ISSN 0006-2979, Biochemistry (Moscow), 2025, Vol. 90, No. 11, pp. 1764-1773 © The Author(s) 2025. This article is an open access publication.
Published in Russian in Biokhimiya, 2025, Vol. 90, No. 11, pp. 1887-1896.
1764
DISCUSSION
In Search of Novel Diagnostic Biomarkers
for Psychoneurological and Neurodegenerative Diseases:
Translation Factors DENR and eIF2D
Kseniya A. Zamyatnina
1,2
1
Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University,
119234 Moscow, Russia
2
Faculty of Biology, Lomonosov Moscow State University, 119234 Moscow, Russia
e-mail: zamksju@rambler.ru
Received August 15, 2025
Revised October 28, 2025
Accepted October 29, 2025
Abstract— A rising global prevalence of psychoneurological and neurodegenerative disorders emphasizes the
critical need for effective therapeutics and methods for early and highly sensitive diagnostics in order to
ensure efficient and timely treatment of these disorders. Expanding the range of available biomarkers for
better characterization of disease features and progression is a promising direction in modern diagnostics.
The discovery of novel biomarkers depends on elucidating molecular mechanisms underlying disease devel-
opment and pathogenesis. Numerous psychoneurological and neurodegenerative disorders are associated with
the dysregulation of protein translation. The review summarizes information on the action mechanisms of
translation factors DENR and eIF2D and evaluates their potential as diagnostic biomarkers for psychoneuro-
logical and neurodegenerative diseases.
DOI: 10.1134/S000629792560259X
Keywords: psychoneurological and neurodegenerative disorders, translation, DENR, eIF2D, biomarkers
INTRODUCTION
An increasing prevalence of psychoneurological
and neurodegenerative disorders necessitates the
development of effective treatment strategies and
diagnostic systems for the early detection of these
pathologies. For a long time, the primary diagnostic
methods have been psychological tests and physical
examinations, e.g., electroencephalography (EEG).
However, these approaches lack accuracy and do not
allow early disease diagnostics. Currently, the studies
on the identification of biomarkers for psychoneuro-
logical and neurodegenerative diseases are coming to
the fore. The search for biomarkers of neurological
disorders requires elucidation of associated genetic
mechanisms. Such studies pave the way for the de-
velopment of early diagnostics methods, prediction
of disease risk, monitoring of disease progression,
and assessment of treatment efficacy in patients.
Mutations, single-nucleotide polymorphisms (SNPs),
and alterations in the transcriptome play a key role in
the pathogenesis of nervous system disorders. Recent
advancements in DNA and RNA sequencing technol-
ogies, such as the next-generation sequencing (NGS)
and Nanopore technology, have made it possible to
identify both rare and common genetic variations as-
sociated with neurological diseases [1]. Transcriptome
analysis enables tracking of changes in gene expres-
sion in various neurological disorders. Furthermore,
non-coding RNAs have been shown as critical factors
in neurodegenerative processes. Other epigenetic
mechanisms, such as DNA methylation and histone
acetylation, also play an important role in the devel-
opment of neurological diseases [1].
Currently, researchers actively search for bio-
markers that can be used in the diagnostics of psy-
choneurological and neurodegenerative diseases. The
heterogeneity of these disorders makes identification
of universal biomarkers particularly challenging [2].
In addition to the diagnostic efficacy, the promis-
ing biomarkers should possess the following key
properties: they should be suitable for early disease
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BIOCHEMISTRY (Moscow) Vol. 90 No. 11 2025
diagnostics, serve as predictors of disease progres-
sion and treatment efficacy, and be cost-efficient to
allow their clinical use. Hence, scientists continue
their efforts in discovering candidate genes, metabo-
lites, and proteins that can be used as biomarkers for
various psychoneurological and neurodegenerative
pathologies.
Dysregulation of translation processes plays an
important role in the pathogenesis of neurological
disorders [3]. In particular, mutations in genes en-
coding components of the translational apparatus and
changes in the expression of these genes have been
observed in the Charcot–Marie–Tooth disease, cere-
bellar ataxia, Parkinson’s disease, and Huntington’s
disease [4-7]. For example, the translation initiation
factor eIF4G1 is associated with the pathogenesis of
the Parkinson’s disease and a specific type of demen-
tia, whereas dysregulation of the translational factor
eIF2α was found in patients with amyotrophic lateral
sclerosis (ALS) [8, 9].
This review discusses two translation factors, eIF2D
and DENR, presumed to be involved in the non-canon-
ical initiation of translation [10, 11]. According to the
published studies, eIF2D and DENR play an important
role in the functioning of the nervous system. Mu-
tations in the corresponding genes or dysregulation
of their expression lead to severe psychoneurological
and neurodegenerative diseases. The data on the re-
lationship between eIF2D and DENR and pathologies
of the nervous system are summarized in Table 1.
Despite the information indicating the association of
these factors with a number of neurological diseases,
their role in the pathogenesis of these disorders re-
mains poorly understood.
This review examines neurological diseases asso-
ciated with the DENR and eIF2D translation factors
and proposes underlying molecular mechanisms.
It systematizes and summarizes current informa-
tion on the role of eIF2D and DENR in the patho-
genesis of psychoneurological and neurodegenerative
disorders, which may help to address the existing
gap in knowledge in this research field. Also, a po-
tential use of DENR and eIF2D in the diagnostics of
psychoneurological and neurodegenerative diseases
is discussed.
THE STRUCTURE AND FUNCTIONS
OF EIF2D AND DENR TRANSLATION FACTORS
eIF2D and DENR are components of the transla-
tional machinery. While eIF2D acts alone, DENR forms
a heterodimer with MCTS1 (malignant T-cell amplified
sequence 1) protein. This interaction is mediated by
the N-terminal Zn-binding domain of DENR, which
binds to the C-terminal domain of MCTS1 [25]. A re-
markable feature of these proteins is a near-identical
domain organization of eIF2D and the MCTS1-DENR
dimer (Fig. 1). The N-terminal region of eIF2D con-
tains the DUF1947 and PUA domains (which are also
present in MCTS1) factor, while the C-terminal region
harbors the SUI1 domain, which is homologous to the
SUI1 domain of DENR [27]. The PUA domain acts as
the RNA-binding domain and has been found in var-
ious protein families [28, 29]. It is frequently located
after the DUF1947 domain (as in MCTS1 and eIF2D).
According to the studies of the eIF2D and MCTS1–DENR
complexes with the 40S ribosomal subunit, these do-
mains are responsible for the protein association with
the ribosome and participate in stabilization of the
tRNA acceptor stem [25, 30]. The SUI1 domain has
been identified only in three families of eukaryotic
proteins: eIF2D, DENR, and translation initiation fac-
tor eIF1. The SUI1 domains of all three factors occupy
the same site on the ribosome [26, 30, 31], but the
proteins are otherwise structurally different. In eIF2D,
the SUI1 domain is preceded by the SWIB/MDM2
domain connected to it through a linker [26, 32],
Fig. 1. Domain organization of eIF2D, MCTS1, and DENR [25, 26]. Structural domains are shown as rectangles. Homologous
domains are indicated with the same colors.
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Table 1. Involvement of DENR and eIF2D in the nervous system functioning and associated disorders
TRANSLATION
FACTOR
PSYCHONEUROLOGICAL DISEASES
DENR
Disease/Dysfunction Mechanism References
schizophrenia mutation [12]
autism spectrum disorder (ASD) mutation [13, 14]
clinical depression dysregulation of gene expression [15]
NEURODEGENERATIVE DISEASES
Disease/Dysfunction Mechanism References
Parkinson’s disease dysregulation of gene expression [16]
OTHER CHANGES INDIRECTLY AFFECTING NERVOUS SYSTEM FUNCTIONING
Disease/Dysfunction Mechanism References
regulation of circadian rhythms
1. dysregulation of gene expression
2. regulation of CLOCK gene expression
[17-19]
impairment of terminal arborization
of cortical neurons
mutation [20]
impaired migration of cortical neurons mutation [20]
regulation of RAN translation dysregulation of gene expression* [21, 22]
eIF2D
PSYCHONEUROLOGICAL DISEASES
Disease/Dysfunction Mechanism References
schizophrenia dysregulation of gene expression [23]
OTHER CHANGES INDIRECTLY AFFECTING NERVOUS SYSTEM FUNCTIONING
Disease/Dysfunction Mechanism References
regulation of RAN translation dysregulation of gene expression* [22, 24]
Note. * Caused by gene knockdown.
the two domains and the linker forming a single, rig-
id structure. In the analogous position, DENR contains
the zinc-binding domain that mediates its interaction
with MCTS1 [25, 33].
The functions of eIF2D and DENR remain obscure.
Based on the accumulated body of evidence, these
proteins are involved in the non-canonical translation
initiation, with the functional activity of DENR being
different from that of eIF2D. DENR in the content of
the dimer is capable of initiating translation of open
reading frames (ORFs) preceded by short upstream
ORFs (uORFs) located in the 5′-untranslated regions
(5′-UTRs) [10, 11]. Yeast orthologs of eIF2D and DENR
are involved in the ribosome recycling and mediate
dissociation of the complex formed by the 40S ribo-
somal subunit, deacylated tRNA, and mRNA [34, 35].
Hence, it is possible that eIF2D and DENR participate
in the ribosome recycling in humans as well.
Although the functions of eIF2D and DENR-MCTS1
dimer are poorly understood, the early studies of
these factors have unequivocally demonstrated their
involvement in the tRNA positioning in the ribosomal
P-site [27, 36]. The precise role of these proteins re-
mains ambiguous: it is unclear whether they stabilize
tRNA in the P-site to promote translation initiation
or trigger tRNA dissociation to enable ribosome recy-
cling. Furthermore, the question of how these func-
tions are divided between eIF2D and MCTS1–DENR
heterodimer remains unresolved, given their similar
domain architecture.
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BIOCHEMISTRY (Moscow) Vol. 90 No. 11 2025
The dysregulation of the eIF2D and DENR expres-
sion is frequently associated with pathologies. Thus,
DENR expression is increased in various types of can-
cer [37]. Upregulated DENR expression is associated
with late-stage malignancies, including lung, breast,
renal, and colorectal carcinomas. It was reported
that elevated DENR expression may be a risk factor
in the glioma development in dogs [38]. In contrast,
eIF2D expression is downregulated in certain cancer
types [39]. Furthermore, according to the obtained
data, DENR might be involved in the regulation of
cell cycle, as well as in DNA repair and splicing [38].
Mutations in the DENR and eIF2D genes and their
altered expression are associated with neurological
diseases, including, for example, schizophrenia and
autism spectrum disorders (ASDs) [12, 13, 23].
EIF2D AND DENR
AS POTENTIAL BIOMARKERS
OF PSYCHONEUROLOGICAL DISORDERS
Translational control in neurons is essential for
cognitive brain functions. The critical importance of
protein synthesis regulation for normal brain func-
tioning is indicated by the existence of a broad
spectrum of disorders linked to altered translation
rates, such as autism and neurodegenerative diseas-
es. It is currently believed that the translation initi-
ation factor eIF2α, mTORC1 complex, and translation
elongation factor eEF2 are the principal regulators
of neuronal translation [40]. The fundamental sig-
nificance of translational control in neurons strong-
ly suggests that the inventory of regulatory factors
essential for normal neuronal function is destined
to grow.
The eIF2D and DENR genes have been identified
as biomarkers for diagnosing psychoneurological dis-
orders. It was demonstrated that the eIF2D expression
is typically elevated in patients suffering from schizo-
phrenia for more than ten years. The expression of
eIF2D can be assessed in blood samples, which elim-
inates the need for brain biopsy, a procedure gener-
ally unacceptable in clinical practice [23]. However, it
is important to mention that during the early stages
of schizophrenia, the eIF2D expression is typically
downregulated [23].
Recently, it was found that DENR is a risk gene in
schizophrenia, and that the C37Y missense mutation
in its Zn-binding domain is associated with ASD [12,
13]. According to the study by a research group from
Finland [14], this mutation was associated with ASD
in two out of three patients with NFID (Northern Fin-
land intellectual disability). Therefore, available data
indicate a link between DENR and both schizophrenia
and ASD.
The association of DENR with schizophrenia and
autism suggests that this protein may play a role in
the pathogenesis of these disorders. Molecular ge-
netics studies have identified a substantial genetic
overlap between schizophrenia and ASD. For exam-
ple, it was shown that individuals with deletions or
duplications in the 22q11.2 locus have a significant-
ly increased risk of developing both these disorders,
while disruptions in the locus containing the C4 (com-
plement component 4) gene were found in patients
with schizophrenia, as well as in those with ASD [41].
Further studies in this direction will confirm whether
DENR represents another example of genetic overlap
between schizophrenia and autism and can serve as
a composite biomarker for the diagnostics and risk
prediction for both disorders.
The functional impairments of DENR have a no-
ticeable impact on the nervous system activity. Beside
the known ASD-linked C37Y mutation in the zinc-bind-
ing domain, it was demonstrated that the de novo mis-
sense mutations C37Y and P121L disrupt the terminal
arborization of cortical neurons [20]. DENR was found
to affect migration of cortical neurons in mice in vivo
[20]. Furthermore, DENR expression was found to be
upregulated in depression, resulting in a higher DENR
concentration in blood samples [15].
Therefore, the functional significance of DENR in
neuronal processes points out two promising research
directions: investigation of links between mutations
in the DENR gene, alterations in its expression, and
psychoneurological disorders and, if these links are
confirmed, assessment of the diagnostic potential of
DENR as a composite biomarker for these disorders.
Currently, the lack of experimental data on eIF2D pre-
vents it from being considered as a reliable biomark-
er of psychoneurological diseases.
DENR, SLEEP DISORDERS,
AND PATHOGENESIS
OF NEURODEGENERATIVE DISEASES
Sleep dysfunction negatively affects brain and be-
havioral functions. In particular, it disrupts circadian
rhythms, which impairs the clearance of misfolded
neurotoxic proteins involved in the development of
neurodegenerative disorders, such as Alzheimer’s and
Parkinson’s diseases [42]. As shown in young mice,
the levels of DENR in the cortical neurons increase
during sleep [17]. Sleep disruption downregulates ex-
pression of translation-related genes, including DENR
[18]. DENR participates in the regulation of circadian
rhythms through the control of CLOCK biosynthesis,
although the exact mechanism remains unclear [19].
The dysfunction of CLOCK is associated with common
psychoneurological disorders, such as schizophrenia,
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BIOCHEMISTRY (Moscow) Vol. 90 No. 11 2025
Fig. 2. The role of DENR in neurodegenerative (upper panel) and psychoneurological (bottom panel) pathologies associated
with sleep disorders: gray and green, diseases presumably linked, directly or indirectly, respectively, with sleep disorders;
red, disorders with reported changes in the DENR expression or mutations in DENR (references provided).
ASD, attention deficit hyperactivity disorder (ADHD),
major depressive disorder, bipolar disorder, etc. [43].
As a member of circadian clock gene family expressed
in the hypothalamic suprachiasmatic nucleus, the
CLOCK gene, along with other genes, plays a pivotal
role in the transcription–translation feedback loop.
These genes are necessary for sustaining the sleep-
wake cycle [44]. The knockdown of DENR reduces
translation of the CLOCK mRNA, which might lead to
the circadian clock dysfunction [19].
In addition to impairments in the CLOCK gene
function, alterations in the DENR expression and mu-
tations in this gene have been found in a number of
psychoneurological and neurodegenerative disorders.
Thus, it was shown that the DENR expression is sup-
pressed in patients with the Parkinson’s disease. Based
on the experimental data and results of bioinformatic
analysis, DENR was proposed as a potential biomark-
er for the Parkinson’s disease [16]. In contrast, DENR
expression in patients with depression is upregulated
[15]. DENR has also been considered in the context
of pathogenesis of psychoneurological diseases. For
example, DENR has recently been identified as a risk
gene in schizophrenia, and a missense mutation in its
zinc-binding domain is associated with ASD [12, 13].
Taken together, these data suggest that DENR
could be an important contributor to the molecular
mechanisms underlying various psychoneurological
and neurodegenerative disorders. As illustrated in
Fig. 2, numerous pathologies associated with sleep
disorders are characterized by mutations in the DENR
gene or changes in its expression. Current evidence
suggests that DENR can serve as a multifunctional
biomarker for assessing the risk of a broad range of
psychoneurological and neurodegenerative disorders.
EIF2D, DENR, AND DYSREGULATION
OF NON-CANONICAL TRANSLATION
INITIATION IN PATHOGENESIS
OF NEURODEGENERATIVE DISORDERS
It has been suggested that abnormal expansion
of specific nucleotide repeats in a genome might be
the underlying cause of neurodegenerative disorders,
including ALS and spinocerebellar ataxia [45, 46].
Nucleotide repeat expansion results in the transla-
tion of repetitive RNA sequences, thus generating pep-
tides with repeated amino acid motifs. These aberrant
translation products exhibit a propensity for aggrega-
tion and neurotoxicity. The translation initiation for
such repeats occurs via a mechanism independent
of the canonical AUG start codon and is known as
the repeat-associated non-AUG (RAN) translation.
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Dysregulation of the RAN translational machinery
has been detected in the myotonic dystrophy type 2
and Huntington’s disease [47-50]. It has been shown
that in Huntington’s disease, RAN translation takes
place in the protein-coding genomic regions [51]. The
studies of familial ALS have revealed mutations in the
non-protein-coding C9orf72 locus, which also under-
goes RAN translation [52, 53].
Multiple studies have identified non-canonical
translation initiation factors as participants in the
RAN translation. Specifically, the knockdown of eIF2D
in Caenorhabditis elegans enhanced RAN translation
of the C9orf72 locus by more than 50% [21], whereas
the knockdown of DENR in HEK293 cells reduced it
by 50% [22]. The same effect was observed for the
knockdown of the MCTS1 gene encoding the heterod-
imerization partner of DENR, but not for the eIF2D
knockdown [22].
In Drosophila, the knockdown of DENR suppressed
translation of expanded repeats in the C9orf72 locus,
while decreased DENR expression promoted the via-
bility of flies expressing these repeats [22]. DENR may
represent a promising therapeutic target in the treat-
ment of diseases driven by the expansion of C9orf72
repeats, such as ALS and spinocerebellar ataxia.
Future research may include investigating the role
of DENR as a regulatory factor of RAN translation in
other disorders associated with repeat expansion in
various genomic regions.
The participation of eIF2D in the RAN translation
in the C9orf72 locus has been questioned [24]; there-
fore, the role of this protein in the RAN translation
requires further investigation.
Collectively, the data obtained indicate that DENR
could be a potential biomarker for diagnosing RAN
translation-associated disorders, such as the Hunting-
ton’s disease and myotonic dystrophy type 2. Howev-
er, its validation will require additional studies of the
RAN translation mechanisms to elucidate the regula-
tory function of DENR and to define its role in the
pathogenesis of neurodegenerative disorders linked to
the RAN translation. The evidence on the eIF2D in-
volvement in the RAN translation remains conflicting,
which emphasizes the need for additional studies in
order to define its exact function in this process and
related neurodegenerative pathogenesis. New exper-
imental evidence could help evaluate the prospects
of using eIF2D as a potential biomarker for neurode-
generative disorders.
CONCLUSION
A growing prevalence of psychoneurological
and neurodegenerative disorders necessitates time-
ly therapeutic interventions, which in turn requires
the availability of effective early diagnostic systems.
Current evidence indicates that the efficacy of con-
ventional diagnostic approaches based on psycholog-
ical testing and physical examinations is inadequate,
while available biochemical and molecular genetic
diagnostic systems have yet to achieve a satisfactory
performance. In this regard, the development of new
diagnostic approaches should continue, including of
those aimed at the biomarker identification.
Understanding molecular mechanisms of diseas-
es facilitates identification of candidates for biological
markers. Here, we analyzed the role of translation
factors DENR and eIF2D in the development and
pathogenesis of psychoneurological and neurodegen-
erative diseases. Both DENR and eIF2D genes have
been identified as promising biomarkers for the Par-
kinson’s disease and schizophrenia [34, 21]. Given
potential action mechanisms analyzed in this work,
DENR could soon be considered a biomarker for a
broad range of psychoneurological and neurodegener-
ative diseases to improve the accuracy of diagnostics
and enable earlier therapeutic interventions. While
eIF2D has been identified as a biomarker for schizo-
phrenia, its utility for diagnosing other diseases re-
mains uncertain. Therefore, further investigation into
the role of eIF2D in the pathogenesis of psychoneuro-
logical and neurodegenerative disorders is required.
It is important to emphasize that DENR has already
been suggested as a biomarker for a broad spectrum
of disorders, whereas eIF2D represents a more specif-
ic yet promising candidate biomarker.
Abbreviations
ALS amyotrophic lateral sclerosis
ASD autism spectrum disorder
RAN
translation repeat-associated non-AUG
translation
Funding
This work was supported by the State Assign-
ment for the Lomonosov Moscow State University
(no.123063000013-3).
Ethics approval and consent to participate
This work does not contain any studies involving hu-
man subjects or animals.
Conflict of interest
The author of this work declares that she has no con-
flicts of interest.
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