Survival of Motor Neuron (SMN) is a protein found throughout the body that is essential for the health and function of the nervous system. It is particularly important for motor neurons, the specialized nerve cells that govern muscle movement. These cells originate in the spinal cord and extend to muscles, transmitting the signals that enable voluntary actions. Without sufficient levels of this protein, these motor neurons cannot be maintained, leading to significant consequences for motor function.
The Function of SMN Protein
The SMN protein’s primary role is facilitating the assembly of small nuclear ribonucleoproteins (snRNPs), the building blocks of a cellular machine called the spliceosome. The spliceosome processes messenger RNA (mRNA), which carries genetic instructions from DNA. This process, called splicing, edits the instructions by removing non-coding regions (introns) before they can be used to make proteins.
As part of the SMN complex, the protein ensures that snRNPs are built correctly. This complex brings together protein components and specific RNA molecules to form the functional snRNP units. This assembly process begins in the cell’s cytoplasm before the completed snRNPs are transported to the nucleus to perform their splicing duties.
While this is a task required by every cell, motor neurons are uniquely sensitive to a reduction in this capacity. It is believed that these long, highly active cells have a high demand for efficient splicing to maintain their complex structure and function.
Genetic Production of SMN Protein
The genetic instructions for producing SMN protein are encoded in two nearly identical genes: SMN1 and SMN2. The SMN1 gene is the primary producer, responsible for creating most of the full-length, stable SMN protein required by the body. A healthy individual has two copies of the SMN1 gene, ensuring a robust supply of the protein.
The SMN2 gene serves as a backup to SMN1. While nearly identical, a single nucleotide change in a region known as exon 7 disrupts the splicing process for the SMN2 gene itself. As a result, approximately 90% of the protein produced from SMN2 is a shorter, unstable version that is rapidly degraded.
Despite this inefficiency, the SMN2 gene produces about 10% of the full-length, stable SMN protein. The number of SMN2 copies an individual has can vary. This number becomes a significant factor when the SMN1 gene is non-functional, as the output from all available SMN2 copies becomes the sole source of functional SMN protein.
Consequences of SMN Protein Deficiency
The absence of functional SMN1 genes leads to a severe deficiency in SMN protein. When an individual inherits two non-working copies of the SMN1 gene, their body must rely entirely on the inefficient SMN2 gene. This results in drastically reduced levels of full-length SMN protein, falling short of the amount needed for normal operations in motor neurons.
This shortage of SMN protein directly triggers the degeneration and death of motor neurons in the spinal cord. With insufficient SMN protein, the production of snRNPs is impaired, leading to widespread errors in the splicing of numerous genes. As motor neurons degenerate, the connection between the brain and the muscles is progressively lost.
The muscles no longer receive the nerve signals required for contraction and movement. This leads to the characteristic muscle weakness and atrophy seen in the genetic disorder Spinal Muscular Atrophy (SMA).
Therapeutic Approaches Targeting SMN Protein
Modern therapeutic strategies for SMA are designed to address the root cause of the disease: the lack of functional SMN protein. These approaches work by increasing the amount of this protein in the body’s cells, particularly in motor neurons.
One strategy is gene replacement therapy, which involves delivering a new, functional copy of the SMN1 gene into the patient’s cells. This is achieved using a harmless, modified virus (an adeno-associated virus vector) as a delivery vehicle. Once inside the cell’s nucleus, this new gene can be used as a template for producing the full-length SMN protein, bypassing the faulty native SMN1 genes.
Another approach involves modulating the splicing of the SMN2 gene. Therapies like antisense oligonucleotides or small molecule drugs are designed to correct the splicing error that makes SMN2 inefficient. These drugs bind to the pre-mRNA transcribed from the SMN2 gene and mask the sequence that signals for the exclusion of exon 7.
By doing so, they guide the cell’s splicing machinery to include this exon. This results in the cell producing a much higher percentage of the full-length, functional SMN protein from the existing SMN2 genes.