hnrnpm

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

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]:

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

• 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

• 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

• 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

• 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

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

• 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]:

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

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

• 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

• 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

• 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

• 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

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

See Also

• [hnRNP Family](/proteins/hnrnp-family-proteins)
• [Alternative Splicing](/mechanisms/alternative-splicing)
• [RNA Processing](/mechanisms/rna-processing)
• [Tau Protein](/proteins/tau-protein)
• [ALS](/diseases/als)
• [Alzheimer's Disease](/diseases/alzheimers-disease)
• [Parkinson's Disease](/diseases/parkinsons-disease)

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

Glycine-Rich Domain (GRD):

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

• 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

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

• 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 Regulation Mechanisms

Exon Definition:

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

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

• 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

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

• 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

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

• 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

• Replication proteins
• Transcription factors
• Translation machinery

Mitochondrial Dynamics

HNRNP M affects:

Fission/Fusion:

• Regulates Drp1 splicing
• Influences Mfn and OPA1 isoforms
• Affects mitochondrial morphology

• PGC-1α processing
• TFAM expression
• Mitochondrial DNA replication

• 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

• Enhanced mitochondrial ROS
• Oxidative stress susceptibility
• DNA damage accumulation

• 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

• 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

• 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

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

• 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

• Restore tau-mediated mislocalization
• Enhance nuclear import
• Boost spliceosome function

Combination Approaches

With Other RNA-Binding Proteins:

• TDP-43 targeting
• FUS modulation
• Coordinated approaches

• 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

• 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

• 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

• Patient-derived organoids
• Differentiation protocols
• Disease modeling

Biomarker Development

Splicing Signatures

Diagnostic Signatures:

• Specific exon inclusion patterns
• Predict disease state
• Distinguish disease subtypes

• Longitudinal changes
• Correlate with severity
• Treatment response

Protein Levels

CNS Biomarkers:

• CSF HNRNPM measurement
• Brain imaging correlation
• Peripheral correlates

• 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

• 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

• 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: