Image reveals Purkinje cells (gray) and their dendrites, as well as an accumulation of protein deposits (red dots). [Ackerman Lab/UC San Diego]
Image reveals Purkinje cells (gray) and their dendrites, as well as an accumulation of protein deposits (red dots). [Ackerman Lab/UC San Diego]

Researchers from the University of California, San Diego, and the Scripps Research Institute report that they have identified a gene, Ankrd16, that helps prevent the protein aggregates observed in neurological disorders such as Alzheimer's and Parkinson's diseases.

It is known that abnormal aggregates can result when cells fail to transmit proper genetic information to proteins. Usually, the information transfer from gene to protein is carefully controlled—biologically “proofread” and corrected—to avoid the production of improper proteins. The current study (“ANKRD16 Prevents Neuron Loss Caused by an Editing-Defective tRNA Synthetase”), published in Nature, reports that Ankrd16 rescued specific neurons (Purkinje cells) that die when proofreading fails.

Without normal levels of Ankrd16, these nerve cells, located in the cerebellum, incorrectly activate the amino acid serine, which is then improperly incorporated into proteins and causes protein aggregation. 

“Editing domains of aminoacyl tRNA synthetases correct tRNA charging errors to maintain translational fidelity. A mutation in the editing domain of alanyl tRNA synthetase (AlaRS) in Aarssti mutant mice results in an increase in the production of serine-mischarged tRNAAla and the degeneration of cerebellar Purkinje cells. Here, using positional cloning, we identified Ankrd16, a gene that acts epistatically with the Aarssti mutation to attenuate neurodegeneration. ANKRD16, a vertebrate-specific protein that contains ankyrin repeats, binds directly to the catalytic domain of AlaRS. Serine that is misactivated by AlaRS is captured by the lysine side chains of ANKRD16, which prevents the charging of serine adenylates to tRNAAla and precludes serine misincorporation in nascent peptides,” write the investigators.

“The deletion of Ankrd16 in the brains of Aarssti/sti mice causes widespread protein aggregation and neuron loss. These results identify an amino-acid-accepting co-regulator of tRNA synthetase editing as a new layer of the machinery that is essential to the prevention of severe pathologies that arise from defects in editing.”

“Simplified, you may think of Ankrd16 as acting like a sponge or a 'failsafe' that captures incorrectly activated serine and prevents this amino acid from being improperly incorporated into proteins, which is particularly helpful when the ability of nerve cells to proofread and correct mistakes declines,” said Susan Ackerman, Ph.D., the Stephen W. Kuffler Chair in Biology, who also holds positions in the UC San Diego School of Medicine and the Howard Hughes Medical Institute.

The levels of Ankrd16 are normally low in Purkinje cells, making these neurons vulnerable to proofreading defects. Elevating the level of Ankrd16 protects these cells from dying, while removing Ankrd16 from other neurons in mice with a proofreading deficiency caused widespread buildup of abnormal proteins and ultimately neuronal death.

The researchers note that only a few modifier genes of disease mutations such as Ankrd16 have been identified, and a modifier-based mechanism for understanding the underlying pathology of neurodegenerative diseases may be a promising route to understand disease development. 

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