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LRRK2 and RAB7L1 coordinately regulate axonal morphology and lysosome integrity in diverse cellular contexts

Kuwahara, Tomoki, Inoue, Keiichi, D’Agati, Vivette D., Fujimoto, Tetta, Eguchi, Tomoya, Saha, Shamol, Wolozin, Benjamin, Iwatsubo, Takeshi, Abeliovich, Asa·2016·Scientific Reports
DOI 10.1038/srep29945PMC PMC4947924
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Abstract

Leucine-rich repeat kinase 2 (LRRK2) has been linked to several clinical disorders including Parkinson’s disease (PD), Crohn’s disease and leprosy. Furthermore in rodents, LRRK2 deficiency or inhibition leads to lysosomal pathology in kidney and lung. Here we provide evidence that LRRK2 functions together with a second PD-associated gene, RAB7L1, within an evolutionarily conserved genetic module in diverse cellular contexts. In C. elegans neurons, orthologues of LRRK2 and RAB7L1 act coordinately in an ordered genetic pathway to regulate axonal elongation. Further genetic studies implicated the AP-3 complex, which is a known regulator of axonal morphology as well as of intracellular protein trafficking to the lysosome compartment, as a physiological downstream effector of LRRK2 and RAB7L1. Additional cell-based studies implicated LRRK2 in the AP-3 complex-related intracellular trafficking of lysosomal membrane proteins. In mice, deficiency of either RAB7L1 or LRRK2 leads to prominent age-associated lysosomal defects in kidney proximal tubule cells, in the absence of frank CNS pathology. We hypothesize that defects in this evolutionarily conserved genetic pathway underlie the diverse pathologies associated with LRRK2 in humans and in animal models.

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  • Knockdown or knockout of RAB29 causes deficits in retrograde sorting events between the late endosome and the Golgi complex, which is crucial for the correct trafficking of lysosomal enzymes and associated with defects in lysosomal homeostasis.

    “However, knockdown or knockout of RAB29 causes deficits in retrograde sorting events between the late endosome and the Golgi complex, which is crucial for the correct trafficking of lysosomal enzymes and associated with defects in lysosomal homeostasis [22,27,74].”

    From Distinct Roles for RAB10 and RAB29 in Pathogenic LRRK2-Mediated Endolysosomal Trafficking Alterations (2020) · cites this paper as [74]

  • Deficits in the trafficking/degradation of the EGFR may not have been evident owing to the incomplete and/or transient nature of the RAB29 knockdown, because alterations in the correct processing of lysosomal hydrolases have only been described in RAB29 knockout contexts, and may thus only arise as a consequence of the prolonged missorting of cargo.

    “Deficits in the trafficking/degradation of the EGFR may not have been evident owing to the incomplete and/or transient nature of the RAB29 knockdown, because alterations in the correct processing of lysosomal hydrolases have only been described in RAB29 knockout contexts, and may thus only arise as a consequence of the prolonged missorting of cargo [27,74].”

    From Distinct Roles for RAB10 and RAB29 in Pathogenic LRRK2-Mediated Endolysosomal Trafficking Alterations (2020) · cites this paper as [74]

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Metadata

Authors
Kuwahara, T., Inoue, K., D’Agati, V. D., Fujimoto, T., Eguchi, T., Saha, S., Wolozin, B., Iwatsubo, T., & Abeliovich, A.
Venue
Scientific Reports
Publisher
Springer Science and Business Media LLC
Published
2016-07-18
Volume
6
Issue
1
ISSN
2045-2322
DOI
10.1038/srep29945
PMC
PMC4947924
Cited by
125
References
0
Language
en
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