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Identification of a neuroprotector linked to a degenerative neuromuscular disease.

In Kennedy’s disease, the muscle cells and motor neurons, which are also linked to muscle function, are damaged as a result of the accumulation of androgen receptor fibers, a process that causes them to die.  Many aspects of diseases involving aggregates, such as Alzheimer’s and Parkinson’s, are unknown.  In this regard, Kennedy’s disease is in a worse position because it is a rare condition that affects only men between 40 and 50 years of age.  The onset of this genetically inherited disease occurs in late adulthood, affecting one in every 40,000 men and causing progressive deterioration of all muscles. Although not fatal, the condition is debilitating, and 20% of those affected eventually need a wheel chair with no specific treatment available.  Now, a study from researchers at the Institute for Research in Biomedicine and the University of Florence identifies a molecular system of protection that involves the androgen receptor protein, a molecule that is mutated in patients with Kennedy’s disease and which causes progressive muscle wastage.  The team state that their findings bring in-depth molecular insights that can lead to new studies and bring the global medical community closer to finding a therapeutic target for Kennedy’s disease. The opensource study is published in the Biophysical Journal.

Previous studies show that the mutation carried by those affected by Kennedy’s disease causes a repeated and excessively long chain of a specific amino acid, namely polyglutamine, which impairs the activity of the androgen receptor. This protein, which activates the hormone testosterone, is responsible for triggering the genetic programme that favours the differential characteristics of men, such as more hair, deep voice, and larger hands.  During adolescence, and depending on the extent to which they are affected, boys with the mutation do not fully develop the male phenotype. In adulthood muscle degeneration begins, where it has been known that the longer the polyglutamine chain, the earlier the onset of muscle atrophy.  However, it is still unclear why this harmful effect is triggered when the length of the polyglutamine exceeds 38 residues.  The current study investigates a 156-residue proteolytic fragment of the androgen receptor that contains the polyglutamine (polyQ) tract associated with the disease spinobulbar muscular atrophy, also known as Kennedy disease.

The current study uses NMR to study the protein in a test tube, to show that right next to the polyglutamine chain there is a region comprised of four leucine residues which protect against the effects of the mutation.  Results show the leucine molecules favour the folding of the polyglutamine chain into a helix, a structure which prevents the chains from adhering to one another. Data findings show that the impact of the leucine molecule on the glutamine region is limited, and if there are too many glutamine amino acids, the chains do not fold; they stretch out like rods, stick to each other, and end up forming a fibrous wall.

Results show that a Leu-rich region preceding the polyQ tract causes it to become a-helical and appears to protect the protein against aggregation, which, to the lab’s knowledge, represents a new mechanism by which sequence context can minimize the deleterious properties of these repetitive regions.  The team state that their findings may have implications in drug discovery for polyQ diseases because they suggest that the residues flanking these repetitive sequences may represent viable therapeutic targets.

The team surmise that this protein has a self-protective mechanism through which the deleterious effects of the mutation are delayed.  For the future, the researchers state that one way of delaying the aggregation could be to use drugs to strengthen the effect of the leucine residues that influence the mutation site which causes the protein to stick together.

Source: Institute for Research in Biomedicine (IRB Barcelona)

Protein Androgen Receptor forms aggregatesthat damage muscle and motor neuron cells in Kennedy's Disease.  Credit: (B. Eftekharzadeh, IRB Barcelona).
Protein Androgen Receptor forms aggregatesthat damage muscle and motor neuron cells in Kennedy’s Disease. Credit: (B. Eftekharzadeh, IRB Barcelona).


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