GABARAPL1 Protein
Overview GABARAPL1 (GABA Receptor Associated Protein Like 1) is an [autophagy](/entities/autophagy)-related protein involved in cellular clearance.
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Structure ...
GABARAPL1 Protein
Overview GABARAPL1 (GABA Receptor Associated Protein Like 1) is an [autophagy](/entities/autophagy)-related protein involved in cellular clearance.
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Structure GABARAPL1 is a member of the Atg8 family of [autophagy](/mechanisms/autophagy-lysosomal-pathway) proteins[@weiergrber2006]. The protein has a conserved ubiquitin-like fold:
N-terminal helical region for membrane interaction
Core ubiquitin-like domain (~110 aa)
C-terminal glycine for lipidation (conjugation to phosphatidylethanolamine)
Conserved LIR (LC3-interacting region) docking site[@johansen2011]
Normal Function GABARAPL1 is a multifunctional protein involved in autophagy and cellular homeostasis:
Autophagosome Formation : Participates in [autophagy](/mechanisms/autophagy-lysosomal-pathway) initiation and elongationSubstrate Recognition : Binds to LIR motifs on autophagy receptors (p62, NDP52, OPTN)[@wild2011]Mitochondrial Quality Control : Mediates [mitophagy](/mechanisms/autophagy-lysosomal-pathway) through receptor recognitionGABA Receptor Trafficking : Associates with GABAA receptors for synaptic localizationCellular Stress Response : Upregulated during nutrient deprivation and cellular stress[@chakrama2010]Role in Neurodegeneration
Alzheimer's Disease GABARAPL1 is critically involved in [Alzheimer's disease](/diseases/alzheimers-disease) pathogenesis:
Autophagy Dysregulation : Impaired GABARAPL1 function contributes to defective [autophagy](/mechanisms/autophagy-lysosomal-pathway) in AD[@nixon2013][Tau](/proteins/tau) Clearance : GABARAPL1-mediated autophagy helps clear hyperphosphorylated [tau](/proteins/tau)[Amyloid-beta](/proteins/amyloid-beta-protein) Clearance : Autophagy receptors (p62/SQSTM1) work with GABARAPL1 to clear [Aβ](/proteins/amyloid-beta) aggregates[@salminen2013]Neuronal Vulnerability : Reduced GABARAPL1 in AD brain correlates with disease severity[@pickford2008]Parkinson's Disease
[α-Synuclein](/proteins/alpha-synuclein) Clearance : GABARAPL1-mediated [autophagy](/mechanisms/autophagy-lysosomal-pathway) targets [alpha-synuclein](/proteins/alpha-synuclein) aggregates[@xilouri2013]Mitophagy : PINK1/Parkin-mediated mitophagy utilizes GABARAPL1 for mitochondrial clearance[@narendra2010]Dopaminergic Neuron Survival : GABARAPL1 expression protects substantia nigra [neurons](/entities/neurons)[@klionsky2021]Amyotrophic Lateral Sclerosis
Dysregulated [autophagy](/mechanisms/autophagy-lysosomal-pathway) in [ALS](/diseases/amyotrophic-lateral-sclerosis) involves GABARAPL1 alterations[@liu2016]
Motor neuron degeneration linked to impaired autophagic clearance
[TDP-43](/proteins/tdp-43-protein) proteinopathy may be cleared via GABARAPL1 pathway
Huntington's Disease
Mutant [Huntingtin](/proteins/huntingtin) Clearance : GABARAPL1 participates in clearing aggregated [huntingtin](/proteins/huntingtin-protein)[@rui2015]Autophagy induction is a therapeutic strategy in [Huntington's disease](/diseases/huntington-disease)
Therapeutic Targeting
Autophagy Induction : [Rapamycin](/therapeutics/rapamycin-tauopathy), [everolimus](/therapeutics/everolimus-neurodegeneration), [metformin](/therapeutics/metformin-neurodegeneration)[@galluzzi2017]GABARAPL1 Enhancers : Small molecules to boost GABARAPL1 expressionCombination Approaches : Autophagy inducers with [NAD+](/therapeutics/nad-precursors-neurodegeneration) precursorsGene Therapy : AAV-mediated GABARAPL1 overexpression (preclinical)[@spencer2019]
See Also
GABARAPL1 Gene
[Autophagy-Lysosomal Pathway](/mechanisms/autophagy-lysosome-neurodegeneration)
MAP1LC3 (LC3) Protein
[Alzheimer's Disease](/diseases/alzheimers-disease)
[Parkinson's Disease](/diseases/parkinsons-disease)
[p62/SQSTM1 Protein](/proteins/p62-sqstm1-protein)
External Links
[UniProt: gabarapl1](https://www.uniprot.org/)
[PubMed: gabarapl1](https://pubmed.ncbi.nlm.nih.gov/?term=gabarapl1+neurodegeneration)
References
[Weiergräber, O.H. et al., (2006). The Atg8 Family (2006)](https://pubmed.ncbi.nlm.nih.gov/17030180/)
[Unknown, Johansen, T. & Lamark, T. (2011). Selective Autophagy Mediated by LIR Domains (2011)](https://pubmed.ncbi.nlm.nih.gov/21136617/)
[Wild, P. et al., (2011). Phosphorylation of p62 Activates Selective Autophagy (2011)](https://pubmed.ncbi.nlm.nih.gov/21884931/)
[Chakrama, F.Z. et al., (2010). GABARAPL1: Autophagy and Beyond (2010)](https://pubmed.ncbi.nlm.nih.gov/20818167/)
[Unknown, Nixon, R.A. (2013). The Role of Autophagy in Neurodegeneration (2013)](https://pubmed.ncbi.nlm.nih.gov/23958784/)
[Salminen, A. et al., (2013). Autophagy in Alzheimer's Disease Pathogenesis (2013)](https://pubmed.ncbi.nlm.nih.gov/23518510/)
[Pickford, F. et al., (2008). The Autophagy Modulator Beclin-1 in AD (2008)](https://pubmed.ncbi.nlm.nih.gov/18419748/)
[Xilouri, M. et al., (2013). Autophagy and Alpha-Synuclein (2013)](https://pubmed.ncbi.nlm.nih.gov/23934431/)
[Narendra, D.P. et al., (2010). p62/SQSTM1 in Mitophagy (2010)](https://pubmed.ncbi.nlm.nih.gov/21135082/)
[Klionsky, D.J. et al., (2021). Guidelines for Autophagy Research (2021)](https://pubmed.ncbi.nlm.nih.gov/33730858/)
Liu, Y.J. et al., (2016). Autophagy Dysfunction in ALS (2016)
[Rui, Y.N. et al., (2015). Huntingtin Phosphorylation and Autophagy (2015)](https://pubmed.ncbi.nlm.nih.gov/26360057/)
[Galluzzi, L. et al., (2017). Pharmacological Modulation of Autophagy (2017)](https://pubmed.ncbi.nlm.nih.gov/28529333/)
[Spencer, B. et al., (2019). Beclin-1 Gene Therapy for Neurodegeneration (2019)](https://pubmed.ncbi.nlm.nih.gov/31078715/) Show full description