3. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characteri

Question

3. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the deterioration of motor neurons. While the pathogenesis of ALS is still poorly understood, one hypothesis of the mechanism of ALS is glutamate receptor-mediated excitotoxicity. One subunit of this glutamate receptor has an amino acid residue that could be a Gln or Arg. A. What is the protein that causes the change of the Gln to an Arg? B. Does this change occur on a DNA, mRNA, or protein level? What is the molecular change that occurs (specifically which nucleotide or amino acid)? How does this Gln to Arg change affect the function of the glutamate receptor?. C. D. How does a deleterious mutation in ADAR cause the excitotoxicity observed in ALS?

Explanation / Answer

A)  Adenosine deaminases acting on RNA 2 (ADAR2) change the amino acid glutamine (Gln) to agrinine (Agr) in Glut2A subunit of tetrameric AMPA receptor, a type of glutamate receptor.

B) The change in amino acid takes place at mRNA level. ADAR2 edits the mRNA that encodes for Glut2A subunit at Q/R site. The editing converts adenosine (A) to inosine (I) by deamination replacing the genomically encoded glutamine (Q) with arginine.

C) Arginine, which is larger than glutamine as well positively charged, reduces the permeability of glutamate receptor for calcium. The prevention of calcium entry into the cell is proposed to guard against excitotoxicity.

D) Mutations in ADAR2 decreases ADAR2 mediated GluA2 mRNA editing at Q/R site. This increases the Ca2+ influxes and subsequently results in glutamate receptor mediated excitotoxicity.

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