Chromosome-centric Human Proteome Project: Deciphering Proteins Associated with Glioma and Neurodegenerative Disorders on Chromosome 12

In
line with the aims of the Chromosome-centric Human Proteome
Project (C-HPP) to completely annotate proteins of each chromosome
and biology/disease driven HPP (B/D-HPP) to decipher their relation
to diseases, we have generated a nonredundant catalogue of protein-coding
genes for Chromosome 12 (Chr. 12) and further annotated proteins associated
with major neurological disorders. Integrating high level proteomic
evidence from four major databases (neXtProt, Global Proteome Machine
(GPMdb), PeptideAtlas, and Human Protein Atlas (HPA)) along with Ensembl
data resource resulted in the identification of 1066 protein coding
genes, of which 171 were defined as “missing proteins”
based on the weak or complete absence of experimental evidence. With
functional annotations using DAVID and GAD, about 40% of the proteins
could be grouped as brain related with implications in cancer or neurological
disorders. We used published and unpublished high confidence mass
spectrometry data from our group and other literature consisting of
more than 5000 proteins derived from clinical specimens from patients
with human gliomas, Alzheimer’s disease, and Parkinson’s
disease and mapped it onto Chr. 12. We observed a total of 202 proteins
mapping to human Chr. 12, 136 of which were differentially expressed
in these disease conditions as compared to the normal. Functional
grouping indicated their association with cell cycle, cell-to-cell
signaling, and other important processes and networks, whereas their
disease association analysis confirmed neurological diseases and cancer
as the major group along with psycological disorders, with several
overexpressed genes/proteins mapping to 12q13-15 amplicon region.
Using multiple strategies and bioinformatics tools, we identified
103 differentially expressed proteins to have secretory potential,
17 of which have already been reported in direct analysis of the plasma
or cerebrospinal fluid (CSF) from the patients and 21 of them mapped
to cancer associated protein (CAPs) database that are amenable to
selective reaction monitoring (SRM) assays for targeted proteomic
analysis. Our analysis also reveals, for the first time, mass spectrometric
evidence for two “missing proteins” from Chr. 12, namely,
synaptic vesicle 2-related protein (SVOP) and IQ motif containing
D (IQCD). The analysis provides a snapshot of Chr. 12 encoded proteins
associated with gliomas and major neurological conditions and their
secretability which can be used to drive efforts for clinical applications.