Smelling the Dark Proteome: Functional Characterization of PITH Domain-Containing Protein 1 (C1orf128) in Olfactory Metabolism

The
Human Proteome Project (HPP) consortium aims to functionally
characterize the dark proteome. On the basis of the relevance of olfaction
in early neurodegeneration, we have analyzed the dark proteome using
data mining in public resources and omics data sets derived from the
human olfactory system. Multiple dark proteins localize at synaptic
terminals and may be involved in amyloidopathies such as Alzheimer’s
disease (AD). We have characterized the dark PITH domain-containing
protein 1 (PITHD1) in olfactory metabolism using bioinformatics, proteomics,
in vitro and in vivo studies, and neuropathology. PITHD1–/– mice exhibit olfactory bulb (OB) proteome changes related to synaptic
transmission, cognition, and memory. OB PITHD1 expression increases
with age in wild-type (WT) mice and decreases in Tg2576 AD mice at
late stages. The analysis across 6 neurological disorders reveals
that olfactory tract (OT) PITHD1 is specifically upregulated in human
AD. Stimulation of olfactory neuroepithelial (ON) cells with PITHD1
alters the ON phosphoproteome, modifies the proliferation rate, and
induces a pro-inflammatory phenotype. This workflow applied by the
Spanish C-HPP and Human Brain Proteome Project (HBPP) teams across
the ON-OB-OT axis can be adapted as a guidance to decipher functional
features of dark proteins. Data are available via ProteomeXchange
with identifiers PXD018784 and PXD021634.