Peering into the Proteome of SMA

Spinal Muscular Atrophy (SMA) is a devastating neuromuscular disorder that, in the vast majority of cases, is directly linked to a deletion in exon 7 of the survival of motor neuron 1 (SMN1) gene.¹ SMA is one of the most common autosomal recessive disorders with an estimated carrier frequency of 1 in 50 to 100 of the general population.² The onset and severity of SMA symptoms vary and define the clinical classification of the disorder:

• Type 0: neonatal, fatal
• Type I: infant, severe muscle weakness and difficulty breathing/swallowing
• Type II: 0.5 to 2-year-old, muscle weakness and inability to walk
• Type III: toddler/juvenile, progressively limited mobility
• Type IV: adult, mild motor impairment

Genetic testing can reveal whether SMN1 mutations are present, but the manifestation or clinical subtype of SMA is currently not clearly linked to SMN1 genotype alone.

To identify molecular determinants or markers of the different SMA subtypes, Brown et al. compared the proteome of fibroblasts from patients with SMA Type I, II, III and age-matched controls. While the authors did not find a straightforward proteomic signature unique to each subtype, they were able to use their data to identify proteins which may correlate to SMA severity (four of which they examined). The collected proteomes are valuable datasets that can be further mined to understand and develop treatments for SMA.

As of November 2022, a few FDA-approved therapeutics are available for SMA patients. Zolgensma (onasemnogene abeparvovec) is an AAV9-based therapy for restoring SMN1 protein levels. Spinraza (nusinersen) and Evrysdi (risdiplam) are antisense oligo-based treatments that work by modulating mRNA splicing of SMN2. SMN2 is nearly identical to SMN1 but normally, due to differences in splicing, does not result in functional SMN protein expression.

Citation

Title: The Proteome Signatures of Fibroblasts from Patients with Severe, Intermediate and Mild Spinal Muscular Atrophy Show Limited Overlap
Authors: Sharon Brown, Rachel Kline et al.
Journal: Cells, Volume 11, 23 August 2022.
DOI: 10.3390/cells11172624
Product Usage: A plasmid encoding the full-length SMN1 gene tagged with GFP was electroporated into fibroblast cell lines established from patients with SMA Type I, II and III using the Ingenio® EZporator® Electroporation System. The fibroblast cells were resuspended at a density of 1 million per ml in 250 µL of Ingenio® Electroporation Solution and electroporated with 5 µg DNA at 220 V in a 0.4-cm gap-width cuvette.

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