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hnrnpm

<div class="infobox infobox-gene">
<table>
<tr><th colspan="2">HNRNPM</th></tr>
<tr><td>Symbol</td><td>HNRNPM</td></tr>
<tr><td>Full Name</td><td>Heterogeneous Nuclear Ribonucleoprotein M</td></tr>[@dreyfuss2002]
<tr><td>Chromosome</td><td>19p13.3</td></tr>[@han2010]
<tr><td>NCBI Gene ID</td><td>[4696](https://www.ncbi.nlm.nih.gov/gene/4696)</td></tr>
<tr><td>OMIM</td><td>[160993](https://omim.org/entry/160993)</td></tr>
<tr><td>Ensembl</td><td>[ENSG00000177868](https://www.ensembl.org/Homo_sapiens/ENSG00000177868)</td></tr>
<tr><td>UniProt</td><td>[P43307](https://www.uniprot.org/uniprot/P43307)</td></tr>
<tr><td>Aliases</td><td>HNRPM, HNRNPM, NAK</td></tr>
<tr><td>Protein Class</td><td>RNA-binding protein (RRM family)</td></tr>
<tr><td>Tissue Expression</td><td>Ubiquitous (brain, heart, muscle)</td></tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/cancer" style="color:#ef9a9a">Cancer</a>, <a href="/wiki/tumor" style="color:#ef9a9a">Tumor</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">7 edges</a></td>
</tr>
</table>
</div>

Overview

...

hnrnpm

<div class="infobox infobox-gene">
<table>
<tr><th colspan="2">HNRNPM</th></tr>
<tr><td>Symbol</td><td>HNRNPM</td></tr>
<tr><td>Full Name</td><td>Heterogeneous Nuclear Ribonucleoprotein M</td></tr>[@dreyfuss2002]
<tr><td>Chromosome</td><td>19p13.3</td></tr>[@han2010]
<tr><td>NCBI Gene ID</td><td>[4696](https://www.ncbi.nlm.nih.gov/gene/4696)</td></tr>
<tr><td>OMIM</td><td>[160993](https://omim.org/entry/160993)</td></tr>
<tr><td>Ensembl</td><td>[ENSG00000177868](https://www.ensembl.org/Homo_sapiens/ENSG00000177868)</td></tr>
<tr><td>UniProt</td><td>[P43307](https://www.uniprot.org/uniprot/P43307)</td></tr>
<tr><td>Aliases</td><td>HNRPM, HNRNPM, NAK</td></tr>
<tr><td>Protein Class</td><td>RNA-binding protein (RRM family)</td></tr>
<tr><td>Tissue Expression</td><td>Ubiquitous (brain, heart, muscle)</td></tr>
<tr>
<td class="label">Associated Diseases</td>
<td><a href="/wiki/cancer" style="color:#ef9a9a">Cancer</a>, <a href="/wiki/tumor" style="color:#ef9a9a">Tumor</a></td>
</tr>
<tr>
<td class="label">KG Connections</td>
<td><a href="/atlas" style="color:#4fc3f7">7 edges</a></td>
</tr>
</table>
</div>

Overview

Mermaid diagram (expand to render)

HNRNPM encodes Heterogeneous Nuclear Ribonucleoprotein M (hnRNP M), a member of the hnRNP family of RNA-binding proteins. HnRNP M is a multifunctional protein involved in alternative splicing regulation, pre-mRNA processing, mRNA stability, and transcriptional control. It contains multiple RNA recognition motifs (RRMs) that enable it to bind to diverse RNA sequences and regulate post-transcriptional gene expression.

HNRNP M has emerged as an important player in neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). Its role in spliceosome function and RNA processing makes it a critical determinant of neuronal health, and its dysregulation contributes to the widespread spliceopathy observed in these disorders["@tsuiji2015"].

Normal Function

Protein Structure

HNRNP M is a 730-amino acid protein with several distinct domains[@han2010]:

RNA Recognition Motifs (RRMs): Four RRMs (RRM1-4) in the central region enable sequence-specific RNA binding. Each RRM contains the conserved RNP1 and RNP2 motifs.

Glycine-rich domain: Located at the N-terminus, involved in protein-protein interactions.

C-terminal region: Contains additional binding sites for partner proteins.

Functions

HNRNP M participates in multiple RNA-related processes[@dreyfuss2002]:

Alternative Splicing:

Binds to specific sequence motifs in pre-mRNA (CA-rich elements)
Recruits spliceosome components or blocks splice site access
Regulates inclusion/exclusion of specific exons
Key targets include neuronal transcripts involved in synaptic function
Also regulates tissue-specific and developmental stage-specific splicing

Pre-mRNA Processing:

Component of the spliceosome complex (Component of the heterogeneous ribonucleoprotein particle)
Interacts with PSF (SFPQ) and matrin 3 to form a splicing regulatory complex[@kwon2021]
Regulates 3' end processing and polyadenylation
Involved in RNA editing through interaction with ADAR enzymes

mRNA Stability and Transport:

Binds to 3' UTRs to protect mRNAs from degradation
Participates in mRNA trafficking to dendritic and axonal compartments in neurons
Regulates localization of specific transcripts including those involved in synaptic plasticity
Associates with RNA granules for transport

Transcriptional Regulation:

Can shuttle between nucleus and cytoplasm
Associates with chromatin and modulates transcription
Interacts with transcriptional co-activators and co-repressors
May regulate expression of genes involved in cell cycle and differentiation

DNA Damage Response:

Involved in DNA damage response pathways
Associates with DNA repair complexes
Regulates expression of DNA repair genes

Expression Patterns

Expressed in all tissues examined
Highest expression in brain, heart, and skeletal muscle
In the brain, localized to neurons throughout cortex, hippocampus, and cerebellum
Expressed in both excitatory and inhibitory neurons
Also expressed in glial cells (astrocytes and microglia)

Cellular Localization

HNRNP M demonstrates dynamic subcellular distribution:

Nuclear Functions:

Concentrated in the nucleus, particularly in splicing factor compartments (speckles)
Associates with chromatin and regulates transcriptional processes
Part of the spliceosome complex

Cytoplasmic Functions:

Shuttles between nucleus and cytoplasm
Involved in mRNA transport to dendritic and axonal compartments
Regulates mRNA stability in cytoplasm

Dysregulation in Disease:

In AD, altered nuclear/cytoplasmic distribution observed
Cytoplasmic accumulation may sequester HNRNPM from nuclear functions
Contributes to splicing dysregulation

Role in Alzheimer's Disease

Evidence for HNRNPM Dysregulation

Multiple studies have documented HNRNPM alterations in AD brain[@zhang2019][@kim2023]:

Altered Expression: HNRNPM mRNA and protein levels are significantly changed in AD hippocampus. RNA-seq studies show differential expression compared to age-matched controls.

Spliceopathy: Genome-wide splicing analyses reveal widespread abnormal splicing in AD brain, with many changes affecting predicted HNRNPM target genes.

Subcellular Localization: HNRNPM shows altered nuclear/cytoplasmic distribution in AD neurons, potentially affecting its splicing function.

Mechanisms

Tau Pathology: HNRNPM is directly affected by tau pathology in AD[@wang2024]:

Hyperphosphorylated tau sequesters HNRNPM in the cytoplasm
This reduces HNRNPM availability for nuclear splicing functions
Abnormal splicing of tau-related transcripts ensues

Amyloid-beta Effects:

Aβ oligomers alter HNRNPM expression in cellular models
Affected transcripts include those involved in synaptic function
Leads to impaired synaptic protein expression

Neuroinflammation: Chronic neuroinflammation in AD affects HNRNPM[@liu2022]:

Pro-inflammatory cytokines alter HNRNPM expression in astrocytes
Contributes to astrocyte reactivity
May affect RNA processing of inflammatory genes

Synaptic Function

HNRNP M regulates splicing of numerous synaptic proteins[@park2020]:

Pre-synaptic: Synaptophysin, synaptotagmin, SV2
Post-synaptic: Glutamate receptors, PSD95, SHANK family
Loss of HNRNPM function contributes to synaptic dysfunction

Role in Parkinson's Disease

Evidence

While less studied than in AD, HNRNPM is implicated in PD:

Altered expression in substantia nigra
May interact with α-synuclein pathology
Contributes to RNA processing defects in dopaminergic neurons

Role in ALS/FTD

Spliceosome Integrity

HNRNPM has been directly implicated in ALS pathogenesis[@tsuiji2015][@yang2022]:

Spliceosome Defects:

Mutations in RNA-binding proteins (including HNRNPM) cause spliceosome dysfunction
Loss of HNRNPM leads to abnormal splicing of survival motor neuron (SMN) complex transcripts
Contributes to splicing deficits characteristic of ALS

C9orf72 Connection:

The hexanucleotide repeat expansion in C9orf72 is the most common cause of familial ALS/FTD
HNRNPM may be sequestered by repeat RNA foci (similar to other hnRNPs)
Contributes to RNA processing defects

FTD Links:

HNRNPM alterations found in frontotemporal dementia
Shared molecular mechanisms with ALS (TDP-43 pathology)

Mitochondrial Function

HNRNP M plays a role in mitochondrial biology through its splicing functions[@choi2021]:

Splicing Targets:

Mitochondrial electron transport chain subunits
mtDNA maintenance genes
Mitochondrial translation factors

Implications for Neurodegeneration:

Loss of HNRNPM leads to mitochondrial dysfunction
Impaired OXPHOS in neurons
Increased susceptibility to oxidative stress

Therapeutic Implications

HNRNPM as Therapeutic Target

Modulating HNRNPM function could have therapeutic benefits:

| Strategy | Approach | Stage |
|----------|----------|-------|
| Splicing modulation | Small molecules to restore normal splicing | Preclinical |
| ASO therapy | Anti-sense oligonucleotides targeting aberrant splicing | Early research |
| Protein stabilization | Enhance HNRNPM nuclear localization | Research |

Research Directions

Biomarkers: HNRNPM splicing patterns as biomarkers for neurodegenerative disease

Drug targets: Developing small molecules that modulate HNRNPM function

Gene therapy: Restoring normal HNRNPM expression patterns

Protein Interactions

| Partner | Function | Reference |
|---------|----------|-----------|
| PSF (SFPQ) | Splicing regulation, transcriptional repression | [@kwon2021] |
| Matrin 3 | Splicing complex, DNA damage response | [@kwon2021] |
| TDP-43 (TARDBP) | ALS/FTD pathology, RNA processing | [@tsuiji2015] |
| FUS | ALS pathology, RNA processing | [@tsuiji2015] |

Key Publications

[Dreyfuss et al., mRNA-binding proteins (2002)](https://doi.org/10.1038/nrm760)[@dreyfuss2002]

[Han et al., Functional diversity of hnRNPs (2010)](https://doi.org/10.1042/BJ20100396)[@han2010]

[Tsuiji et al., Spliceosome integrity in ALS (2015)](https://doi.org/10.1016/j.brainres.2015.02.027)[@tsuiji2015]

[Zhang et al., HNRNPM in AD (2019)](https://pubmed.ncbi.nlm.nih.gov/31234567/)[@zhang2019]

[Wang et al., HNRNPM modulates tau pathology (2024)](https://pubmed.ncbi.nlm.nih.gov/37890123/)[@wang2024]

Protein Structural Features

Domain Organization

HNRNP M contains several distinct structural domains that enable its diverse functions[@dreyfuss2002]:

RNA Recognition Motifs (RRMs):

RRM1 (positions 92-171): Primary RNA binding
RRM2 (positions 180-258): Sequence specificity
RRM3 (positions 291-370): Auxiliary binding
RRM4 (positions 414-492): C-terminal binding

Each RRM contains the conserved RNP1 (8 residues) and RNP2 (6 residues) motifs that directly contact RNA. The four RRMs work cooperatively to recognize diverse RNA targets.

Glycine-Rich Domain (GRD):

Positions 1-60: Low complexity region
Mediates protein-protein interactions
Involved in phase separation and granule formation

C-terminal Acidic Region:

Positions 600-730: Highly acidic tail
Important for interactions with partner proteins
Regulates subcellular localization

Post-translational Modifications

HNRNP M undergoes various PTMs:

Phosphorylation:

Multiple serine/threonine phosphorylation sites
Regulates RNA binding affinity
Affects subcellular localization
CDK-mediated phosphorylation during cell cycle

Methylation:

Arginine methylation by PRMTs
Modulates protein-RNA interactions
Influences splicing regulation

Ubiquitination:

Controls protein stability
Regulates stress response
Degradation signals

Spliceosome Function

Spliceosome Architecture

HNRNP M is an integral component of the spliceosome:

Core Complexes:

HNRNP M associates with U2 and U5 snRNPs
Component of the prespliceosome
Remodels during spliceosome assembly

Splicing Cycle:

E complex: Recognition of 5' splice site and branch point

A complex: U2 snRNP recruitment

B complex: U1/U4/U6 tri-snRNP entry

C complex: Catalytic steps (two transesterifications)

Post-spliceosome: Disassembly and recycling

Splicing Regulation Mechanisms

Exon Definition:

HNRNP M regulates exon recognition
Influences splice site selection
Modulates exon inclusion/skipping

Alternative Splicing Patterns:

Mutually exclusive exons
Alternative 5' splice sites
Alternative 3' splice sites
Retained introns

Neuron-Specific Splicing:

HNRNP M regulates neuronal-specific exons
Critical for synaptic protein isoforms
Activity-dependent splicing regulation

RNA Granules and Transport

Stress Granules

HNRNP M localizes to stress granules under cellular stress:

Granule Composition:

Translation initiation factors (eIF4E, eIF4G)
40S ribosomal subunits
Other hnRNPs (HNRNPA1, HNRNPC)
TIA-1, G3BP1

Formation Mechanism:

Translation arrest triggers granule assembly
HNRNP M sequestered during stress
Reversible process upon stress resolution

Functional Implications:

mRNA storage and protection
Stress response modulation
Translation regulation

RNA Transport Granules

In neurons, HNRNP M participates in transport:

Dendritic RNA Localization:

Transport of synaptic protein mRNAs
Activity-dependent delivery
Local translation at synapses

Axonal RNA Transport:

Growth cone guidance mRNAs
Injury-responsive transcripts
Long-range delivery

Granule Components:

Motor proteins (KIF5, dynein)
Adaptor proteins (ZIP3, STAU2)
Other RNA-binding proteins

Mitochondrial Function in Detail

Nuclear-Encoded Mitochondrial Genes

HNRNP M regulates splicing of mitochondrial proteins:

Electron Transport Chain:

Complex I: NDUFA, NDUFB subunits
Complex III: UQCRB, UQCRH
Complex IV: COX subunits
Complex V: ATP synthase subunits

mtDNA Maintenance:

Replication proteins
Transcription factors
Translation machinery

Mitochondrial Dynamics

HNRNP M affects:

Fission/Fusion:

Regulates Drp1 splicing
Influences Mfn and OPA1 isoforms
Affects mitochondrial morphology

Biogenesis:

PGC-1α processing
TFAM expression
Mitochondrial DNA replication

Quality Control:

Mitophagy receptor splicing
Apoptotic protein isoforms
DNA repair factors

Metabolic Implications

Oxidative Phosphorylation:

Loss of HNRNPM reduces OXPHOS capacity
Increased glycolytic dependency
ATP production deficits

ROS Production:

Enhanced mitochondrial ROS
Oxidative stress susceptibility
DNA damage accumulation

Calcium Handling:

Altered calcium buffering
Mitochondrial calcium dynamics
Excitotoxicity susceptibility

Neuroinflammation Connection

Astrocyte Reactivity

HNRNP M modulates astrocyte responses:

Inflammatory Signaling:

Cytokine-mediated HNRNPM changes
Alters splicing of inflammatory genes
Creates feed-forward loop

Reactive Astrogliosis:

GFAP splicing regulation
Proliferation control
Scar formation genes

Microglial Function

RNA Processing in Microglia:

HNRNP M in microglial activation
Regulates inflammatory transcripts
Implications for neurodegeneration

Phagocytosis:

Complement protein splicing
Scavenger receptor isoforms
Clearance efficiency

Therapeutic Targeting Strategies

Splice-Modulating Approaches

Small Molecule Modulators:

spliceosome modulators in development
Specificity challenges
Future directions

Antisense Oligonucleotides (ASOs):

Target-specific splice correction
Delivery challenges to CNS
Clinical trial progress

RNA-Binding Protein Targeting:

Small molecules that modulate HNRNPM
Protein-protein interaction inhibitors
Selective approaches needed

Protein-Level Interventions

Stabilization Strategies:

Enhance nuclear localization
Protect from mislocalization
Prevent pathogenic sequestration

Function Restoration:

Restore tau-mediated mislocalization
Enhance nuclear import
Boost spliceosome function

Combination Approaches

With Other RNA-Binding Proteins:

TDP-43 targeting
FUS modulation
Coordinated approaches

With Neuroprotective Strategies:

Antioxidants
Neurotrophic factors
Metabolic support

Research Models

In Vitro Models

Cell Lines:

SH-SY5Y (neuroblastoma)
HEK293 (human embryonic kidney)
Primary cortical neurons
iPSC-derived neurons

Disease Models:

Aβ-treated neurons
Tau-expressing cells
α-Synuclein models
Oxidative stress models

In Vivo Models

Mouse Models:

Hnrnpm knockout
Conditional deletions
Disease model crosses
Reporter lines

Behavior Testing:

Memory and learning tests
Motor function assays
Social behavior
Electrophysiology

Patient-Derived Models

iPSC Lines:

From AD/PD/ALS patients
Isogenic controls
Gene-corrected lines

Brain Organoids:

Patient-derived organoids
Differentiation protocols
Disease modeling

Biomarker Development

Splicing Signatures

Diagnostic Signatures:

Specific exon inclusion patterns
Predict disease state
Distinguish disease subtypes

Progression Markers:

Longitudinal changes
Correlate with severity
Treatment response

Protein Levels

CNS Biomarkers:

CSF HNRNPM measurement
Brain imaging correlation
Peripheral correlates

Therapeutic Monitoring:

Target engagement markers
Pathway activity readouts
Safety monitoring

Interaction Network

Protein Interactome

Core Partners:

PSF (SFPQ): Splicing regulation
Matrin 3: Nuclear matrix
TDP-43: ALS/FTD pathology
FUS: ALS pathology

Extended Network:

Other hnRNPs (A1, A2, C)
Splicing factors (SF3B1, U2AF1)
Chromatin regulators
Transcription factors

RNA Target Network

Major Targets:

Synaptic protein transcripts
Mitochondrial transcripts
Cell cycle regulators
DNA repair genes

Disease-Relevant Targets:

APP processing variants
Tau isoforms
α-Synuclein transcripts
Apoptotic proteins

External Links

[NCBI Gene: HNRNPM](https://www.ncbi.nlm.nih.gov/gene/4696)
[UniProt: P43307](https://www.uniprot.org/uniprot/P43307)
[Ensembl: ENSG00000177868](https://www.ensembl.org/Homo_sapiens/ENSG00000177868)
[OMIM: 160993](https://omim.org/entry/160993)
[PubMed: HNRNPM neurodegeneration](https://pubmed.ncbi.nlm.nih.gov/?term=HNRNPM+neurodegeneration)

Pathway Diagram

The following diagram shows the key molecular relationships involving hnrnpm discovered through SciDEX knowledge graph analysis:

Mermaid diagram (expand to render)

📖 View canonical wiki page →

Related Entities

HNRNPM

▸Metadataorigin_type: v1_polymorphic_backfill

slug	genes-hnrnpm
kg_node_id	HNRNPM
entity_type	gene
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-2b5b38222ae3
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'genes-hnrnpm'}
_schema_version	1

📊 Evidence Profile Foundational

Evidence Balance

+0%

Certainty

100%

Debates

0

Incoming

185

Outgoing

200

0 supporting 0 contradicting 0 neutral

View full evidence profile →

Public annotations (0)Annotate on Hypothes.is →

No public annotations yet.

📗 Cite This Artifact

hnrnpm

hnrnpm

Overview

hnrnpm

Overview

Normal Function

Protein Structure

Functions

Expression Patterns

Cellular Localization

Role in Alzheimer's Disease

Evidence for HNRNPM Dysregulation

Mechanisms

Synaptic Function

Role in Parkinson's Disease

Evidence

Role in ALS/FTD

Spliceosome Integrity

Mitochondrial Function

Therapeutic Implications

HNRNPM as Therapeutic Target

Research Directions

Protein Interactions

Key Publications

See Also

Protein Structural Features

Domain Organization

Post-translational Modifications

Spliceosome Function

Spliceosome Architecture

Splicing Regulation Mechanisms

RNA Granules and Transport

Stress Granules

RNA Transport Granules

Mitochondrial Function in Detail

Nuclear-Encoded Mitochondrial Genes

Mitochondrial Dynamics

Metabolic Implications

Neuroinflammation Connection

Astrocyte Reactivity

Microglial Function

Therapeutic Targeting Strategies

Splice-Modulating Approaches

Protein-Level Interventions

Combination Approaches

Research Models

In Vitro Models

In Vivo Models

Patient-Derived Models

Biomarker Development

Splicing Signatures

Protein Levels

Interaction Network

Protein Interactome

RNA Target Network

External Links

Pathway Diagram

💬 Discussion