ArticleDisease models & mechanisms2014
Novel ethyl methanesulfonate (EMS)-induced null alleles of the Drosophila homolog of LRRK2 reveal a crucial role in endolysosomal functions and autophagy in vivo.
Article in Disease models & mechanisms, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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31 citing papers in PubMed, 57 citations in OpenAlex.
- Role of Oxidative Stress in Human Neurodegenerative Pathologies: Lessons from theCurrent topics in medicinal chemistry · 2026Review
- Is Glial Dysfunction the Key Pathogenesis ofBiomolecules · 2023Review
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- LRRK2 and Proteostasis in Parkinson's Disease.International journal of molecular sciences · 2022Review
- Oligomerization of Lrrk controls actin severing and α-synuclein neurotoxicity in vivo.Molecular neurodegeneration · 2021Article
- Review
- The Importance ofCells · 2021Review
- α-synuclein impairs autophagosome maturation through abnormal actin stabilization.PLoS genetics · 2021Article
- Autophagy in Neurodegenerative Diseases: A Hunter for Aggregates.International journal of molecular sciences · 2020Review
- The Parkinson's Disease Protein LRRK2 Interacts with the GARP Complex to Promote Retrograde Transport to the trans-Golgi Network.Cell reports · 2020Article
- Clinically Precedented Protein Kinases: Rationale for Their Use in Neurodegenerative Disease.Frontiers in aging neuroscience · 2020Review
- The Emerging Functions of LRRK2 and Rab GTPases in the Endolysosomal System.Frontiers in neuroscience · 2020Review
- Progress inFrontiers in neuroscience · 2020Review
- LRRK2 and the Endolysosomal System in Parkinson's Disease.Journal of Parkinson's disease · 2020Review
- "LRRK2: Autophagy and Lysosomal Activity".Frontiers in neuroscience · 2020Review
- The unlikely partnership between LRRK2 and α-synuclein in Parkinson's disease.The European journal of neuroscience · 2019Review
- Autophagy and LRRK2 in the Aging Brain.Frontiers in neuroscience · 2019Review
- Analysis of macroautophagy related proteins in G2019S LRRK2 Parkinson's disease brains with Lewy body pathology.Brain research · 2018Article
- Lrrk promotes tau neurotoxicity through dysregulation of actin and mitochondrial dynamics.PLoS biology · 2018Article
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Authors and funding
5 authors at 1 institution in 1 country.
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No grant is acknowledged in the PubMed record.
Abstract
Mutations in LRRK2 cause a dominantly inherited form of Parkinson's disease (PD) and are the most common known genetic determinant of PD. Inhibitor-based therapies targeting LRRK2 have emerged as a key therapeutic strategy in PD; thus, understanding the consequences of inhibiting the normal cellular functions of this protein is vital. Despite much interest, the physiological functions of LRRK2 remain unclear. Several recent studies have linked the toxicity caused by overexpression of pathogenic mutant forms of LRRK2 to defects in the endolysosomal and autophagy pathways, raising the question of whether endogenous LRRK2 might play a role in these processes. Here, we report the characterization of multiple novel ethyl methanesulfonate (EMS)-induced nonsense alleles in the Drosophila LRRK2 homolog, lrrk. Using these alleles, we show that lrrk loss-of-function causes striking defects in the endolysosomal and autophagy pathways, including the accumulation of markedly enlarged lysosomes that are laden with undigested contents, consistent with a defect in lysosomal degradation. lrrk loss-of-function also results in the accumulation of autophagosomes, as well as the presence of enlarged early endosomes laden with mono-ubiquitylated cargo proteins, suggesting an additional defect in lysosomal substrate delivery. Interestingly, the lysosomal abnormalities in these lrrk mutants can be suppressed by a constitutively active form of the small GTPase rab9, which promotes retromer-dependent recycling from late endosomes to the Golgi. Collectively, our data provides compelling evidence of a vital role for lrrk in lysosomal function and endolysosomal membrane transport in vivo, and suggests a link between lrrk and retromer-mediated endosomal recycling.
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