Rab2 drives axonal transport of dense core vesicles and lysosomal organelles

Lund, Viktor K.; Lycas, Matthew D.; Schack, Anders; Andersen, Rita C.; Gether, Ulrik; Kjærulff, Ole

doi:10.1101/2020.06.03.131672

Cited by 9 publications

(7 citation statements)

References 76 publications

(117 reference statements)

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“…A recent study shows that regulators of axonal transport of these different cargos are distinct. Loss of the small GTPase Rab2 in Drosophila disrupts axonal transport of DCVs and endo‐lysosomes without altering mitochondrial trafficking 72 . Alternatively, increasing evidence suggests that the endoplasmic reticulum (ER) plays a critical role in the regulation of endo‐lysosomal size and positioning, 73–76 and disruption of ER dynamics could potentially specifically disrupt endo‐lysosomes.…”

Section: Discussionmentioning

confidence: 99%

Defective axonal transport of endo‐lysosomes and dense core vesicles in a Drosophila model of C9‐ALS/FTD

Lloyd

2022

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A GGGGCC (G 4 C 2 ) repeat expansion in the C9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Although disruptions in axonal transport are implicated in the pathogenesis of multiple neurodegenerative diseases, the underlying mechanisms causing these defects remain unclear. Here, we performed live imaging of Drosophila motor neurons expressing expanded G 4 C 2 repeats in third-instar larvae and investigated the axonal transport of multiple organelles in vivo. Expression of expanded G 4 C 2 repeats causes an increase in static axonal lysosomes, while it impairs trafficking of late endosomes (LEs) and dense core vesicles (DCVs). Surprisingly, however, axonal transport of mitochondria is unaffected in motor axons expressing expanded G 4 C 2 repeats. Thus, our data indicate that expanded G 4 C 2 repeat expression differentially impacts axonal transport of vesicular organelles and mitochondria in Drosophila models of C9orf72associated ALS/FTD. SynopsisAxonal transport is an indispensable cellular process responsible for movement of cargos along the axon in order to maintain the long-distance communication between soma and synapses. For decades, it has been reported that axonal transport defects are observed in motor neuron diseases, including ALS. In this study, we report that Drosophila motor neurons expressing expanded GGGGCC repeats to model C9orf72associated ALS show specific disruptions in organelle transport for endo-lysosomes and dense core vesicles, but not for mitochondria.

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Section: Discussionmentioning

confidence: 99%

Defective axonal transport of endo‐lysosomes and dense core vesicles in a Drosophila model of C9‐ALS/FTD

Lloyd

2022

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“…This phase is characterized by cargo exchange between endo-lysosomal compartments and immature vesicles budding off from the trans-Golgi network (Topalidou et al, 2016). Recent studies (Gondré-Lewis et al, 2012; Lund, Lycas, Schack, Andersen, & Gether, 2020) suggest that RAB2 and associated proteins are involved in this exchange. However, we do not know if these components participate in routing DILPs and AKH to DCVs in the CC.…”

Section: Discussionmentioning

confidence: 99%

A local insulin reservoir ensures developmental progression in condition of nutrient shortage in Drosophila

Ghosh

Leng

Wilsch‐Bräuninger

et al. 2021

Preprint

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Insulin/IGF signalling (IIS) controls many aspects of development and physiology. In Drosophila, a conserved family of insulin-like peptides (Ilp) is produced by brain neurosecretory cells and exerts systemic functions. Here, we describe the local uptake and storage of Ilps in the Corpora Cardiaca (CC), a group of alpha cell homolog that produces the glucagon-like hormone AKH. Dilp uptake relies on the expression of Impl2, an IGF-BP that accumulates in the CCs. During nutrient shortage, this specific reserve of Ilps is released and activates IIS in a paracrine manner in the prothoracic gland, securing accelerated entry into pupal development through the production of the steroid hormone ecdysone. We therefore uncover a sparing mechanism whereby local Ilp storage and release activates the production of steroids and ensures early developmental progression in adverse food conditions.

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“…Since lysosomes are essential for maintaining synapses (Farfel-Becker et al, 2019;Goo et al, 2017;Lund et al, 2021;Padamsey et al, 2017) and we found that lysosomes are dysfunctional in aged neurons, we decided to investigate if lysosomal dysfunction caused synapse loss in aged neurons.…”

Section: Lysosome Dysfunction Contributes To the Aging-dependent Loss...mentioning

confidence: 99%

Deacidification of distal lysosomes by neuronal aging drives synapse loss

Burrinha

Cunha

Almeida

2022

Preprint

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Previously, we found that age-dependent beta-amyloid accumulation is not enough to cause synaptic decline. Here, we characterized endolysosomes (late-endosomes and lysosomes) in aged neurons and the aged brain, which might drive synaptic decline since lysosomes are a cellular aging target and relevant for synapses. Neuronal aging induces enlarged endolysosome accumulation in the aged neurons and brain, especially distally, related to the increased anterograde movement. Aged lysosomes abound in neurites but are less degradative due to deacidification despite cathepsin D buildup, leading to late-endosome accumulation. Increasing the acidification of aged lysosomes by ML-SA1 treatment increased degradation and reverted synaptic decline, while lysosome alkalinization by chloroquine treatment mimicked age-dependent lysosome dysfunction and synaptic decline. We identify the deacidification of distal lysosomes as a neuronal mechanism of age-dependent synapse loss. Our findings suggest that future therapeutic strategies to address lysosomal defects might be able to delay age-related synaptic decline.

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Rab2 drives axonal transport of dense core vesicles and lysosomal organelles

Cited by 9 publications

References 76 publications

Defective axonal transport of endo‐lysosomes and dense core vesicles in a Drosophila model of C9‐ALS/FTD

Defective axonal transport of endo‐lysosomes and dense core vesicles in a Drosophila model of C9‐ALS/FTD

A local insulin reservoir ensures developmental progression in condition of nutrient shortage in Drosophila

Deacidification of distal lysosomes by neuronal aging drives synapse loss

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