Research into SMA-LED
Research into SMA-LED
Page last updated: 21st January 2025
There are two forms of SMA-LED: SMA-LED1 caused by mutations in DYNC1H1 and SMA-LED2 caused by mutations in BICD2.
It is not possible to tell the two forms apart by symptoms alone – a genetic test is needed to identify which subtype of SMA-LED someone has. Both forms of SMA-LED are inherited in an autosomal dominant manner, and this happens due to changes in the structure of DYNC1H1 or BICD2 protein that causes them to lose their ability to function properly.
DYNC1H1 and BICD2 proteins are both involved in a process known as axonal transport. Nerve cells need to deliver a wide range of substances, such as proteins, up and down their structures if they are to remain alive and healthy1. This delivery system is called axonal transport, and has been reported to be affected in several different experimental models of SMA-LED1 and SMA-LED22-4. However, it is currently unclear whether these disruptions in axonal transport are what cause SMA-LED, since the DYNC1H1 and BICD2 proteins have additional functions in nerve cells, especially before birth.
There are several mouse models available to study SMA-LED5-6, which will help to solve the question of why do mutations in DYNC1H1 and BICD2 specifically affect the lower motor neurons
The SMA-LED mouse models have mutations in the mouse DYNC1H1 and BICD2 genes. Generally, the SMA-LED mice show symptoms that resemble the human condition. For example, the mice show impairments in muscle function and loss of lower motor neurons compared to their healthy siblings5.
In recent work using mice with mutations in BICD2, an interesting hypothesis was put forward on how SMA-LED develops. Surprisingly, BICD2 in muscles, but not motor neurons, was shown to be important for the survival of the motor neurons7. The scientists showed that BICD2 is important for the passage of key survival proteins from the muscle to the motor nerves, suggesting that the SMA-LED motor neurons do not get enough of the positive signals. Further work is needed, but this study highlights the importance of treating muscles in SMA-LED when future therapies are developed.
1. Sleigh (2020) Axonal Transport: The Delivery System Keeping Nerve Alive. Front Young Minds 8: 12.
2. Hafezparast et al. (2003) Mutations in dynein link motor neuron degeneration to defects in retrograde transport. Science 300: 808-812.
3. Huynh & Vale (2017) Disease-associated mutations in human BICD2 hyperactivate motility of dynein-dynactin. J Cell Biol 216: 3501-3060.
4. Hoang et al. (2017) DYNC1H1 mutations associated with neurological diseases compromise processivity of dynein-dynactin-cargo adaptor complexes. Proc Natl Acad Sci U S A 114: E1597-E1606.
5. Schiavo et al. (2013) Cytoplasmic dynein heavy chain: the servant of many masters. Trends Neurosci 36: 641-651.
6. Jaarsma et al. (2014) A role for Bicaudal-D2 in radial cerebellar granule cell migration. Nat Commun 5: 3411.
7. Rossor et al. (2020) Loss of BICD2 in muscle drives motor neuron loss in a developmental form of spinal muscular atrophy. Acta Neuropathol Commun 8: 34.