INSIGHTS | PERSPECTIVES
Many human cognitive and neuro- degenerative diseases are caused by alterations in the amounts of specific neuronal proteins, which are maintained at proper levels by regulation of their synthesis and
turnover. For example, fragile X syndrome,
a neurologic disease characterized by intellectual impairment and many behavioral
symptoms including autism (1), results
from loss of fragile X mental retardation
protein (FMRP). FMRP normally reduces
the synthesis of synaptic and other proteins (2). It achieves this by stalling ribo-
Ribosome rescue and
A mutation in a brain-specific tRNA reveals the link
between ribosome maintenance and neuronal cell death
By Jennifer C. Darnell somes that are translating messenger RNA
(mRNA) into protein. Aberrant protein
synthesis that arises from the absence of
FMRP is linked to neuron dysfunction. On
page 455 of this issue, Ishimura et al. (3) reveal that loss of a protein that functions to
release similar stalled ribosomes is linked
to neuronal degeneration, but surprisingly,
only in the presence of a second mutation
in the protein synthesis machinery. This
finding informs both critical translation
mechanisms in the brain and the impact of
modifying genes on disease symptoms. It
thereby establishes a paradigm for understanding how a person’s genetic makeup affects whether a specific mutation will lead
to disease or be tolerated.
Ribosomes move along a strand of mRNA
one codon at a time, decoding each group of
three nucleotides into an amino acid that is
added to a growing polypeptide chain. This
decoding involves transfer RNA (tRNA)
molecules that recognize a specific mRNA
codon by base pairing through their “
anticodon” loop. To mediate the translation of
mRNA code into a protein, the tRNAs must
be “charged” with the appropriate amino
acid specified by the anticodon, a reaction
catalyzed by very specific enzymes called
tRNA synthetases. Neurodegeneration can
result from mutation in the domain of a
tRNA synthetase responsible for confirming the correct amino acid specified by the
anticodon. Such mutations cause the incorporation of the wrong amino acids into
neuronal proteins (4).
Ishimura et al. set out to identify the
genomic mutation underlying a form of
neurodegeneration. They discovered that
neuronal death in mice resulted from a
mutation that caused loss of the guanosine
triphosphate–binding protein 2 (GTPBP2).
GTPBP2 is similar to a class of proteins
called ribosome release factors that free
ribosomes from mRNA when they have
stopped translating protein. Some of these
release factors help terminate the newly
synthesized protein when the ribosome
reaches a codon instructing it to stop. Others rescue stalled ribosomes that have encountered aberrant early stop codons (5),
have reached the 3; end of mRNAs lacking
a stop codon (6), or are stalled at codons
Isodecoder mutation. The predicted secondary
structure of a brain-specific tRNA for arginine (in the
mouse) is shown (3). The box indicates the mutation in
the T-stem loop that is linked to neurodegeneration.
enforcement with biodiversity and livelihood conservation. However, such global
efforts will only be sustained if the policies
they create are enacted with strong funding
and unfaltering political engagement.
At local and regional scales, policies that
strengthen resource tenure may address
both causes and consequences of wildlife
conflict. Local governments have headed off
social tension created by uncertain resource
tenure by giving fishers and hunters exclusive rights to harvest grounds. Fiji’s fishery,
structured around territorial use rights, offers one example of effective management
(11). Locally controlled management zones
in Namibia have also demonstrated the ability of proactive policies to reduce poaching,
stem wildlife decline, and improve local
livelihoods (12). Government willingness to
allow stakeholders to retain the bulk of revenues from harvests has been critical to the
persistence of these programs.
Reducing or preventing wildlife conflict
by strengthening local resource tenure has
broad application but requires strong governance and an international commitment to
recognize user rights. Organizations working to stem social conflict must address
wildlife decline as a possible driver. Similarly, policies aimed at addressing wildlife
decline must consider the social context of
wildlife use and the feedbacks between wildlife scarcity and social conflict. Leadership
must move beyond superficial reactions to
elephant and rhino poaching and consider
the complicated fate of the billions of people
who rely on our planet’s rapidly disappearing wildlife for food and income. ■
REFERENCES AND NOTES
1. Office of the President, National Strategy for Combating
Wildlife Trafficking (U.S. Office of the President,
Washington, DC, 2014).
2. Fisheries and Agriculture Department, The State of World
Fisheries and Aquaculture 2012 (Food and Agriculture
Organization of the United Nations, Rome, 2012).
3. J. E. Fa, S. F. Ryan, D. J. Bell, Biol. Conserv. 121, 167 (2005).
4. U. N. Office on Drugs and Crime, Transnational Organized
Crime in the Fishing Industry (UNDOC, Vienna, 2011).
5. U.S. Department of Labor, Findings on the Worst Forms
of Child Labor (2012); www.dol.gov/ilab/reports/
6. J. S. Brashares et al ., Science 306, 1180 (2004).
7. L. R. Douglas, K. Alie, Biol. Conserv. 171, 270 (2014).
8. M. L. Gore,
Conserv.Biol. 25, 659 (2011).
9. J. Bahadur, The Pirates of Somalia (Pantheon Books, New
10. J. Vidal, “Will overfishing by foreigners drive Senegalese
fishermen to piracy?” [blog], The Guardian, 3 April 2012.
11. R. Weeks,S.D.Jupiter, Conserv. Biol. 27,1234(2013).
12. Namibian Association of Community-Based Natural
Resource Management Support Organizations, The State
of Community Conservation in Namibia, Annual Report
2012 (NASCO, Windhoek, Namibia, 2013).
This article was greatly improved by suggestions from four
anonymous reviewers and supported by a NSF Dynamics of
Coupled Natural and Human Systems grant.