Haines JL, Mugnaini E, Pericak-Vance MA, Siddique T.
Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia.
Nature. 2011 Sep 8;477(7363):211-5.
PubMed.
Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, Chou TT, Bruce J, Schuck T, Grossman M, Clark CM, McCluskey LF, Miller BL, Masliah E, Mackenzie IR, Feldman H, Feiden W, Kretzschmar HA, Trojanowski JQ, Lee VM.
Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis.
Science. 2006 Oct 6;314(5796):130-3.
PubMed.
Schmidt WM, Kraus C, Höger H, Hochmeister S, Oberndorfer F, Branka M, Bingemann S, Lassmann H, Müller M, Macedo-Souza LI, Vainzof M, Zatz M, Reis A, Bittner RE.
Mutation in the Scyl1 gene encoding amino-terminal kinase-like protein causes a recessive form of spinocerebellar neurodegeneration.
EMBO Rep. 2007 Jul;8(7):691-7.
PubMed.
Tsao W, Jeong YH, Lin S, Ling J, Price DL, Chiang PM, Wong PC.
Rodent models of TDP-43: recent advances.
Brain Res. 2012 Jun 26;1462:26-39.
PubMed.
This is an interesting and potentially very insightful paper by Stephane Pelletier and colleagues exploring the role of the COPI-associated protein pseudokinase Scyl1 in mammalian development and in motor neuronal health and survival. This avenue of research is supported by the recent linkage of Scyl1 loss of function to the phenotype observed in “muscle deficient” (MDF) mice (Schmidt et al., 2007) developed and characterized in the early 1980s by Womack et al. and Sweet et al.
The authors explored the Scyl1 loss-of-function hypothesis by engineering C57/B6 mice bearing null alleles of Scyl1 and mice with conditional tissue-specific deletions of Scyl1. All mice engineered appeared to be viable, fertile, and yielded progeny in normal Mendelian ratios.
Descriptively, the null mice were evocative of the relatively commonly studied Tg(SOD1*G93A)1Gur (SOD1-G93A) mouse model of amyotrophic lateral sclerosis. Like SOD1-G93A mice, the Scyl1-/- mice gain less weight than wild-type littermates. In addition, other clinical attributes shared across the SOD1-G93A and Scyl1-/- mice are tremor when suspended by the tail, abnormal gait, and partial and complete paralysis of the hindlimbs. The lifespan of Scyl1-/- mice remains unclear from the report, with average clinical severity scores reported out to 12 weeks, and histopathological reports ranging to 20 weeks, similar to the median lifespan of SOD1-G93A mice.
Scyl1-/- mouse muscle histopathology was consistent with neurogenic atrophy and showed a clear muscle-fiber-type switch from fast to slow. Other reported changes that seem consistent with motor neuron degeneration were decreased frequency of larger axons in sciatic nerve and reduction in motor neurons observed in the ventral horn of the spinal cord.
The investigators built on the hypothesis that Scyl1 is important for motor neuron survival by demonstrating that neural-specific deletion of Scyl1 caused motor dysfunction, while skeletal muscle-specific deletion did not.
While the investigators introduced links between Scyl1 deletion and TDP43, and ubiquilin 2 mislocalization to the cytoplasm in motor neurons, it is unclear whether the misregulation of the latter two proteins is the cause of the neurodegeneration observed in the model. Scyl1 plays important roles in general intracellular protein trafficking to and from the Golgi and endoplasmic reticulum. Disruption of these functions has long been implicated in amyotrophic lateral sclerosis pathogenesis. Further investigation along these avenues may inform the molecular and cellular basis of some motor neuron disorders.
No known mutations in SCYL1 have been linked to neurodegeneration in humans, but Scyl1-/- mice may be valuable tools to study motor neuron-specific disorders and pathways for therapeutic development. Even if the specific genetic insult is not present in human clinical cases, it is likely that elements of downstream pathogenesis have overlap and might be treatable and translatable. However, the pitfalls associated with the use of any rodent model of human disease are applicable to the Scyl1-/- mice as well. It is often the case in mouse models of neurodegeneration that clinical and pathological phenotypes will drift as colonies are expanded and generations pass. That is less of a risk with these Scyl1-/- mice, given that they are reported to be on a congenic C57/B6 background and are knockout mice rather than transgenic overexpresser mice with predispositions to lose copies of transgene. However, even if the mice are genetically stable, it is unclear from this report whether the first generation of Scyl1-/- mice has a homogeneous enough phenotype to allow for optimization of this mouse model as a therapeutic testing tool.
References:
Schmidt WM, Kraus C, Höger H, Hochmeister S, Oberndorfer F, Branka M, Bingemann S, Lassmann H, Müller M, Macedo-Souza LI, Vainzof M, Zatz M, Reis A, Bittner RE.
Mutation in the Scyl1 gene encoding amino-terminal kinase-like protein causes a recessive form of spinocerebellar neurodegeneration.
EMBO Rep. 2007 Jul;8(7):691-7.
PubMed.
Pelletier and colleagues show that a constitutive loss of function of Scyl1 in newly established mouse lines leads to a specific type of motor neuron disease (MND) with prominent degeneration of spinal motor neurons innervating type II skeletal fibers. This type of MND differs from amyotrophic lateral sclerosis (ALS), where degeneration of both upper and lower motor neurons occurs. While this report erases any doubt that the similar phenotype observed in mouse muscle deficient (MDF) lines due to a frameshift mutation in the MDF gene might be due to only a partial loss of function (Blot et al., 1995; Schmidt et al., 2007), the sketchy TDP-43 pathology shown to be occurring in these mice might be secondary to degeneration and would be interesting to compare with other mouse models of MND such as Wobbler mice due to mutation in the Vps54 gene (Dennis and Citron, 2009).
Importantly, the fact that the conditional deletion of Scyl1 from skeletal muscles does not lead to any phenotype, and only a partial phenotype when specifically deleted from the neural tissue, strongly suggests a concurrent non-neuronal cell-autonomous injury, which is strongly reminiscent of SOD1—and perhaps of TDP-43 ALS models.
References:
Blot S, Poirier C, Dreyfus PA.
The mouse mutation muscle deficient (mdf) is characterized by a progressive motoneuron disease.
J Neuropathol Exp Neurol. 1995 Nov;54(6):812-25.
PubMed.
Schmidt WM, Kraus C, Höger H, Hochmeister S, Oberndorfer F, Branka M, Bingemann S, Lassmann H, Müller M, Macedo-Souza LI, Vainzof M, Zatz M, Reis A, Bittner RE.
Mutation in the Scyl1 gene encoding amino-terminal kinase-like protein causes a recessive form of spinocerebellar neurodegeneration.
EMBO Rep. 2007 Jul;8(7):691-7.
PubMed.
Dennis JS, Citron BA.
Wobbler mice modeling motor neuron disease display elevated transactive response DNA binding protein.
Neuroscience. 2009 Jan 23;158(2):745-50. Epub 2008 Oct 30
PubMed.
Robert Hermann Louisiana State University Health Sciences Center
Posted:
It is fascinating that knocking out Scyl1 selectively in neurons precipitated TDP-43 and ubiquilin 2 neuropathology, suggesting Scyl1 is acting upstream. This could be an important new model of motor neuron disease with comprehensive neuropathology relative to existing models. It could also be important for studying deficient Golgi-ER trafficking or nuclear transport. One potential caveat would be if the induced disease state is somehow a function of a developmental defect versus neurodegeneration.
Comments
NIH/NINDS
Pelletier and colleagues demonstrate that mice deficient in Scyl1 may be a new model for early onset progressive motor neuron disease with some features reminiscent of amyotrophic lateral sclerosis (ALS). The study confirms previous work by Schmidt et al., which had shown that the underlying gene defect of the mouse mutant "muscle deficient" is a loss-of-function mutation in Scyl1. SCYL1 is a ubiquitously expressed protein with a number of suggested cellular “housekeeping” functions, including COP1-mediated retrograde protein trafficking and the cytoplasmic shuttling of transfer RNA (Chafe and Mangroo, 2010). Remarkably, mice with constitutive deletion of the gene are viable and display a motor neuron-centric phenotype. In contrast, homozygous deletion of several other housekeeping genes associated with ALS and other motor neuron diseases typically results in embryonic lethality. Pelletier et al. speculate that other members of the SCYL family may be able to compensate for the loss of SCYL1.
Intriguingly, spinal cord motor neurons of Scyl1-/- mice display cytoplasmic inclusions of TAR DNA-binding protein 43 (TDP-43) and ubiquilin 2, two proteins linked to ALS. Cytoplasmic TDP-43 inclusions are a pathological hallmark of most ALS cases, frontotemporal lobar degeneration with ubiquitin aggregates, and some other neurodegenerative diseases (Neumann et al., 2006; Deng et al, 2011). Similarly, ubiquilin 2 builds up in cytoplasmic inclusions found in many ALS cases (Deng et al, 2011). The presence of this type of neuropathology in Scyl1-deficient mice is striking, and provides further evidence that the mislocalization of TDP-43 and ubiquilin 2 may be a central event in motor neuron degeneration. However, it is still unclear whether neurodegeneration is triggered by a loss of function of these proteins after aggregation, gain of a toxic property, or a combination of the two. Researchers have developed a number of transgenic rodent models that express wild-type or mutant human TDP-43 and display a range of motor deficits (reviewed in Tsao et al., 2012). Many of these models exhibit intranuclear TDP-43 aggregates as well as diffuse cytoplasmic ubiquitin staining, while cytoplasmic TDP-43 inclusions are much rarer. This observation suggests that the formation of cytoplasmic TDP-43 inclusions per se is not essential for the development of disease, and that sequestration into nuclear inclusions may also result in loss of function leading to increased neuronal vulnerability. In addition, TDP-43 may adopt new toxic properties once mislocalized. Two more questions are whether SCYL1 regulates the homeostasis of TDP-43 and ubiquilin 2 directly and what the molecular mechanisms thereof may be.
Although so far there are no reports of Scyl1 mutations in human disease, a more complete understanding of SCYL1’s role in maintaining motor neuron viability in mice will likely provide important insights into the mechanisms of motor neuron disease. Without a doubt, this new mouse model provides a valuable tool for investigating the molecular basis of motor neuron degeneration.
References:
Chafe SC, Mangroo D. Scyl1 facilitates nuclear tRNA export in mammalian cells by acting at the nuclear pore complex. Mol Biol Cell. 2010 Jul 15;21(14):2483-99. PubMed.
Deng HX, Chen W, Hong ST, Boycott KM, Gorrie GH, Siddique N, Yang Y, Fecto F, Shi Y, Zhai H, Jiang H, Hirano M, Rampersaud E, Jansen GH, Donkervoort S, Bigio EH, Brooks BR, Ajroud K, Sufit RL, Haines JL, Mugnaini E, Pericak-Vance MA, Siddique T. Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia. Nature. 2011 Sep 8;477(7363):211-5. PubMed.
Neumann M, Sampathu DM, Kwong LK, Truax AC, Micsenyi MC, Chou TT, Bruce J, Schuck T, Grossman M, Clark CM, McCluskey LF, Miller BL, Masliah E, Mackenzie IR, Feldman H, Feiden W, Kretzschmar HA, Trojanowski JQ, Lee VM. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science. 2006 Oct 6;314(5796):130-3. PubMed.
Schmidt WM, Kraus C, Höger H, Hochmeister S, Oberndorfer F, Branka M, Bingemann S, Lassmann H, Müller M, Macedo-Souza LI, Vainzof M, Zatz M, Reis A, Bittner RE. Mutation in the Scyl1 gene encoding amino-terminal kinase-like protein causes a recessive form of spinocerebellar neurodegeneration. EMBO Rep. 2007 Jul;8(7):691-7. PubMed.
Tsao W, Jeong YH, Lin S, Ling J, Price DL, Chiang PM, Wong PC. Rodent models of TDP-43: recent advances. Brain Res. 2012 Jun 26;1462:26-39. PubMed.
ALS Therapy Development Institute (ALS TDI)
This is an interesting and potentially very insightful paper by Stephane Pelletier and colleagues exploring the role of the COPI-associated protein pseudokinase Scyl1 in mammalian development and in motor neuronal health and survival. This avenue of research is supported by the recent linkage of Scyl1 loss of function to the phenotype observed in “muscle deficient” (MDF) mice (Schmidt et al., 2007) developed and characterized in the early 1980s by Womack et al. and Sweet et al.
The authors explored the Scyl1 loss-of-function hypothesis by engineering C57/B6 mice bearing null alleles of Scyl1 and mice with conditional tissue-specific deletions of Scyl1. All mice engineered appeared to be viable, fertile, and yielded progeny in normal Mendelian ratios.
Descriptively, the null mice were evocative of the relatively commonly studied Tg(SOD1*G93A)1Gur (SOD1-G93A) mouse model of amyotrophic lateral sclerosis. Like SOD1-G93A mice, the Scyl1-/- mice gain less weight than wild-type littermates. In addition, other clinical attributes shared across the SOD1-G93A and Scyl1-/- mice are tremor when suspended by the tail, abnormal gait, and partial and complete paralysis of the hindlimbs. The lifespan of Scyl1-/- mice remains unclear from the report, with average clinical severity scores reported out to 12 weeks, and histopathological reports ranging to 20 weeks, similar to the median lifespan of SOD1-G93A mice.
Scyl1-/- mouse muscle histopathology was consistent with neurogenic atrophy and showed a clear muscle-fiber-type switch from fast to slow. Other reported changes that seem consistent with motor neuron degeneration were decreased frequency of larger axons in sciatic nerve and reduction in motor neurons observed in the ventral horn of the spinal cord.
The investigators built on the hypothesis that Scyl1 is important for motor neuron survival by demonstrating that neural-specific deletion of Scyl1 caused motor dysfunction, while skeletal muscle-specific deletion did not.
While the investigators introduced links between Scyl1 deletion and TDP43, and ubiquilin 2 mislocalization to the cytoplasm in motor neurons, it is unclear whether the misregulation of the latter two proteins is the cause of the neurodegeneration observed in the model. Scyl1 plays important roles in general intracellular protein trafficking to and from the Golgi and endoplasmic reticulum. Disruption of these functions has long been implicated in amyotrophic lateral sclerosis pathogenesis. Further investigation along these avenues may inform the molecular and cellular basis of some motor neuron disorders.
No known mutations in SCYL1 have been linked to neurodegeneration in humans, but Scyl1-/- mice may be valuable tools to study motor neuron-specific disorders and pathways for therapeutic development. Even if the specific genetic insult is not present in human clinical cases, it is likely that elements of downstream pathogenesis have overlap and might be treatable and translatable. However, the pitfalls associated with the use of any rodent model of human disease are applicable to the Scyl1-/- mice as well. It is often the case in mouse models of neurodegeneration that clinical and pathological phenotypes will drift as colonies are expanded and generations pass. That is less of a risk with these Scyl1-/- mice, given that they are reported to be on a congenic C57/B6 background and are knockout mice rather than transgenic overexpresser mice with predispositions to lose copies of transgene. However, even if the mice are genetically stable, it is unclear from this report whether the first generation of Scyl1-/- mice has a homogeneous enough phenotype to allow for optimization of this mouse model as a therapeutic testing tool.
References:
Schmidt WM, Kraus C, Höger H, Hochmeister S, Oberndorfer F, Branka M, Bingemann S, Lassmann H, Müller M, Macedo-Souza LI, Vainzof M, Zatz M, Reis A, Bittner RE. Mutation in the Scyl1 gene encoding amino-terminal kinase-like protein causes a recessive form of spinocerebellar neurodegeneration. EMBO Rep. 2007 Jul;8(7):691-7. PubMed.
University of Antwerp
Pelletier and colleagues show that a constitutive loss of function of Scyl1 in newly established mouse lines leads to a specific type of motor neuron disease (MND) with prominent degeneration of spinal motor neurons innervating type II skeletal fibers. This type of MND differs from amyotrophic lateral sclerosis (ALS), where degeneration of both upper and lower motor neurons occurs. While this report erases any doubt that the similar phenotype observed in mouse muscle deficient (MDF) lines due to a frameshift mutation in the MDF gene might be due to only a partial loss of function (Blot et al., 1995; Schmidt et al., 2007), the sketchy TDP-43 pathology shown to be occurring in these mice might be secondary to degeneration and would be interesting to compare with other mouse models of MND such as Wobbler mice due to mutation in the Vps54 gene (Dennis and Citron, 2009).
Importantly, the fact that the conditional deletion of Scyl1 from skeletal muscles does not lead to any phenotype, and only a partial phenotype when specifically deleted from the neural tissue, strongly suggests a concurrent non-neuronal cell-autonomous injury, which is strongly reminiscent of SOD1—and perhaps of TDP-43 ALS models.
References:
Blot S, Poirier C, Dreyfus PA. The mouse mutation muscle deficient (mdf) is characterized by a progressive motoneuron disease. J Neuropathol Exp Neurol. 1995 Nov;54(6):812-25. PubMed.
Schmidt WM, Kraus C, Höger H, Hochmeister S, Oberndorfer F, Branka M, Bingemann S, Lassmann H, Müller M, Macedo-Souza LI, Vainzof M, Zatz M, Reis A, Bittner RE. Mutation in the Scyl1 gene encoding amino-terminal kinase-like protein causes a recessive form of spinocerebellar neurodegeneration. EMBO Rep. 2007 Jul;8(7):691-7. PubMed.
Dennis JS, Citron BA. Wobbler mice modeling motor neuron disease display elevated transactive response DNA binding protein. Neuroscience. 2009 Jan 23;158(2):745-50. Epub 2008 Oct 30 PubMed.
Louisiana State University Health Sciences Center
It is fascinating that knocking out Scyl1 selectively in neurons precipitated TDP-43 and ubiquilin 2 neuropathology, suggesting Scyl1 is acting upstream. This could be an important new model of motor neuron disease with comprehensive neuropathology relative to existing models. It could also be important for studying deficient Golgi-ER trafficking or nuclear transport. One potential caveat would be if the induced disease state is somehow a function of a developmental defect versus neurodegeneration.
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