Difference between revisions of "Introduction to ALD"

Latest revision as of 14:14, 27 April 2022

LagLivLab Adrenoleukodystrophy ALD - Theory

By Morten Pedersen Hauger​

Revised by Nigar Abbasova

Cellular cause: Adrenoleukodystrophy is caused by a build-up of very long chain fatty acids (VLCFA for short). VLCFAs are fatty acids with a carbon chain longer than 22 carbon atoms. This build up is caused by a failure of the ABC family of proteins, in humans most often this is a failure of the ABCD1 (also called ALDP), that transports the VLCFA over the peroxisomal membrane. The peroxisome is responsible for the breakdown of these fatty acids and several other forms of cellular waste. Shorter fatty acid chains are degraded in the cytosol (the watery media within the cell) and mitochondria (the powerhouse of the cell) and are a major source of energy in most cells. The proteins themselves are integral membrane proteins in the peroxisome (meaning it is integrated into the double membrane of the peroxisome) that forms a dimer (a temporary complex of 2 proteins) with another ABCD1 protein or ABCD protein with similar transport substrate. The following buildup of VLCFA that occurs in the cells is thought to be toxic to tissues at high concentrations, though the threshold for toxic effects appears to vary depending on the tissue. In some tissues like neural and endocrinal (the hormonal system) as well as some tissues in the testis (male reproductive organ). This effect is especially pronounced. It is also known that this build-up can induce an immune reaction, with local immune cells responding to the characteristics of cells with such buildup. Though which of these effects is the most significant in disease development is currently unknown and can vary depending on tissue. Current evidence supports both models.

Genetics: There are some 700 identified unique mutations in the ABCD1 gene, all of which cause changes in the ABCD1 protein that are thought to prevent or alter its function in some way - either by altering the area for binding the dimers or the VLCFA. The most common way that mutations do this is by altering any group of three amino acids, called a codon, to a different codon that represents another amino acid, or by deleting or inserting new amino acid (which also alters the binding to the partner protein in the dimer or altering the binding site). If these mutations happen to any number other than 3 or 3*x nucleic acids (x = any natural number), it will cause a frameshift mutation. This causes extreme alterations of the protein as the gene is read in the wrong manner. This can cause the protein synthesis to stop too early, too late, or starting at the wrong point leading to an incomplete or exaggerated messenger RNA (mRNA for short). Several deletions have also resulted in the deletion of 1 or more exons (the expressed parts of a gene after the start codon).

Sources/further reading:

Horn, Morten Andreas. 2015. X-linked adrenoleukodystrophy in Norway Clinical and epidemiological aspects. https://www.duo.uio.no/bitstream/handle/10852/48906/PhD-Horn-+DUO.pdf?sequence=1&isAllowed=y

Adrenoleukodystrophy information. https://adrenoleukodystrophy.info/clinical-+diagnosis/facts-on-ald

Cellular causes and interactions: Singh I, Pujol A. Pathomechanisms underlying X-adrenoleukodystrophy: a three-hit hypothesis. Brain Pathol. 2010 Jul;20(4):838-44. doi: 10.1111/j.1750-3639.2010.00392.x. PMID: 20626745; PMCID: PMC3021280. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3021280/