Functional characterization of the interaction of TAR DNA binding protein 43 (TDP-43) and poly(A) binding protein nuclear 1 (PABPN1) Public
Alexeeva, Olga M. (2012)
Published
Abstract
Abstract
Functional characterization of the interaction of TAR DNA binding
protein 43 (TDP-43) and poly(A)
binding protein nuclear 1 (PABPN1)
Abnormalities in RNA metabolism are emerging as a characteristic
pathological feature of many
neurodegenerative diseases, especially following the recent
discovery of the RNA-binding protein TAR
DNA binding protein 43 kDa (TDP-43) as the major component of
disease-related protein aggregates in
the brains of patients with amyotrophic lateral sclerosis (ALS) and
frontotemporal dementia (FTD). TDP-
43 function in health and disease has not been fully characterized,
which limits our understanding of the
disease process. In this study, we investigate the physiological
role of TDP-43 by characterizing its
interaction with poly(A) binding protein nuclear 1 (PABPN1),
identified previously as a putative
interaction partner in a yeast two-hybrid screen. PABPN1 is an
RNA-binding protein that regulates
polyadenylation of nascent mRNA tails whose mutant version carrying
a polyalanine expansion causes
autosomal dominant oculopharyngeal muscular dystrophy (OPMD). Due
to several similar features
between TDP-43 and PABPN1, including ubiquitous expression,
predominantly nuclear localization,
involvement in mRNA transport, and association in respective
protein-aggregation diseases, we
hypothesized that TDP-43 and PABPN1 directly interact in a
physiologically relevant way. TDP-
43/PABPN1 interaction was confirmed by independent in vitro
methods, as well as by colocalization
analysis in intact primary neurons. PABPN1 was found for the first
time to be present in axons and
localized to cytoplasmic stress granules with TDP-43, suggesting
the possibility of an extranuclear
functional relationship in mRNA transport and/or protection. We
also found that PABPN1 can alter the
localization and aggregation properties of a pathological
C-terminal fragment of TDP-43 when
overexpressed in cells. These findings provide important first
steps towards the characterization of a
functional relationship between the two proteins, which will be
critical in understanding their cellular
roles in health and disease.
Table of Contents
Table of Contents
Introduction..................................................................................................................................................
1
Methods
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6
Figure 1
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6
Results.........................................................................................................................................................
10
Table 1
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10
Figure 2
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11
Figure 3
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12
Figure 4
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13
Figure 5
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15
Table 2
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17
Figure 6
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19-20
Figure 7
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21
Figure 8
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23
Discussion
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24
References
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30
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