(SMN1), which is found in the lower part of the spinal cord. 1 There are several different types of
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1 SMA and the role of the Survival Motor Neuron 1 Gene Jacqueline Seals Copyright May, 2015, Jacqueline Seals and Koni Stone Spinal muscular atrophy (SMA) is one of the leading causes of infant mortality. It is a hereditary genetic disease caused by the loss or alteration of the Survival Motor Neuron 1 (SMN1), which is found in the lower part of the spinal cord. 1 There are several different types of spinal muscular atrophy but type 1 is the most severe. There is no cure as of yet for this disorder but several types of treatment have been implemented, most of which consist of splicing the SMN2 pre mrna to increase the production of the SMN protein. 2 SMA is a degenerative neurological disease whose research can be characterized as centered around three main topics: the causes of deletion or mutation of the survival motor neuron 1 gene, the importance of the survival neuron 1 gene itself, and what experimentation is being done to prevent mutation or deletion of the survival motor neuron 1 gene. SMA is an autosomal recessive disorder passed on to children from their parents. Because the disease is autosomal, both parents must be carriers of one of the defective SMN1 genes in order for it to be inherited by the children. Fortunately the body also produces the SMN2 gene, 1 which is almost identical to the SMN1 gene with the exception of its splicing pattern. The defects in the SMN2 splicing pattern result in the gene s inability to produce an adequate amount of the SMN protein needed for motor function. The malfunction occurs at position 6 of the nucleotide, at the Cytosine and Tyrosine transition in exon 7. Exon 7 contains the stop codon needed for efficient DNA translation, and is responsible for ending a translation. The signal to terminate a translation is processed by proteins that recognize the stop codon and
2 cause the ribosome subunits to disassociate and release the amino acid chain. 2 However if the stop codon is not present, as is seen in SMA because of the loss of exon 7, then alternative splicing of mrna occurs, which in turn produces only part of the SMN protein. This splicing, taking place in the SMN2 gene, refers to the fact that 90% of the SMN protein produced by the SMN2 gene is either cut off or shortened and results in an unstable form of the protein lacking the 16 amino acids present in exon 7. The truncated form of this protein is referred to as SMN 7, 3 and it has been determined that the loss of the SMN1 gene causes death by an unknown mechanism to the motor neurons. Researchers have determined this unknown mechanism is most likely a result of alternate mrna splicing. 1 The SMN1 gene is responsible for providing the information needed to produce the SMN protein, upon which the survival of motor neurons is highly dependent; without it they die rather quickly. Like the SMN gene messenger RNA (mrna) are also detrimental to the central makeup of eukaryotic gene expression. There are three RNA polymerase involved in eukaryotic gene expression. RNA polymerase II is the most fragile of the three and is responsible for synthesis of pre mrna. The mrna contain exons and introns needed for both intervening and expressed coding sequences, both of which are needed for affective mrna splicing. The production of the SMN protein is essential to the processing of the pre mrna needed to promote cell function and growth as well as brain and nerve development. 2 When the pre mrna fails to receive the pertinent processing information provided by the SMN protein, then normal protein function is also disrupted and nerve impulses cease to be passed between the brain and the muscles.
3 Synthesis of pseudocantharidins is an experiment that was used to create several phosphatase activity modulators and assays which in turn may be used in the promotion of exon 7 inclusion of the SMN2 gene. As the promotion of exon 7 inclusion is necessary for the production of a fully functional SMN protein. A mixture of the cantharidins was collected and heated at low pressure, and after undergoing several dilutions the crude product was purified by recrystallization and then analyzed by chromatography using a pseudocantharidin. 4 The melting point of the purified product was obtained at the end of the analysis. Glycogen Phosphorylase Phosphatase along with PP1 and PP2A were purified from the skeletal muscle of a rabbit and used for comparison. Analysts concluded that the mutation of threonine to alanine promoted exon 7 inclusion and the formation of the SMN protein in fibroblasts as a result of the dephosphorylation that occurs at thr- 33 caused by the PP2A activators. 4 RT- PCR was also performed with this experiment using SV40pA RT for reverse transcription, and both pcl and SMNex8rev were used with PCR. Polymerase Chain Reaction (PCR) is a quantitative technique that uses one copy of a DNA strand and makes thousands of copies of that strand quickly and efficiently using DNA polymerase and a primer. The DNA strands are first separated by high temperature conditions and then a heat resistant enzyme is used to synthesize two strands of DNA. Once the heating process is complete the strands are cooled and the process repeats, creating a chain reaction. The reverse transcription process required the RNA to be incubated in RT buffer which included Taq polymerase buffer as well as forward and reverse primers. PCR was performed with the initial denaturation starting at 4 minutes, and after 28 thirty- second trials, products were obtained and the results for the percentage of exon 7 inclusion at various concentrations of psuedocantharidin A were
4 observed. 5 Psuedocantharidin A is a phosphatase activity modulator synthesized from cantharidin, to test its effectiveness on alternative splicing. Cantharidin is a small molecule that specifically targets phosphatase and changes alternative splicing. 5 The results concluded that cantharidins, when combined with phosphatase assays can be used to help change alternate splicing patterns of the pre mrna of the SMN 2 gene by inhibiting PP1 and PP2 activators. Inclusion of exon 7 showed a 40% increase upon synthesis with pseudocantharidin. Phosphatase mechanisms that are normally used and seen as inhibitors can be changed into activators necessary for splicing reactions that promote exon 7 inclusion in the SMN2 gene. 4 Other experiments performed have attempted to identify small molecule upregulators of the Survival Motor Neuron protein (SMN). Due to their rarity and difficulty in identifying them, a high- throughput approach to screening has been developed. 5 The screening process focused on identifying SMN protein abundance in SMA patient fibroblast cells (which were the desired final product) without bias. A modified enzyme- linked immunosorbent assay (ELISA) was used to accurately calculate the SMN protein levels in the patient fibroblasts. Two libraries were screened with the process: a library containing active central nervous system compounds unable to cross the blood- brain barrier (BBB), as well as a library of compounds with the ability to cross the blood- brain barrier. A mechanistic study was also conducted to investigate SMN protein up- regulation by activated RAS. 6 Ras proteins belong to a group of small proteins known as G- proteins. G- proteins bind GTP and GDP nucleotides. GTPase activity that the ras proteins contain, converts GTP to GDP through the hydrolyzation of the gamma phosphate on the GTP. This allows ras proteins the ability to alternate between active and inactive or on and off rather easily. When the protein is active and GDP is exchanged for GTP, then a signal
5 is allowed to pass through the cell membrane, which allows transcription factors to modify RNA expression patterns in the nucleus. 7 One experiment conducted was a high- throughput screening of 69,189 compounds (specifically small molecules) to determine their utility in the treatment of SMN. A modified ELISA was optimized for microtiter- based screening using SMA patient fibroblasts. ELISA is an Enzyme Linked ImmunosSorbent Assay. ELISA is a biochemical technique used determine the concentration of analyte, namely and antigen or antibody, in a solution. It utilizes the non- specific interactions that occur between the analyte and a solid surface (usually polysterene) to produce qualitative results observed by a change in color of the end product. The information obtained for ELISA was used to predict the BBB penetration potential of each compound using 109 compounds with experimentally determined log BB ratios. Predictions gave no false negatives, meaning that each compound was in fact capable of crossing the blood brain barrier. Primary screening was performed in triplicate in 9677 SMA patient fibroblast cells in 3840 well format, and the study showed a median signal greater than 2 standard deviations from the untreated mean. 7 The passing compounds were retested according to their response, and the 105 candidates showing positive response activity in at least two cell lines were tested by Western Blot. There were three compounds that were found with significantly increased SMN protein levels. A mechanistic investigation was then conducted on the best suited compound, a bromobenzophenone analogue which was designated cuspin- 1. It was this investigation that led to the determination that small molecules could affect difference on SMN translation.
6 Another experiment performed focused on the molecular genetics and early diagnosis of Spinal Muscular Atrophy. It is known that this disease is caused by the deletion or mutation of the survivor motor neuron 1 gene. (SMN1) Individuals with SMA type 1 generally show signs of severe muscle weakness and lack of motility in the first six months of life, while types 2-4 can begin surfacing as early as 18 months of life. Researchers have hypothesized two separate scenarios: that SMN is involved in the basic development of snrnp and mrna splicing or that SMN has specific functionality independent of snrnp assembly and mrna transport. Experiments performed included Real Time Polymerase Chain Reaction and MLPA. 8 Multiplex ligation- dependent probe amplification is a different type of polymerase chain reaction that allows various targets to be amplified with the use of only one primer. 8 Each probe used contains an oligonucleotide to recognize the sequence of the reverse primer and an oligonucleotide to recognize the sequence of the forward primer, which is labeled by fluorescence. Once the oligonucleotides complete their task the probe is ligated. The length of the probe is specific so that the sequences can be correctly identified by electrophoresis and compared to the fluorescent peak patterns of several obtained reference samples. 9 Researchers have concluded that the SMN protein is essential to the assembly of core class proteins that contain the main components of cellular particles responsible for pre- mrna splicing. The synthesized pseudocantharidins analyzed produced lower toxicity results of exon 7 inclusion, at concentrations almost 250 times higher than that of cantharidin. These results suggest that exon 7 inclusion can be promoted in vivo. 7 Several determinations were made as a result of the screening and mechanistic studies, importantly it was found that increased RAS signaling does not affect the rate of SMN degradation but does affect translation rates. Three
7 novel SMN- upregulating compounds were discovered using the aforementioned screening process, and the investigation of cuspin- 1 was what led to the discovery that RAS signaling regulates SMN protein abundance. 9 Small molecule upregulators can now be identified quite easily using the methods outlined in this study, which will more easily allow targeted upregulation of specific proteins thanks to further discovery of small molecule activators. The purpose of the experiments analyzed and treatments given has been to achieve one goal; a complete SMN protein. The SMN1 gene has been the underlying deterrent thus far. Spinal Muscular Atrophy is a degenerative neurological disease for which there is no cure. However analysts and researchers have made astounding progress through experimentation in determining the causes of deletion or mutation of the survival motor neuron 1 gene, the importance of the SMN 1 gene itself as well as having developed therapeutic treatment to promote the longevity of life.
8 References: 1. Lorson, L. Christian., Rindt, Hansjorg., and Shababi, Monir. Spinal Muscular Atrophy: Mechanisms and therapeutic Strategies. Human Molecular Genetics 19 (2010): R111- R D Amico, Adele., Mercuri, Eugenio., Tiziano, Francesco D., and Bertini, Enrico. Spinal Muscular Atrophy. Orphanet Journal of Rare Diseases. 6 (2011) Shababi, Monir., Lorson, L. Christian., and Rudnick- Schoneborn, RS. Sabine. Spinal Muscular Atrophy: A Motor Neuron Disorder or Multi- Organ disease? Journal of Anatomy. 10 (2013) Zhang, Zhaiyl., Kelemen, Olga., Santen, A. Maria., Yelton, M. Sharon., Wendlandt, E. Alison., Vitality, M. Sviripa., Bollen, Mattieu., Beullens, Monique., Luhmann, Reinhard., Watt, S. David, and Stamm, Sefan. Synthesis and Characterization of Pseudocantharidins, Novel Phosphatase Modulators That Promote the Inclusion of Exon 7 into the SMN (Survival of Motor Neuron Pre- mrna. Journal of Biological Chemistry (2011): Davis, P. Charles. Polymerase Chain Reaction introduction- to- elisa.html Xiao, Jingbo., Marugan, J. Juan., Zheng, Wei., Titus, Steve., Southall, Noel., Cherry, J. Jonathan., Evans, Mathew., Androphy, J. Elliot., and Austin, P. Christopher. Discovery, Synthesis, and Biological Evaluation of Novel SMN Protein Modulators. Journal of Medicinal Chemistry. 54. (2011): Letso, Reka., Howard Hughes Medical Institute, department of biological sciences. Bauer, Andras., Lunn, Mitchell., Yung, Wan., and Stockwell, Brent. Small Molecule Screen Reveals Regulation of Survivor Motor Neuron Protein Abundance by Ras Proteins. ACS Chemical Biology. 8 (2013)
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