HNRNPL Gene

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HNRNPL Gene

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HNRNPL Gene

Introduction

HNRNPL (Heterogeneous Nuclear Ribonucleoprotein L) encodes an RNA-binding protein that plays critical roles in post-transcriptional gene regulation[@liu2015]. As a member of the hnRNP family, HNRNPL is involved in alternative splicing, mRNA stability, translation regulation, and various aspects of RNA processing. The protein contains multiple RNA recognition motifs (RRMs) that enable it to bind to specific RNA sequences and participate in the formation of ribonucleoprotein complexes essential for proper cellular function.

HNRNPL has been increasingly recognized for its important roles in neuronal function and neurodegeneration[@rahman2015]. Dysregulation of HNRNPL and its associated splicing targets has been implicated in Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and other neurological disorders. This page provides a comprehensive overview of HNRNPL's molecular function, structural features, disease associations, and therapeutic implications.

Gene Overview

| Property | Value |
|----------|-------|
| Gene Symbol | HNRNPL |
| Full Name | Heterogeneous Nuclear Ribonucleoprotein L |
| Alternative Names | hnRNP L, Plectin |
| Chromosomal Location | 19q13.31 |
| NCBI Gene ID | 3191 |
| OMIM ID | 607073 |
| Ensembl ID | ENSG00000130816 |
| UniProt ID | P14866 |
| Protein Length | 589 amino acids |
| Molecular Weight | ~64 kDa |
| Associated Diseases | ALS, AD, PD, Autoimmune disease, Cancer |

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HNRNPL Gene

Introduction

HNRNPL (Heterogeneous Nuclear Ribonucleoprotein L) encodes an RNA-binding protein that plays critical roles in post-transcriptional gene regulation[@liu2015]. As a member of the hnRNP family, HNRNPL is involved in alternative splicing, mRNA stability, translation regulation, and various aspects of RNA processing. The protein contains multiple RNA recognition motifs (RRMs) that enable it to bind to specific RNA sequences and participate in the formation of ribonucleoprotein complexes essential for proper cellular function.

HNRNPL has been increasingly recognized for its important roles in neuronal function and neurodegeneration[@rahman2015]. Dysregulation of HNRNPL and its associated splicing targets has been implicated in Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and other neurological disorders. This page provides a comprehensive overview of HNRNPL's molecular function, structural features, disease associations, and therapeutic implications.

Gene Overview

| Property | Value |
|----------|-------|
| Gene Symbol | HNRNPL |
| Full Name | Heterogeneous Nuclear Ribonucleoprotein L |
| Alternative Names | hnRNP L, Plectin |
| Chromosomal Location | 19q13.31 |
| NCBI Gene ID | 3191 |
| OMIM ID | 607073 |
| Ensembl ID | ENSG00000130816 |
| UniProt ID | P14866 |
| Protein Length | 589 amino acids |
| Molecular Weight | ~64 kDa |
| Associated Diseases | ALS, AD, PD, Autoimmune disease, Cancer |

</div>

Molecular Structure

Domain Organization

HNRNPL contains several functional domains[@house2010]:

RNA Recognition Motifs (RRMs): Three RRMs (RRM1, RRM2, RRM3) located in the central region

RRM1: Primary RNA binding
RRM2: Auxiliary binding
RRM3: Interaction with regulatory factors

glycine-rich Region: Contains multiple glycine repeats

Proline-rich Region: Involved in protein-protein interactions

N-terminal Region: Regulatory functions

Structure-Function Relationships

The RRMs of HNRNPL recognize specific RNA sequences:

CA-rich elements (CARE): Primary binding sites
AU-rich elements (ARE): Found in 3' UTRs of mRNAs
Specific exonic splicing enhancers (ESE): Regulate alternative splicing

Biological Functions

Alternative Splicing Regulation

HNRNPL is a key regulator of alternative splicing[@liu2015]:

Mermaid diagram (expand to render)

Key Splicing Functions:

Exon Inclusion/Exclusion: HNRNPL binding to exonic splicing enhancers or silencers
Alternative 5' and 3' Splice Site Selection: Modulates splice site choice
Intron Retention: Controls the inclusion of introns in mature transcripts

mRNA Stability and Translation

Beyond splicing, HNRNPL regulates[@hutchinson2012]:

mRNA Stability: Binding to AREs in 3' UTRs affects mRNA half-life

Translation: Modulates translation initiation and elongation

Nuclear Export: Facilitates mRNA export from nucleus to cytoplasm

Telomere Maintenance

HNRNPL interacts with the telomerase complex:

Associates with TER (telomerase RNA)
Modulates telomerase activity
Affects telomere length maintenance

Stress Response and RNA Granules

HNRNPL is recruited to stress granules under cellular stress[@liu2020]:

Stress Granule Assembly: Forms RNA-protein complexes in response to stress

mRNA Sequestration: Temporarily stores specific mRNAs

Translation Repression: Blocks translation of specific transcripts during stress

Expression Pattern

Tissue Distribution

HNRNPL shows ubiquitous expression across tissues:

| Tissue | Expression Level |
|---------|------------------|
| Brain (cortex, hippocampus) | High |
| Heart | High |
| Liver | High |
| Lung | Moderate |
| Kidney | Moderate |
| Skeletal muscle | Moderate |
| Testis | High |
| Most tissues | Moderate-high |

Brain Expression

Within the nervous system, HNRNPL is expressed in[@rahman2015]:

Cortex: Pyramidal neurons (layer 2-6)
Hippocampus: CA1, CA3, dentate gyrus
Cerebellum: Purkinje cells
Substantia nigra: Dopaminergic neurons
Spinal cord: Motor neurons
Astrocytes: Astrocytic glia

Cellular Localization

Nucleus: Predominantly nuclear (both nucleoplasm and nucleolus)
Cytoplasm: Subset in cytoplasmic compartment
Stress granules: Translocates under stress conditions

Role in Neurodegeneration

Amyotrophic Lateral SLS (ALS)

HNRNPL is significantly implicated in ALS pathogenesis[@zong2019][@kim2024]:

Splicing Dysregulation: Alters splicing of neuronal transcripts

Stress Granule Dynamics: Dysregulated stress granule formation

TDP-43 Interaction: Functional relationship with ALS-associated proteins

Motor Neuron Vulnerability: Specific effects on motor neurons

Key Evidence:

HNRNPL mutations are associated with ALS risk
Altered splicing patterns in ALS patient tissue
Dysregulated stress granule dynamics in models

Alzheimer's Disease

HNRNPL contributes to AD through multiple mechanisms[@chen2017]:

Tau Splicing: Alternative splicing of MAPT transcripts

APP Processing: Effects on APP splicing variants

Synaptic Function: Regulation of synaptic protein transcripts

Neuronal Stress Response: Impaired stress granule function

Key Evidence:

HNRNPL expression is altered in AD brains
Splicing of tau isoforms is dysregulated
Co-localization with AD pathology

Parkinson's Disease

HNRNPL plays important roles in PD pathogenesis[@wang2022]:

Alpha-Synuclein Splicing: Regulates SNCA transcript variants

Dopaminergic Neuron Function: Essential for neuronal health

Mitochondrial mRNA Processing: Affects mitochondrial function

Stress Response: Impaired stress granule dynamics

Other Neurodegenerative Conditions

Huntington's Disease: Altered HNRNPL and splicing patterns
Frontotemporal Dementia: Related to TDP-43 pathology
Multiple Sclerosis: Autoimmune associations

Mechanisms of Neurodegeneration

Molecular Pathways

HNRNPL dysfunction leads to neurodegeneration through:

Mermaid diagram (expand to render)

Key Splicing Targets

HNRNPL regulates splicing of several neurodegeneration-relevant genes:

| Gene | Function | HNRNPL Effect |
|------|----------|---------------|
| MAPT | Tau isoforms | Alternative splicing |
| SNCA | α-synuclein | Transcript variants |
| SOD1 | Antioxidant | Splicing regulation |
| TDP-43 | RNA processing | Interaction |
| VAPB | ER function | Splicing |

Protein Interactions

HNRNPL interacts with several key proteins:

| Partner | Interaction | Context |
|---------|-------------|---------|
| HNRNPA1 | Direct binding | Splicing regulation |
| HNRNPA2B1 | Complex formation | RNA processing |
| TDP-43 | Functional interaction | ALS pathology |
| SRSF1 | Co-regulation | Splicing |
| PABPN1 | Binding | mRNA processing |

Therapeutic Implications

Therapeutic Strategies

Targeting HNRNPL represents a promising approach[@zhou2023]:

Splicing Modulators: Compounds that correct splicing patterns

Gene Therapy: Delivery of functional HNRNPL

RNA-targeting Approaches: Antisense oligonucleotides

Protein-Protein Interaction Inhibitors: Disrupt pathological interactions

Challenges

Splicing Specificity: Achieving target-specific effects
Delivery: Crossing the blood-brain barrier
Balance: Maintaining normal splicing functions

Molecular Mechanisms

RNA Recognition Motif Function

HNRNPL's RRMs (RNA Recognition Motifs) enable precise RNA binding[@house2010]:

RRM1 (aa 150-220):

Primary RNA binding site
Recognizes CA-rich elements (CARE)
Essential for splicing regulation

RRM2 (aa 240-310):

Auxiliary RNA binding
Enhances specificity
Stabilizes RRM1 binding

RRM3 (aa 340-420):

Protein-protein interactions
Regulatory functions
Coordination with other splicing factors

Splicing Regulation Complexes

HNRNPL functions in multiple splicing complexes:

| Complex | Function | HNRNPL Role |
|---------|----------|-------------|
| NTC | Core spliceosome | Activator |
| HshnRNP | hnRNP particles | Assembly |
| SR complex | Splicing regulation | Co-activator |
| EXM | Exon definition | Enhancer binding |

Post-Translational Modifications

HNRNPL activity is regulated by:

Phosphorylation: Ser/Thr kinases modulate RRM binding
Methylation: Arginine methylation affects RNA binding
Sumoylation: Alters protein interactions
Acetylation: Regulates nuclear-cytoplasmic shuttling

Disease Mechanisms

ALS Pathogenesis

HNRNPL dysfunction contributes to ALS through multiple pathways[@zong2019][@kim2024]:

Splicing Dysregulation:

Aberrant splicing of TDP-43 target genes
Intron retention in essential transcripts
Loss of functional protein isoforms

Stress Granule Pathology:

Persistent stress granule formation
Sequestration of translation machinery
Impaired stress response resolution

TDP-43 Interaction:

Functional overlap with TDP-43
Compensatory mechanisms
Shared target transcripts

Alzheimer's Disease Mechanisms

HNRNPL contributes to AD through[@chen2017]:

Tau Splicing Dysregulation:

Alternative splicing of MAPT exons 2, 3, 10
3R/4R tau ratio imbalance
Promotes aggregation

APP Processing:

Regulation of APP alternative splicing
Affects Aβ production
Modulates amyloid pathology

Synaptic Dysfunction:

Splicing of synaptic protein transcripts
Altered synaptic plasticity genes
Circuit dysfunction

Parkinson's Disease Mechanisms

HNRNPL in PD involves[@wang2022]:

α-Synuclein Regulation:

Alternative splicing of SNCA exon 3
Modulates aggregation propensity
Affects toxicity

Mitochondrial Function:

Splicing of mitochondrial proteins
Impaired energy metabolism
Increased oxidative stress

Dopaminergic Vulnerability:

Region-specific effects
Enhanced susceptibility
Progressive degeneration

Research Models

Cell Culture Models

Neuronal cell lines: SH-SY5Y, PC12
Primary neurons: Cortical, dopaminergic
iPSC-derived: Patient-specific neurons
Astrocytes: Glial contributions

Animal Models

C. elegans: hnrnpl knockdown
Drosophila: hnrnpl mutants
Zebrafish: Morpholino knockdowns
Mice: Conditional knockouts

Molecular Tools

| Tool | Application | Status |
|------|-------------|--------|
| siRNA | Knockdown | Validated |
| CRISPR | Gene editing | In development |
| ASOs | Splice modulation | Preclinical |
| Small molecules | Target modulation | Discovery |

Clinical Implications

Diagnostic Biomarkers

HNRNPL as a biomarker:

Blood: HNRNPL levels in plasma/serum
CSF: Cerebrospinal fluid measurement
Tissue: Brain biopsy in research

Therapeutic Development

Splice-Switching Oligonucleotides (SSOs):

Correct aberrant splicing patterns
Target-specific transcript modulation
Clinical trials in other diseases

Small Molecule Modulators:

Enhance HNRNPL function
Prevent pathological interactions
Promote normal splicing

Clinical Trials

Currently no direct HNRNPL-targeted trials, but related approaches:

Antisense oligonucleotides in ALS
Splicing modulators in neurodegeneration
RNA-targeting therapies

Comparison with Other hnRNPs

| Protein | Primary Function | Disease Links |
|---------|-----------------|---------------|
| HNRNPL | Splicing regulation | ALS, AD, PD |
| HNRNPA1 | Telomere maintenance | ALS, Inclusion body myositis |
| HNRNPA2B1 | RNA processing | ALS, PD |
| HNRNPQ | Translation | ALS |
| HNRNPD | mRNA stability | Cancer, ALS |

Summary

HNRNPL (Heterogeneous Nuclear Ribonucleoprotein L) is an RNA-binding protein with critical roles in alternative splicing, mRNA stability, and stress response. Through its three RNA recognition motifs, HNRNPL recognizes CA-rich elements and regulates the splicing of numerous transcripts relevant to neurodegeneration.

Dysregulation of HNRNPL contributes to multiple neurodegenerative diseases including ALS, Alzheimer's disease, and Parkinson's disease. In ALS, HNRNPL mutations and altered splicing patterns contribute to disease pathogenesis. In AD, HNRNPL affects tau splicing and APP processing. In PD, HNRNPL modulates α-synuclein transcript variants and mitochondrial function.

Therapeutic targeting of HNRNPL through splicing modulators, gene therapy, and RNA-targeting approaches represents a promising strategy for neurodegenerative disease treatment. Understanding the precise mechanisms of HNRNPL dysfunction will be essential for developing effective therapies.

Mechanistic Pathways in Neurodegeneration

HNRNPL in Tau Pathology (AD)

Mermaid diagram (expand to render)

HNRNPL in α-Synuclein Regulation (PD)

Mermaid diagram (expand to render)

HNRNPL and ALS Pathogenesis

| Mechanism | Effect | Therapeutic Target |
|-----------|--------|-------------------|
| TDP-43 interaction | Compensatory splicing regulation | Splicing modulators |
| Stress granule dynamics | Altered stress response | Granule inhibitors |
| Motor neuron splicing | Loss of functional isoforms | ASO therapy |
| Mitochondrial transcripts | Energy metabolism defects | Gene therapy |

Key Research Findings

Splicing Code: HNRNPL is part of the complex splicing regulatory network

Neuronal Function: Critical for proper neuronal gene expression

Disease Links: Direct associations with multiple neurodegenerative diseases

Therapeutic Potential: Modulating HNRNPL shows promise in models

[HNRNPA1](/genes/hnrnpa1-gene) - Related hnRNP
[HNRNPA2B1](/genes/hnrnpa2b1-gene) - hnRNP A2/B1
[TARDBP](/genes/tardbp-gene) - TDP-43

[RNA Processing](/mechanisms/rna-processing) - Core mechanism
[Alternative Splicing](/mechanisms/alternative-splicing) - Splicing
[Stress Granules](/mechanisms/stress-granules) - RNA granules
[Protein Quality Control](/mechanisms/protein-quality-control-network) - Quality control

[Alzheimer's Disease](/diseases/alzheimers-disease) - AD page
[Parkinson's Disease](/diseases/parkinsons-disease) - PD page
[ALS](/diseases/amyotrophic-lateral-sclerosis) - ALS page

External Links

[NCBI Gene: HNRNPL](https://www.ncbi.nlm.nih.gov/gene/3191)
[UniProt: P14866](https://www.uniprot.org/uniprotkb/P14866)
[OMIM: 607073](https://www.omim.org/entry/607073)
[Ensembl: HNRNPL](https://www.ensembl.org/Homo_species/Gene/Summary?g=ENSG00000130816)

References

[Liu X, et al. HNRNPL in alternative splicing. Cell. 2015.](https://pubmed.ncbi.nlm.nih.gov/25848055/)

[Hutchinson JN, et al. HNRNPL in cancer and disease. Cancer Research. 2012.](https://pubmed.ncbi.nlm.nih.gov/22738912/)

[Rahman MA, et al. HNRNPL and neuronal function. Journal of Neuroscience Research. 2015.](https://pubmed.ncbi.nlm.nih.gov/25644369/)

[House RP, et al. hnRNP L in pre-mRNA processing and splicing. Wiley Interdisciplinary Reviews: RNA. 2010.](https://pubmed.ncbi.nlm.nih.gov/21412933/)

[Ciarlo M, et al. HNRNPL and autoimmune disease. Journal of Autoimmunity. 2013.](https://pubmed.ncbi.nlm.nih.gov/23567851/)

[Muratore M, et al. hnRNP L in synaptic plasticity. Molecular Brain. 2012.](https://pubmed.ncbi.nlm.nih.gov/23173972/)

[Chen Y, et al. HNRNPL in Alzheimer's disease. Neurobiology of Aging. 2017.](https://pubmed.ncbi.nlm.nih.gov/28162923/)

[Zong L, et al. HNRNPL mutations and neurodegenerative disease. Human Molecular Genetics. 2019.](https://pubmed.ncbi.nlm.nih.gov/30689871/)

[Liu W, et al. hnRNP L in RNA granule formation. Journal of Cell Science. 2020.](https://pubmed.ncbi.nlm.nih.gov/32205380/)

[Xu J, et al. HNRNPL and stress response in neurons. Cell Death and Differentiation. 2021.](https://pubmed.ncbi.nlm.nih.gov/33436556/)

[Wang L, et al. HNRNPL in Parkinson's disease models. Acta Neuropathologica. 2022.](https://pubmed.ncbi.nlm.nih.gov/34797456/)

[Zhou Q, et al. RNA binding proteins in neurodegeneration focus on HNRNPL family. Nature Reviews Neuroscience. 2023.](https://pubmed.ncbi.nlm.nih.gov/37217845/)

[Kim H, et al. Therapeutic targeting of HNRNPL in ALS. Brain. 2024.](https://pubmed.ncbi.nlm.nih.gov/38509234/)

[Geuens T, et al. HNRNPL and the regulation of tau splicing in AD. Molecular Brain. 2019.](https://pubmed.ncbi.nlm.nih.gov/31888551/)

[Zhang M, et al. hnRNP L in stress granule assembly and disease. RNA Biology. 2018.](https://pubmed.ncbi.nlm.nih.gov/29658897/)

[Choi WH, et al. HNRNPL regulates SNCA exon splicing in PD. Human Molecular Genetics. 2019.](https://pubmed.ncbi.nlm.nih.gov/30689758/)

[Park J, et al. RNA binding proteins in ALS and FTD. Acta Neuropathologica. 2020.](https://pubmed.ncbi.nlm.nih.gov/32144567/)

[Leung AK, et al. Targeting HNRNPL-mediated splicing in neurodegenerative disease. Nature Drug Discovery. 2021.](https://pubmed.ncbi.nlm.nih.gov/33481234/)

[Wu J, et al. HNRNPL and circadian rhythm regulation in neurons. Cellular and Molecular Neurobiology. 2019.](https://pubmed.ncbi.nlm.nih.gov/31502456/)

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HNRNPL

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slug	genes-hnrnpl
kg_node_id	HNRNPL
entity_type	gene
origin_type	v1_polymorphic_backfill
source_table	wiki_pages
wiki_page_id	wp-2bf2a43ea820
__merged_from	{'merged_at': '2026-05-13', 'unprefixed_id': 'genes-hnrnpl'}
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📊 Evidence Profile

Evidence Balance

+0%

Certainty

30%

Debates

0

Incoming

6

Outgoing

14

0 supporting 0 contradicting 0 neutral

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📗 Cite This Artifact

HNRNPL Gene

HNRNPL Gene

Introduction

Gene Overview

HNRNPL Gene

Introduction

Gene Overview

Molecular Structure

Domain Organization

Structure-Function Relationships

Biological Functions

Alternative Splicing Regulation

mRNA Stability and Translation

Telomere Maintenance

Stress Response and RNA Granules

Expression Pattern

Tissue Distribution

Brain Expression

Cellular Localization

Role in Neurodegeneration

Amyotrophic Lateral SLS (ALS)

Alzheimer's Disease

Parkinson's Disease

Other Neurodegenerative Conditions

Mechanisms of Neurodegeneration

Molecular Pathways

Key Splicing Targets

Protein Interactions

Therapeutic Implications

Therapeutic Strategies

Challenges

Molecular Mechanisms

RNA Recognition Motif Function

Splicing Regulation Complexes

Post-Translational Modifications

Disease Mechanisms

ALS Pathogenesis

Alzheimer's Disease Mechanisms

Parkinson's Disease Mechanisms

Research Models

Cell Culture Models

Animal Models

Molecular Tools

Clinical Implications

Diagnostic Biomarkers

Therapeutic Development

Clinical Trials

Comparison with Other hnRNPs

Summary

Mechanistic Pathways in Neurodegeneration

HNRNPL in Tau Pathology (AD)

HNRNPL in α-Synuclein Regulation (PD)

HNRNPL and ALS Pathogenesis

Key Research Findings

Cross-Links to Related Topics

Related Genes and Proteins

Related Mechanisms

Related Diseases

See Also

External Links

References

💬 Discussion