LARS1

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Overview

lars1
gene = LARS1 name = Leucyl-tRNA Synthetase 1
ncbi_gene_id = 51520 ensembl = ENSG00000143702
Partner Interaction Type
tRNA-Leu Substrate
mTORC1 Signaling
Rag GTPases Signal transduction
Ribosome Translation
Aminoacyl-tRNA synthetases Complex
Partner Interaction Type
tRNA-Leu Substrate
mTORC1 Signaling
Rag GTPases Signal transduction
Ribosome Translation
Aminoacyl-tRNA synthetases Complex
KG Connections 1 edges

LARS1

{{ infobox .infobox-gene | gene = LARS1 | name = Leucyl-tRNA Synthetase 1 | chromosome = 5q32 | ncbi_gene_id = 51520 | ensembl = ENSG00000143702 | uniprot = Q9P2J5 | gene_family = Aminoacyl-tRNA Synthetases | diseases = Infantile-Onset Neurodegenerative Disorder, Alzheimer’s Disease, Parkinson’s Disease }}

Introduction

LARS1 (Leucyl-tRNA Synthetase 1) encodes leucyl-tRNA synthetase, an essential enzyme in protein synthesis that catalyzes the attachment of L-leucine to its cognate tRNA [1/https://pubmed.ncbi.nlm.nih.gov/12411577/). This enzymatic function is crucial for accurate translation of the genetic code during protein synthesis. Beyond its canonical role in translation, LARS1 has emerged as an important leucine sensor for mTORC1 (mechanistic target of rapamycin complex 1) signaling, linking nutrient availability to cellular growth and metabolism [10/https://pubmed.ncbi.nlm.nih.gov/20679438/).

Pathogenic mutations in LARS1 cause a severe infantile-onset neurodegenerative disorder characterized by progressive cerebellar atrophy, developmental regression, and often premature death [4/https://pubmed.ncbi.nlm.nih.gov/25931480/). This disorder, sometimes called LARS1-associated neurodegeneration, highlights the critical importance of LARS1 function for neuronal survival and development. The dual roles of LARS1 in both protein synthesis and nutrient sensing make it a fascinating player in neurodegeneration research.

Gene and Protein Structure

Genomic Organization

The LARS1 gene is located on chromosome 5q32 and encodes a protein of approximately 1,638 amino acids. The gene contains multiple domains with distinct functional activities.

Protein Architecture

LARS1 contains several functional domains 2:

  • Aminoacylation domain: Catalyzes leucine attachment to tRNA

  • tRNA-binding domain: Ensures correct tRNA recognition

  • Editing domain: Corrects mischarged tRNAs ( proofreading)

  • C-terminal domain: Involved in leucine sensing and mTORC1 interaction

Function and Mechanism

Aminoacylation Function

LARS1 performs the essential function of attaching leucine to its cognate tRNA 1 3:

  1. Activation: LARS1 activates leucine using ATP to form leucyl-adenylate

  2. Transfer: The activated leucine is transferred to the 3’ end of tRNA-Leu

  3. Proofreading: The editing domain removes mischarged amino acids

  4. Delivery: The charged tRNA is delivered to the ribosome

This process ensures accurate translation of leucine codons (UUA, UUG, CUU, CUG, CUC, CUA) during protein synthesis.

Leucine Sensing

Beyond translation, LARS1 functions as a cellular leucine sensor for mTORC1 activation 10:

  • Leucine binding to LARS1 induces a conformational change

  • This change promotes LARS1 interaction with Rag GTPases

  • Rag GTPases recruit mTORC1 to the lysosome for activation

  • mTORC1 then regulates cell growth, autophagy, and metabolism

This nutrient-sensing function connects cellular amino acid status to downstream signaling pathways critical for cell survival.

Disease Associations

Infantile-Onset Neurodegenerative Disorder

LARS1 mutations cause a severe autosomal recessive disorder 4 7:

Clinical Features:

  • Progressive cerebellar atrophy

  • Developmental regression

  • Severe motor impairment

  • Often premature death in infancy or early childhood

  • Epileptic seizures in some cases

Mechanism:

  • Loss of aminoacylation activity

  • Impaired leucine sensing

  • Disrupted protein synthesis

  • mTORC1 dysregulation

Alzheimer’s Disease

In [Alzheimer’s disease)(/diseases/alzheimer-disease), LARS1 through mTORC1 signaling may contribute [15/https://pubmed.ncbi.nlm.nih.gov/29453462/):

  • mTORC1 hyperactivation impairs autophagy

  • Dysregulated protein synthesis affects synaptic function

  • Leucine sensing may be altered in AD brains

Parkinson’s Disease

In Parkinson’s disease, LARS1-related pathways are relevant [16/https://pubmed.ncbi.nlm.nih.gov/24791858/):

  • mTORC1 signaling affects dopaminergic neuron survival

  • Autophagy impairment contributes to α-synuclein accumulation

  • Protein synthesis dysregulation affects neuronal function

Role in Neurodegeneration

Protein Synthesis and Neurodegeneration

Proper protein synthesis is essential for neuronal function [11/https://pubmed.ncbi.nlm.nih.gov/20531437/):

  1. Synaptic protein synthesis: Local translation at synapses is critical for plasticity

  2. Axonal transport: Protein synthesis in distal axons supports connectivity

  3. Quality control: Misfolded proteins accumulate when synthesis is impaired

  4. Ribosome stalling: Translation errors can trigger stress responses

mTORC1 Signaling

mTORC1 dysregulation contributes to multiple neurodegenerative processes 17:

  • Autophagy inhibition: mTORC1 blocks autophagic clearance

  • Protein synthesis dysregulation: Altered translation of synaptic proteins

  • Lysosomal function: mTORC1 affects lysosomal degradation

  • Cellular energetics: Metabolic dysregulation

Ribosome Quality Control

LARS1 editing function is crucial for translation accuracy 14 15:

  • Mischarged tRNAs can incorporate wrong amino acids

  • These errors lead to misfolded proteins

  • Accumulated misfolded proteins trigger ER stress

  • Chronic stress leads to neuronal dysfunction

Molecular Pathway: LARS1 in Neurodegeneration

flowchart TD
    A["Leucine<br/>Availability"] --> B["LARS1<br/>Leucine Binding"]
    B --> C{"Function"}
    C -->|"Translation"| D["tRNA Charging<br/>Protein Synthesis"]
    C -->|"Sensing"| E["mTORC1<br/>Activation"]

    D --> F["Accurate<br/>Translation"]
    E --> G["Growth<br/>Metabolism"]
    E --> H["Autophagy<br/>Regulation"]

    F --> I["Synaptic<br/>Function"]
    G --> J["Cellular<br/>Homeostasis"]
    H --> K["Protein<br/>Clearance"]

    L["LARS1<br/>Mutation"] --> M["Loss of<br/>Function"]
    M --> N["Impaired<br/>Translation"]
    M --> O["mTORC1<br/>Dysregulation"]

    N --> P["Misfolded<br/>Proteins"]
    O --> Q["Autophagy<br/>Blockade"]

    P --> R["ER Stress"]
    Q --> S["Aggregate<br/>Accumulation"]
    R --> T["Neuronal<br/>Dysfunction"]
    S --> T
    T --> U["Neurodegeneration"]

    I --> V["Normal<br/>Neuronal Function"]
    J --> V
    K --> V

    style V fill:#0e2e10
    style T fill:#3b1114
    style U fill:#3b1114

Interaction Network

LARS1 participates in several key molecular networks:

Therapeutic Implications

Targeting mTORC1

Modulating LARS1-mTORC1 signaling may have therapeutic potential [24/https://pubmed.ncbi.nlm.nih.gov/24289475/):

  • Rapamycin: mTORC1 inhibitor

  • Leucine restriction: May modulate signaling

  • Autophagy enhancers: Overcome blockade

  • Protein synthesis modulators: Restore balance

Gene Therapy

Future approaches may include:

  • Viral vector delivery of wild-type LARS1

  • CRISPR-based gene correction

  • Protein replacement therapy

Summary

LARS1 plays essential roles in both protein synthesis through its aminoacylation function and nutrient sensing through mTORC1 signaling. Pathogenic mutations cause severe infantile neurodegeneration with cerebellar atrophy, while dysregulated LARS1-mTORC1 signaling contributes to common neurodegenerative diseases like Alzheimer’s and Parkinson’s disease. Understanding LARS1’s dual functions provides insights into protein homeostasis, nutrient sensing, and their disruption in neurodegeneration.

See Also

References

  1. Leucyl-tRNA synthetase: an essential enzyme in protein synthesis (2002)

  2. Crystal structure of leucyl-tRNA synthetase (2004)

  3. Aminoacyl-tRNA synthetases: role in translation (2003)

  4. Leucyl-tRNA synthetase deficiencies cause infantile neurodegeneration (2015)

  5. Leucine sensing by LARS1 and mTORC1 activation (2014)

  6. Role of aminoacyl-tRNA synthetases in translation (2006)

  7. Aminoacyl-tRNA synthetase interactions with ribosome (2007)

  8. LARS1 mutations and cerebellar atrophy (2015)

  9. Amino acid sensing and mTOR signaling (2012)

  10. Leucine as a nutrient signal for mTORC1 (2010)

  11. Protein synthesis and neurodegeneration (2010)

  12. Leucine deficiency and neuronal dysfunction (2015)

  13. tRNA synthetases in protein quality control (2007)

  14. Aminoacyl-tRNA synthetase editing domains (2009)

  15. mTOR signaling in Alzheimer’s disease (2019)

  16. mTOR dysfunction in Parkinson’s disease (2014)

  17. mTOR and autophagy in neurodegeneration (2010)

  18. Lysosomal dysfunction in neurodegenerative diseases (2013)

  19. Protein synthesis inhibitors in neurodegeneration (2010)

  20. Protein homeostasis in aging and neurodegeneration (2011)

  21. Ribosome stalling and neurodegeneration (2014)

  22. Mitochondrial function in neurodegeneration (2008)

  23. ER stress in neurodegenerative diseases (2013)

  24. Synaptic protein synthesis and neurodegeneration (2014)

  25. Targeting mTOR in neurodegenerative diseases (2013)

  26. Amino acid transporters in brain function (2010)

  27. Brain amino acid metabolism (2010)

  28. Genetic causes of cerebellar atrophy (2016)

  29. Epilepsy and neurodegeneration (2015)

  30. [Developmental neurodegeneration mechanisms (2015)](https://pubmed.ncbi.nlm.nih.gov/26284485/flowchart TD A[“Leucine
    Availability”] --> B[“LARS1
    Leucine Binding”] B --> C{“Function”} C -->|“Translation”| D[“tRNA Charging
    Protein Synthesis”] C -->|“Sensing”| E[“mTORC1
    Activation”]

    D --> F[“Accurate
    Translation”] E --> G[“Growth
    Metabolism”] E --> H[“Autophagy
    Regulation”]

    F --> I[“Synaptic
    Function”] G --> J[“Cellular
    Homeostasis”] H --> K[“Protein
    Clearance”]

    L[“LARS1
    Mutation”] --> M[“Loss of
    Function”] M --> N[“Impaired
    Translation”] M --> O[“mTORC1
    Dysregulation”]

    N --> P[“Misfolded
    Proteins”] O --> Q[“Autophagy
    Blockade”]

    P --> R[“ER Stress”] Q --> S[“Aggregate
    Accumulation”] R --> T[“Neuronal
    Dysfunction”] S --> T T --> U[“Neurodegeneration”]

    I --> V[“Normal
    Neuronal Function”] J --> V K --> V

    style V fill:#0e2e10 style T fill:#3b1114 style U fill:#3b1114

Interaction Network

LARS1 participates in several key molecular networks:

Therapeutic Implications

Targeting mTORC1

Modulating LARS1-mTORC1 signaling may have therapeutic potential [24/https://pubmed.ncbi.nlm.nih.gov/24289475/):

  • Rapamycin: mTORC1 inhibitor

  • Leucine restriction: May modulate signaling

  • Autophagy enhancers: Overcome blockade

  • Protein synthesis modulators: Restore balance

Gene Therapy

Future approaches may include:

  • Viral vector delivery of wild-type LARS1

  • CRISPR-based gene correction

  • Protein replacement therapy

Summary

LARS1 plays essential roles in both protein synthesis through its aminoacylation function and nutrient sensing through mTORC1 signaling. Pathogenic mutations cause severe infantile neurodegeneration with cerebellar atrophy, while dysregulated LARS1-mTORC1 signaling contributes to common neurodegenerative diseases like Alzheimer’s and Parkinson’s disease. Understanding LARS1’s dual functions provides insights into protein homeostasis, nutrient sensing, and their disruption in neurodegeneration.

See Also

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