Molecular Mechanisms in Motor Neurone Disease
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Motor neurone disease (MND), or amyotrophic lateral sclerosis (ALS) is a devastating disorder that affects approximately 1 in 100,000 people. MND is normally a disorder of middle age, and is characterized by the degeneration and death of large motor neurones in the brain and spinal cord. This neuronal death results in a gradually worsening muscle weakness, wasting and paralysis, and is usually fatal within 3-5 years of symptom onset.
MND is often called Lou Gehrig's disease in the USA, after a famous baseball player who developed MND in 1939. Stephen Hawking is affected by a particularly slowly progressing form of MND. The causes of MND are largely unknown and treatment options are limited. The only licensed drug treatment, riluzole, had only a modest effect on survival.
There is more information about MND at The Motor Neurone Disease Association (UK) and The ALS Association (USA) websites.
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Motor neurones in the human body. Upper motor neurones in the brain normally send signals to lower motor neurones in the spinal cord, which send signals to muscles. In MND, both upper and lower motor neurones degenerate. Image used with the permission of The Muscular Dystrophy Association of the USA. |
Sporadic MND
The vast majority (90%) of cases of MND do not run in families and are therefore termed sporadic. A number of genetic factors have been associated with sporadic MND, each contributing to disease in a small proportion of individuals.
ALS2 and Alsin
A gene called ALS2 has been discovered to cause a rare inherited form of ALS that onsets in infancy. Parents usually notice that something is wrong when their child does not learn to walk, or sometimes a child that has previously been able to walk unaided starts to stumble and trip. ALS2 is slowly progressive and affected children are often wheelchair bound by 10 years of age, usually with incontinence, involuntary facial and limb movements and poor speaking ability.
ALS2 mutations have also been detected in other conditions related to MND, infantile onset ascending hereditary spastic paraplegia (IAHSP), and juvenile onset primary lateral sclerosis (JPLS).
ALS2 encodes a protein called alsin, whose sequence is highly conserved across species. In the mouse, alsin is expressed primarily in neurones of the central nervous system, with particularly high levels in the granular layer of the cerebellum and the alpha motor neurons of the spinal cord. This is consistent with the expected pattern of neurodegeneration. Gene targeted mouse models of ALS2 recapitulate some aspects of the human condition and will be a useful tool for studying molecular mechanisms of disease.
Expression pattern of the Als2 gene in adult mouse brain. A: the sagittal whole brain section reveals the strongest expression is in the cerebellum (cb), weaker areas of expression are the hippocampus (hc) and cingulate cortex (cc). B: High power magnification showing intense expression in the granular layer of the cerebellum. C: High power magnification of the spinal cord showing the greatest expression levels (blue dots) in the large alpha motor neurons (mn).
Alsin is known to act as an guanine nucleotide exchange factor (GEF), or activator, for the small GTPases Rab5 and Rac1. Rab5 is involved in endocytosis and early endosome fusion, and Rac1 functions in the modulation of the actin cytoskeleton, so alsin may play a role in coordinating these activities. However the precise function of alsin within cells is unknown.
For further information, read about our Research Projects, or find ALS2 and alsin papers in PubMed.
