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In her first study of the sticky mouse, Ackerman traced the sti mutation
to a gene called Aars, which encodes an enzyme involved with attaching
the correct amino acids to a transfer RNA (tRNA) during protein synthesis.
Normally, these enzymes have "editing" domains that make sure the correct amino
acid is loaded (or "charged") onto its carrier tRNA. Ackerman's research
revealed that sticky mutants were defective in their ability to edit
mischarged tRNA, resulting in a deadly buildup of misfolded proteins in brain
cells. Her findings appeared in the September 7, 2006, issue of Nature.
These types of editing errors have yet to be linked to any human
neurodegenerative disease, but Ackerman says the similarity between mouse and
human genomes makes it highly likely that similar genetic mishaps can lead to
neurodegeneration in aging humans.
In a follow-up study, Ackerman crossed sticky mutants with other mouse
strains to see if the neurodegenerative effects would appear in mice with
different genetic backgrounds. Previous studies had shown that when a mutated
gene is crossed into a different strain of mouse, the characteristic traits of
the mutation sometimes disappear. In such cases, the actions of other genes,
called "modifier" genes, can create alternatives, such as compensatory pathways,
that allow cells to deal with the cumulative
damage mutation causes.
That is indeed what happened when Ackerman crossed sticky mice with other
strains. Though all the resultant mice carried a copy of the sti
mutation, most of them scampered into old age unimpaired by motor dysfunction.
That study and others provided Ackerman with a starting point from which to
track modifier genes associated with the accumulation of misfolded proteins in
neurons that can trigger cell death. Recently, the Ackerman team identified a
gene that works to suppress neurodegeneration in sticky mice. Though
sticky mice normally begin losing Purkinje cells at 3 to 4 weeks of age,
preliminary studies reveal that mice with the suppressor gene maintain motor
function at 12 months of age. Brain tissue samples show that, although some
Purkinje cell loss occurs, most of the neurons survive.
How do these cells persevere? Ackerman theorizes that the modifier gene works to
prevent the accumulation of misfolded proteins by enhancing the Purkinje cells' ability to get rid of them.
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