Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s Disease, has received a high level of attention due to the ALS Ice Bucket Challenge that went viral across the internet a few years back. You probably had a friend who accepted the Ice Bucket Challenge on social media, or perhaps did the challenge yourself. But what is exactly hidden under these three-letter acronyms: ALS or SMA (spinal muscular atrophy)?
ALS and SMA are the two common motor neuron diseases, for which the causative cellular and pathological mechanisms are still under investigation. Although the genetic causes of the diseases are different, they share common traits regarding their cellular pathomechanisms: microRNA biogenesis and expression. Because no cure has yet been discovered, it’s interesting to keep a closer eye on miRNA’s role in neurological disorders. The symptoms of ALS, which have an adult onset, typically start around the age of 50 and affect neurons that control voluntary muscles. One of the earliest symptoms is muscle weakness and/or muscle atrophy affecting different parts of the body, usually depending on which motor neurons are damaged first. As a result, muscles start to weaken until patients eventually lose the ability to move their arms, legs and other parts of the body. So far, only 10% of the cases can be traced to genetic factors (1). By contrast, SMA is a genetically and clinically heterogenous group of neuromuscular disorders occurring mostly in infants and young children. The symptoms are similar to ALS, with lack of ability to control muscles. SMA is typically characterized by progressive degeneration of lower alpha motor neurons in the anterior horn of spinal cord (2). With its high numbers of incidence in newborns, it is one of the leading hereditary causes of infant mortality (3).
The role of individual miRNAs in neurological disorders is not fully understood yet, and the knowledge about the role of miRNAs in motor neuron diseases in particular is also limited. Of course, the complexity of the nervous system is enormous, and evidence is growing that miRNAs play a critical role in many neurological disorders such as Alzheimer’s disease, Huntington’s disease, mood disorders andTourette’s syndrome. In recent years, miR-9 has been implicated in SMA (5) and miR-206/miR-338-3p in ALS (6).
miRNA in spinal muscular atrophy pathology
The major determining gene of SMA is the survival of motor neuron 1 (SMN1), a RNA binding protein that forms a multi-protein complex with Gemin proteins. Gemin3 and Gemin4 also bind to Ago2 which forms the core in RISC (RNA induced silencing complex) and plays a role in miRNA biogenesis (4). Numerous miRNAs bind to Gemin3 in human and murine neuronal cells, suggesting that the SMN complex is involved in miRNA biogenesis and function. Dysregulation of miR-9 expression in murine embryonic stem cell-derived motor neurons may be connected with SMA (5).
miRNA in amyotrophic lateral sclerosis pathology
The expression of miR-206, a skeletal muscle-specific miRNA, was found to be involved in nerve regeneration at the contact between a motor neuron and a muscle fiber (neuromuscular junction NMJ) (6). miRNA profiling data from ALS patients’ leukocytes showed that expression of miR-338-3p is increased and expression of seven other miRNAs is decreased (7). In addition, miR-9 expression was found in induced stem cell-derived neurons from ALS patients (8). miR-23a, miR-29b and miR-455 expression is increased in skeletal muscles from ALS patients and may cause dysregulation in mitochondrial gene expression (9).
miRNA expression profiling: Sorting out the good from the bad
Taken together, dysregulation of miRNA expression in neuromuscular systems may lead to neurodegeneration and disease pathology. The question remains of how individual miRNAs are involved, or how their dysregulation may cause ALS and SMA.
QIAGEN has developed The Human Neurological Development & Disease miScript miRNA PCR Array for profiling the expression of 84 miRNAs differentially expressed during neuronal development or the progression of neurological diseases. If you would like to explore pathway-specific siRNAs, real-time PCR assays, and expression vectors visit our ALS pathway information on GeneGlobe. For custom solutions, visit us under Custom miScript miRNA PCR Array.
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- 2. Crawford, T.O. and Pardo, C.A. (1996) The neuro biology of childhood spinal muscular atrophy. Neurobiol. Dis. 3, 97. Link
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- 6. Williams, A.H., Valdez, G., Moresi, V., Qi, X., McAnally, J., Elliott, J.L. et al. (2009) microRNA-206 delays ALS progression and promotes regeneration of neuromuscular synapses in mice. Science 326, 1549. Link
- 7. De Felice, B., Guida, M., Coppola, C., DeMieri, G., and Cotrufo, R. (2012) A miRNA signature in leukocytes from sporadic amyotrophic lateral sclerosis. Gene 508, 35. Link
- 8. Zhang, Z., Almeida, S., Lu, Y., Nishimura, A.L., Peng, L., Sun, D. et al.(2013) Downregulation of microRNA-9 in iPSC-derived neurons of FTD/ALS patients withTDP-43 mutations. PLoS ONE 8, e76055. Link
- 9. Russell, A.P., Wada, S., Vergani, L., Hock, M.B., Lamon, S., Leger, B. et al. (2012) Disruption of skeletal muscle mitochondrial network genes and miRNAs in amyotrophic lateral sclerosis. Neurobiol. Dis. 49C, 107. Link