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Neurology Genetics
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June 2016; 2 (3) ArticleOpen Access

Next-generation profiling to identify the molecular etiology of Parkinson dementia

Adrienne Henderson-Smith, Jason J. Corneveaux, Matthew De Both, Lori Cuyugan, Winnie S. Liang, Matthew Huentelman, Charles Adler, Erika Driver-Dunckley, Thomas G. Beach, Travis L. Dunckley
First published May 24, 2016, DOI: https://doi.org/10.1212/NXG.0000000000000075
Adrienne Henderson-Smith
From the Neurogenomics Division (A.H.-S., J.J.C., M.D.B., L.C., W.S.L., M.H., T.L.D.), Collaborative Sequencing Center (L.C., W.S.L.), Translational Genomics Research Institute, Phoenix; Division of Neurology (C.A., E.D.-D.), Mayo Clinic, Scottsdale; Banner Sun Health Research Institute (T.G.B.), Sun City, AZ.
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Jason J. Corneveaux
From the Neurogenomics Division (A.H.-S., J.J.C., M.D.B., L.C., W.S.L., M.H., T.L.D.), Collaborative Sequencing Center (L.C., W.S.L.), Translational Genomics Research Institute, Phoenix; Division of Neurology (C.A., E.D.-D.), Mayo Clinic, Scottsdale; Banner Sun Health Research Institute (T.G.B.), Sun City, AZ.
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Matthew De Both
From the Neurogenomics Division (A.H.-S., J.J.C., M.D.B., L.C., W.S.L., M.H., T.L.D.), Collaborative Sequencing Center (L.C., W.S.L.), Translational Genomics Research Institute, Phoenix; Division of Neurology (C.A., E.D.-D.), Mayo Clinic, Scottsdale; Banner Sun Health Research Institute (T.G.B.), Sun City, AZ.
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Lori Cuyugan
From the Neurogenomics Division (A.H.-S., J.J.C., M.D.B., L.C., W.S.L., M.H., T.L.D.), Collaborative Sequencing Center (L.C., W.S.L.), Translational Genomics Research Institute, Phoenix; Division of Neurology (C.A., E.D.-D.), Mayo Clinic, Scottsdale; Banner Sun Health Research Institute (T.G.B.), Sun City, AZ.
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Winnie S. Liang
From the Neurogenomics Division (A.H.-S., J.J.C., M.D.B., L.C., W.S.L., M.H., T.L.D.), Collaborative Sequencing Center (L.C., W.S.L.), Translational Genomics Research Institute, Phoenix; Division of Neurology (C.A., E.D.-D.), Mayo Clinic, Scottsdale; Banner Sun Health Research Institute (T.G.B.), Sun City, AZ.
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Matthew Huentelman
From the Neurogenomics Division (A.H.-S., J.J.C., M.D.B., L.C., W.S.L., M.H., T.L.D.), Collaborative Sequencing Center (L.C., W.S.L.), Translational Genomics Research Institute, Phoenix; Division of Neurology (C.A., E.D.-D.), Mayo Clinic, Scottsdale; Banner Sun Health Research Institute (T.G.B.), Sun City, AZ.
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Charles Adler
From the Neurogenomics Division (A.H.-S., J.J.C., M.D.B., L.C., W.S.L., M.H., T.L.D.), Collaborative Sequencing Center (L.C., W.S.L.), Translational Genomics Research Institute, Phoenix; Division of Neurology (C.A., E.D.-D.), Mayo Clinic, Scottsdale; Banner Sun Health Research Institute (T.G.B.), Sun City, AZ.
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Erika Driver-Dunckley
From the Neurogenomics Division (A.H.-S., J.J.C., M.D.B., L.C., W.S.L., M.H., T.L.D.), Collaborative Sequencing Center (L.C., W.S.L.), Translational Genomics Research Institute, Phoenix; Division of Neurology (C.A., E.D.-D.), Mayo Clinic, Scottsdale; Banner Sun Health Research Institute (T.G.B.), Sun City, AZ.
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Thomas G. Beach
From the Neurogenomics Division (A.H.-S., J.J.C., M.D.B., L.C., W.S.L., M.H., T.L.D.), Collaborative Sequencing Center (L.C., W.S.L.), Translational Genomics Research Institute, Phoenix; Division of Neurology (C.A., E.D.-D.), Mayo Clinic, Scottsdale; Banner Sun Health Research Institute (T.G.B.), Sun City, AZ.
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Travis L. Dunckley
From the Neurogenomics Division (A.H.-S., J.J.C., M.D.B., L.C., W.S.L., M.H., T.L.D.), Collaborative Sequencing Center (L.C., W.S.L.), Translational Genomics Research Institute, Phoenix; Division of Neurology (C.A., E.D.-D.), Mayo Clinic, Scottsdale; Banner Sun Health Research Institute (T.G.B.), Sun City, AZ.
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Full PDF
Citation
Next-generation profiling to identify the molecular etiology of Parkinson dementia
Adrienne Henderson-Smith, Jason J. Corneveaux, Matthew De Both, Lori Cuyugan, Winnie S. Liang, Matthew Huentelman, Charles Adler, Erika Driver-Dunckley, Thomas G. Beach, Travis L. Dunckley
Neurol Genet Jun 2016, 2 (3) e75; DOI: 10.1212/NXG.0000000000000075

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Abstract

Objective: We sought to determine the underlying cortical gene expression changes associated with Parkinson dementia using a next-generation RNA sequencing approach.

Methods: In this study, we used RNA sequencing to evaluate differential gene expression and alternative splicing in the posterior cingulate cortex from neurologically normal control patients, patients with Parkinson disease, and patients with Parkinson disease with dementia.

Results: Genes overexpressed in both disease states were involved with an immune response, whereas shared underexpressed genes functioned in signal transduction or as components of the cytoskeleton. Alternative splicing analysis produced a pattern of immune and RNA-processing disturbances.

Conclusions: Genes with the greatest degree of differential expression did not overlap with genes exhibiting significant alternative splicing activity. Such variation indicates the importance of broadening expression studies to include exon-level changes because there can be significant differential splicing activity with potential structural consequences, a subtlety that is not detected when examining differential gene expression alone, or is underrepresented with probe-limited array technology.

GLOSSARY

ATXN2=
ataxin-2;
CAM=
cell adhesion molecule;
CON=
controls;
CRH=
corticotropin-releasing hormone;
CSF3=
granulocyte colony-stimulating factor;
DE=
differential gene expression;
DLB=
dementia with Lewy bodies;
dPSI=
delta PSI;
DSM-IV=
Diagnostic and Statistical Manual of Mental Disorders, 4th edition;
DST=
dystonin;
fc=
fold change;
GO=
gene ontology;
HSPH1=
heat shock protein 105 kDa;
KRT5=
keratin 5;
LRRFIP1=
leucine-rich repeat flightless-interacting protein 1;
NF-κB=
nuclear factor κB;
OPKM=
observations per kilobase of transcript length per million aligned reads;
PD=
Parkinson disease;
PD-D=
Parkinson disease with dementia;
PENK=
proenkephalin;
PSI=
percent spliced in;
qRT=
quantitative real-time;
RBCC=
N-terminal RING finger/B-box/coiled coil;
RELA=
rel-like domain-containing;
RNA-seq=
RNA sequencing;
RPKM=
reads per kilobase of transcript length per million aligned reads;
SELE=
selectin-E;
SRRM1=
serine/arginine repetitive matrix 1;
SST=
somatostatin;
TRIM=
tripartite motif;
TRIM9=
tripartite motif 9;
VGF=
Vgf nerve growth factor

Footnotes

  • ↵† Deceased.

  • Funding information and disclosures are provided at the end of the article. Go to Neurology.org/ng for full disclosure forms. The Article Processing Charge was paid by the authors.

  • Supplemental data at Neurology.org/ng

  • Received October 30, 2015.
  • Accepted in final form March 21, 2016.
  • © 2016 American Academy of Neurology

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially.

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