Limits...
Therapy development for spinal muscular atrophy in SMN independent targets.

Tsai LK - Neural Plast. (2012)

Bottom Line: An effective treatment does not presently exist.Stem cell transplantation in SMA model mice resulted in improvement of motor behaviors and extension of survival, likely from trophic support.Although most therapies are still under investigation, these nonclassical treatments might provide an adjunctive method for future SMA therapy.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan. milikai@ntuh.gov.tw

ABSTRACT
Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disorder, leading to progressive muscle weakness, atrophy, and sometimes premature death. SMA is caused by mutation or deletion of the survival motor neuron-1 (SMN1) gene. An effective treatment does not presently exist. Since the severity of the SMA phenotype is inversely correlated with expression levels of SMN, the SMN-encoded protein, SMN is the most important therapeutic target for development of an effective treatment for SMA. In recent years, numerous SMN independent targets and therapeutic strategies have been demonstrated to have potential roles in SMA treatment. For example, some neurotrophic, antiapoptotic, and myotrophic factors are able to promote survival of motor neurons or improve muscle strength shown in SMA mouse models or clinical trials. Plastin-3, cpg15, and a Rho-kinase inhibitor regulate axonal dynamics and might reduce the influences of SMN depletion in disarrangement of neuromuscular junction. Stem cell transplantation in SMA model mice resulted in improvement of motor behaviors and extension of survival, likely from trophic support. Although most therapies are still under investigation, these nonclassical treatments might provide an adjunctive method for future SMA therapy.

Show MeSH

Related in: MedlinePlus

Schematic diagram of the SMN1 and SMN2 genes. Humans are the only species that carry both SMN1 and SMN2 genes, located in the human 5q11.2–13.3 region [5, 168]. The SMN1 and SMN2 genes differ by five nucleotide exchanges [6]. Among them, a translationally silent cytosine to thymidine exchange at position 6 of exon 7 is responsible for the skipping of exon 7 during splicing of the SMN2 gene [6]. The C-to-T transition abolishes an exonic splice enhancer site and generates a new exonic splicing silencer domain for the last coding exon [169, 170]. Subsequently, through alternative splicing, most of the translating SMN protein from the SMN2 gene lacks the C-terminal residue and becomes less stable and relatively inactive [171]. In normal situation, abundant SMN protein is produced mainly from SMN1 gene with a little amount from SMN2 gene. The spinal motor neuron from a wild-type mouse thus expresses a high level of SMN in both cytoplasm and nucleus with several gems (arrow head) as compared to that in an SMA mouse. With homozygous mutation of the SMN1 genes, all SMA patients still have at least one SMN2 gene copy [6]. While complete loss of SMN expression is embryonically lethal [172], the small amount of full-length SMN protein produced by the SMN2 gene (about 20%) prevents lethality in SMA patients, but has insufficient SMN levels to assist in recovery from spinal motor neuron death [28].
© Copyright Policy - open-access
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3369530&req=5

fig1: Schematic diagram of the SMN1 and SMN2 genes. Humans are the only species that carry both SMN1 and SMN2 genes, located in the human 5q11.2–13.3 region [5, 168]. The SMN1 and SMN2 genes differ by five nucleotide exchanges [6]. Among them, a translationally silent cytosine to thymidine exchange at position 6 of exon 7 is responsible for the skipping of exon 7 during splicing of the SMN2 gene [6]. The C-to-T transition abolishes an exonic splice enhancer site and generates a new exonic splicing silencer domain for the last coding exon [169, 170]. Subsequently, through alternative splicing, most of the translating SMN protein from the SMN2 gene lacks the C-terminal residue and becomes less stable and relatively inactive [171]. In normal situation, abundant SMN protein is produced mainly from SMN1 gene with a little amount from SMN2 gene. The spinal motor neuron from a wild-type mouse thus expresses a high level of SMN in both cytoplasm and nucleus with several gems (arrow head) as compared to that in an SMA mouse. With homozygous mutation of the SMN1 genes, all SMA patients still have at least one SMN2 gene copy [6]. While complete loss of SMN expression is embryonically lethal [172], the small amount of full-length SMN protein produced by the SMN2 gene (about 20%) prevents lethality in SMA patients, but has insufficient SMN levels to assist in recovery from spinal motor neuron death [28].

Mentions: Although pathogenesis of SMA has been investigated extensively, some of the detailed disease mechanisms are still not fully understood. Figure 1 showed the genetics in SMA. The SMN is a 38-kDa protein expressed in both the cytoplasm and nucleus of all cells [21]. SMN serves as a chaperone in the assembly of spliceosome precursors by combining small nuclear RNA (snRNA) molecules with Sm proteins to generate small nuclear ribonucleoproteins (snRNPs) [22, 23]. The snRNP assembly activity is dramatically reduced in spinal cord from SMA model mice and the degree of snRNP assembly impairment correlates with disease severity [24]. Therefore, SMN plays a critical role in pre-mRNA splicing. Evidence shows that SMN is also involved in the stabilization and maturation of the neuromuscular junction and the transportation of axonal mRNAs in motor neurons [25–27]. SMN-deficient motor neurons exhibit severe defects in clustering voltage-gated calcium channels in axonal growth cones [26]. An alteration of calcium channel distribution might influence neurotransmitter release, causing dysfunction and immaturation of neuromuscular junction [25, 28]. In addition, the SMN protein can form granules that are transported and associated with β-actin mRNA in neuronal processes [29]. The close relationship of SMN and β-actin has further demonstrated that motor neurons derived from SMA model mice have shortened axons and small growth cones, which are also deficient in β-actin mRNA and protein [30]. Therefore, SMN has a function in maintaining proper neuronal machinery via assistance in splicing process and establishing adequate communication between the muscles and nerves at the motor end plate through stabilization of the neuromuscular junction. The loss of maintenance and communication might thus trigger the cascade of events that probably results in motor neuron death.


Therapy development for spinal muscular atrophy in SMN independent targets.

Tsai LK - Neural Plast. (2012)

Schematic diagram of the SMN1 and SMN2 genes. Humans are the only species that carry both SMN1 and SMN2 genes, located in the human 5q11.2–13.3 region [5, 168]. The SMN1 and SMN2 genes differ by five nucleotide exchanges [6]. Among them, a translationally silent cytosine to thymidine exchange at position 6 of exon 7 is responsible for the skipping of exon 7 during splicing of the SMN2 gene [6]. The C-to-T transition abolishes an exonic splice enhancer site and generates a new exonic splicing silencer domain for the last coding exon [169, 170]. Subsequently, through alternative splicing, most of the translating SMN protein from the SMN2 gene lacks the C-terminal residue and becomes less stable and relatively inactive [171]. In normal situation, abundant SMN protein is produced mainly from SMN1 gene with a little amount from SMN2 gene. The spinal motor neuron from a wild-type mouse thus expresses a high level of SMN in both cytoplasm and nucleus with several gems (arrow head) as compared to that in an SMA mouse. With homozygous mutation of the SMN1 genes, all SMA patients still have at least one SMN2 gene copy [6]. While complete loss of SMN expression is embryonically lethal [172], the small amount of full-length SMN protein produced by the SMN2 gene (about 20%) prevents lethality in SMA patients, but has insufficient SMN levels to assist in recovery from spinal motor neuron death [28].
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3369530&req=5

fig1: Schematic diagram of the SMN1 and SMN2 genes. Humans are the only species that carry both SMN1 and SMN2 genes, located in the human 5q11.2–13.3 region [5, 168]. The SMN1 and SMN2 genes differ by five nucleotide exchanges [6]. Among them, a translationally silent cytosine to thymidine exchange at position 6 of exon 7 is responsible for the skipping of exon 7 during splicing of the SMN2 gene [6]. The C-to-T transition abolishes an exonic splice enhancer site and generates a new exonic splicing silencer domain for the last coding exon [169, 170]. Subsequently, through alternative splicing, most of the translating SMN protein from the SMN2 gene lacks the C-terminal residue and becomes less stable and relatively inactive [171]. In normal situation, abundant SMN protein is produced mainly from SMN1 gene with a little amount from SMN2 gene. The spinal motor neuron from a wild-type mouse thus expresses a high level of SMN in both cytoplasm and nucleus with several gems (arrow head) as compared to that in an SMA mouse. With homozygous mutation of the SMN1 genes, all SMA patients still have at least one SMN2 gene copy [6]. While complete loss of SMN expression is embryonically lethal [172], the small amount of full-length SMN protein produced by the SMN2 gene (about 20%) prevents lethality in SMA patients, but has insufficient SMN levels to assist in recovery from spinal motor neuron death [28].
Mentions: Although pathogenesis of SMA has been investigated extensively, some of the detailed disease mechanisms are still not fully understood. Figure 1 showed the genetics in SMA. The SMN is a 38-kDa protein expressed in both the cytoplasm and nucleus of all cells [21]. SMN serves as a chaperone in the assembly of spliceosome precursors by combining small nuclear RNA (snRNA) molecules with Sm proteins to generate small nuclear ribonucleoproteins (snRNPs) [22, 23]. The snRNP assembly activity is dramatically reduced in spinal cord from SMA model mice and the degree of snRNP assembly impairment correlates with disease severity [24]. Therefore, SMN plays a critical role in pre-mRNA splicing. Evidence shows that SMN is also involved in the stabilization and maturation of the neuromuscular junction and the transportation of axonal mRNAs in motor neurons [25–27]. SMN-deficient motor neurons exhibit severe defects in clustering voltage-gated calcium channels in axonal growth cones [26]. An alteration of calcium channel distribution might influence neurotransmitter release, causing dysfunction and immaturation of neuromuscular junction [25, 28]. In addition, the SMN protein can form granules that are transported and associated with β-actin mRNA in neuronal processes [29]. The close relationship of SMN and β-actin has further demonstrated that motor neurons derived from SMA model mice have shortened axons and small growth cones, which are also deficient in β-actin mRNA and protein [30]. Therefore, SMN has a function in maintaining proper neuronal machinery via assistance in splicing process and establishing adequate communication between the muscles and nerves at the motor end plate through stabilization of the neuromuscular junction. The loss of maintenance and communication might thus trigger the cascade of events that probably results in motor neuron death.

Bottom Line: An effective treatment does not presently exist.Stem cell transplantation in SMA model mice resulted in improvement of motor behaviors and extension of survival, likely from trophic support.Although most therapies are still under investigation, these nonclassical treatments might provide an adjunctive method for future SMA therapy.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan. milikai@ntuh.gov.tw

ABSTRACT
Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disorder, leading to progressive muscle weakness, atrophy, and sometimes premature death. SMA is caused by mutation or deletion of the survival motor neuron-1 (SMN1) gene. An effective treatment does not presently exist. Since the severity of the SMA phenotype is inversely correlated with expression levels of SMN, the SMN-encoded protein, SMN is the most important therapeutic target for development of an effective treatment for SMA. In recent years, numerous SMN independent targets and therapeutic strategies have been demonstrated to have potential roles in SMA treatment. For example, some neurotrophic, antiapoptotic, and myotrophic factors are able to promote survival of motor neurons or improve muscle strength shown in SMA mouse models or clinical trials. Plastin-3, cpg15, and a Rho-kinase inhibitor regulate axonal dynamics and might reduce the influences of SMN depletion in disarrangement of neuromuscular junction. Stem cell transplantation in SMA model mice resulted in improvement of motor behaviors and extension of survival, likely from trophic support. Although most therapies are still under investigation, these nonclassical treatments might provide an adjunctive method for future SMA therapy.

Show MeSH
Related in: MedlinePlus