{{ 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
}}
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.
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.
LARS1 contains several functional domains 2:
LARS1 performs the essential function of attaching leucine to its cognate tRNA 1 3:
This process ensures accurate translation of leucine codons (UUA, UUG, CUU, CUG, CUC, CUA) during protein synthesis.
Beyond translation, LARS1 functions as a cellular leucine sensor for mTORC1 activation 10:
This nutrient-sensing function connects cellular amino acid status to downstream signaling pathways critical for cell survival.
LARS1 mutations cause a severe autosomal recessive disorder 4 7:
Clinical Features:
Mechanism:
In Alzheimer's disease), LARS1 through mTORC1 signaling may contribute [15/https://pubmed.ncbi.nlm.nih.gov/29453462/):
In Parkinson's disease, LARS1-related pathways are relevant [16/https://pubmed.ncbi.nlm.nih.gov/24791858/):
Proper protein synthesis is essential for neuronal function [11/https://pubmed.ncbi.nlm.nih.gov/20531437/):
mTORC1 dysregulation contributes to multiple neurodegenerative processes 17:
LARS1 editing function is crucial for translation accuracy 14 15:
LARS1 participates in several key molecular networks:
| Partner | Interaction Type | Relevance |
|---|---|---|
| tRNA-Leu | Substrate | Aminoacylation |
| mTORC1 | Signaling | Nutrient sensing |
| Rag GTPases | Signal transduction | Lysosomal localization |
| Ribosome | Translation | Protein synthesis |
| Aminoacyl-tRNA synthetases | Complex | Complex formation |
Modulating LARS1-mTORC1 signaling may have therapeutic potential [24/https://pubmed.ncbi.nlm.nih.gov/24289475/):
Future approaches may include:
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.