Dysregulation of lysosomal morphology by pathogenic LRRK2 is corrected by two-pore channel 2 inhibition

Hockey, Leanne N.; Kilpatrick, Bethan S.; Eden, Emily R.; Lin-Moshier, Yaping; Brailoiu, G. Cristina; Brǎiloiu, Eugen; Futter, Clare E.; Schapira, Anthony H.V.; Marchant, Jonathan S.; Patel, Sandip

doi:10.1242/jcs.164152

Cited by 159 publications

(198 citation statements)

References 44 publications

(57 reference statements)

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“…This mutation manifests with defects in the autophagy/lysosomal degradation pathway (Hockey et al, 2015; Manzoni & Lewis, 2013). We found that in LRRK2 knockout mouse cortical astrocytes the percentage of polyP‐containing lysosomes was significantly decreased (Figure 2c,d; 0.19 ± 0.01, n = 51 for wildtype compared to 0.13 ± 0.02, n = 54 for LRRK2 knockout cultures; p < .001).…”

Section: Resultsmentioning

confidence: 99%

Signal transduction in astrocytes: Localization and release of inorganic polyphosphate

Angelova

Iversen

Teschemacher

et al. 2018

Glia

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Inorganic polyphosphate (polyP) is present in every cell and is highly conserved from primeval times. In the mammalian cells, polyP plays multiple roles including control of cell bioenergetics and signal transduction. In the brain, polyP mediates signaling between astrocytes via activation of purinergic receptors, however, the mechanisms of polyP release remain unknown. Here we report identification of polyP‐containing vesicles in cortical astrocytes and the main triggers that evoke vesicular polyP release. In cultured astrocytes, polyP was localized predominantly within the intracellular vesicular compartments which express vesicular nucleotide transporter VNUT (putative ATP‐containing vesicles), but not within the compartments expressing vesicular glutamate transporter 2 (VGLUT2). The number of lysosomes which contain polyP was dependent on the conditions of astrocytes. Release of polyP from a proportion of lysosomes could be induced by calcium ionophores. In contrast, polyP release from the VNUT‐containing vesicles could be triggered by various physiological stimuli, such as pH changes, polyP induced polyP release and other stimuli which increase [Ca2+]i. These data suggest that astrocytes release polyP predominantly via exocytosis from the VNUT‐containing vesicles. © 2018 Wiley Periodicals, Inc.

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Section: Resultsmentioning

confidence: 99%

Signal transduction in astrocytes: Localization and release of inorganic polyphosphate

Angelova

Iversen

Teschemacher

et al. 2018

Glia

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“…87 In fact, a recent report evidenced altered lysosome morphology in fibroblasts from patients with the common G2019S mutation in LRRK2 (also known as PKR8), which causes an autosomal dominant form of the disease. 46 Patients with this mutation present an endolysosomal system morphology markedly disrupted and characterized by clumped and swollen lysosomes, which could reflect a trafficking defect within the endolysosomal system. 46 Defects in LRRK2…”

Section: Parkinson's Diseasementioning

confidence: 99%

“…46 Patients with this mutation present an endolysosomal system morphology markedly disrupted and characterized by clumped and swollen lysosomes, which could reflect a trafficking defect within the endolysosomal system. 46 Defects in LRRK2…”

Section: Parkinson's Diseasementioning

confidence: 99%

“…46 Such interactions suggest that TPC2 acts downstream of pathogenic LRRK2 to regulate trafficking within the endolysosomal system in a pathway of potential relevance to the pathology of LRRK2-mediated Parkinson disease; and this interactions are of potential therapeutic relevance to Parkinson disease, although it is not yet known whether TPCs deregulate trafficking in neurons. 46 …”

Section: G2019smentioning

confidence: 99%

“…42 As well, recent studies have suggested their possible implication in the pathogenesis of Alzheimer disease, 36 46 Thus, TPCs have become attractive therapeutic targets, although it is necessary to go deeper into their main functions and mechanisms of action not only to clinically relevant compounds could be designed but also to understand the pathophysiology of an increased wide range of diseases related to TPCs function/dysfunction.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Two-pore channels (TPCs): Novel voltage-gated ion channels with pleiotropic functions

Feijóo‐Bandín¹,

García-Vence²,

García-Rúa³

et al. 2016

Channels

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Two-pore channels (TPC1-3) comprise a subfamily of the eukaryotic voltage-gated ion channels (VGICs) superfamily that are mainly expressed in acidic stores in plants and animals. TPCS are widespread across the animal kingdom, with primates, mice and rats lacking TPC3, and mainly act as Ca C and Na C channels, although it was also suggested that they could be permeable to other ions. Nowadays, TPCs have been related to the development of different diseases, including Parkinsons disease, obesity or myocardial ischemia. Due to this, their study has raised the interest of the scientific community to try to understand their mechanism of action in order to be able to develop an efficient drug that could regulate TPCs activity. In this review, we will provide an updated view regarding TPCs structure, function and activation, as well as their role in different pathophysiological processes.

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LRRK2 and Parkinson's disease: from genetics to targeted therapy

Sosero

Gan‐Or

2023

Ann Clin Transl Neurol

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LRRK2 variants are implicated in both familial and sporadic PD. LRRK2-PD has a generally benign clinical presentation and variable pathology, with inconsistent presence of Lewy bodies and marked Alzheimer's disease pathology. The mechanisms underlying LRRK2-PD are still unclear, but inflammation, vesicle trafficking, lysosomal homeostasis, and ciliogenesis have been suggested, among others. As novel therapies targeting LRRK2 are under development, understanding the role and function of LRRK2 in PD is becoming increasingly important. Here, we outline the epidemiological, pathophysiological, and clinical features of LRRK2-PD, and discuss the arising therapeutic approaches targeting LRRK2 and possible future directions for research.

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Dysregulation of lysosomal morphology by pathogenic LRRK2 is corrected by two-pore channel 2 inhibition

Cited by 159 publications

References 44 publications

Signal transduction in astrocytes: Localization and release of inorganic polyphosphate

Signal transduction in astrocytes: Localization and release of inorganic polyphosphate

Two-pore channels (TPCs): Novel voltage-gated ion channels with pleiotropic functions

LRRK2 and Parkinson's disease: from genetics to targeted therapy

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