Neuronal endolysosomal transport and lysosomal functionality in maintaining axonostasis

Roney, Joseph C; Cheng, Xiu‐Tang; Sheng, Zu‐Hang

doi:10.1083/jcb.202111077

Cited by 47 publications

(40 citation statements)

References 166 publications

(289 reference statements)

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“…Spatacsin is present at these sites and its regulation of lysosomal repartition along the axon is concordant with this finding. Moreover, several recent papers have highlighted the importance of axonal lysosomal trafficking in the development of neurodegenerative disease (Lie and Nixon, 2019; Roney et al, 2022). In SPG11 models, previous work has shown that cultured neurons deprived of spatacsin presented axonal instability (Pérez-Brangulí et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

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Spatacsin regulates directionality of lysosome trafficking

Pierga

Matusiak

Cauhape

et al. 2022

Preprint

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The endoplasmic reticulum (ER) forms contacts with the lysosomal compartment, regulating lysosome positioning and motility. The movement of lysosomes are controlled by the attachment of molecular motors to their surface. However, the molecular mechanisms by which ER controls lysosome dynamics are still elusive. Here, we demonstrate that spatacsin is an ER-resident protein that regulates ER-lysosomes contacts to promote lysosome motility, shown by the presence of tubular lysosomes. Tubular lysosomes, which are highly dynamic, are entangled in a network of tubular ER. Screening for spatacsin partners required for tubular lysosome formation showed spatacsin to act by regulating protein degradation. We demonstrate that spatacsin promotes the degradation of its partner AP5Z1, which regulates the relative amount of spastizin and AP5Z1 at lysosomes. Spastizin and AP5Z1 contribute to lysosome trafficking by interacting with anterograde and retrograde motor proteins, kinesin KIF13A and dynein/dynactin subunit p150Glued, respectively. Ultimately, investigations in polarized neurons demonstrated that spatacsin-regulated degradation of AP5Z1 controls the directionality of lysosomes trafficking. Collectively, our results identify spatacsin as a protein regulating the directionality of lysosome trafficking.

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Section: Discussionmentioning

confidence: 99%

“…The coordination of this bidirectional transport is particularly important for polarized cells such as neurons. However, the mechanisms regulating the coordination of anterograde or retrograde transports of lysosomes are not clearly established (Roney et al, 2022).…”

Section: Introductionmentioning

confidence: 99%

Spatacsin regulates directionality of lysosome trafficking

Pierga

Matusiak

Cauhape

et al. 2022

Preprint

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“…Axons are insulated from extracellular fluid by several layers of myelin sheets formed by oligodendroglia that limit their access to extracellular glucose and lactate. Therefore, lactate is supplied by surrounding oligodendroglial processes through their MCT1 to peri-axonal space, from where it is taken up by axonal MCT2 and used for acetyl-CoA and ATP synthesis in axonal mitochondria [ 69 , 70 ]. Fractions of lactate and glucose are also provided by astrocytes that contact axons at nodes of Ranvier’s.…”

Section: Origin and Metabolic Role Of Axonal Acetyl-coamentioning

confidence: 99%

Metabolic and Cellular Compartments of Acetyl-CoA in the Healthy and Diseased Brain

Jankowska-Kulawy

Klimaszewska-Łata

Gul-Hinc

et al. 2022

IJMS

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The human brain is characterised by the most diverse morphological, metabolic and functional structure among all body tissues. This is due to the existence of diverse neurons secreting various neurotransmitters and mutually modulating their own activity through thousands of pre- and postsynaptic interconnections in each neuron. Astroglial, microglial and oligodendroglial cells and neurons reciprocally regulate the metabolism of key energy substrates, thereby exerting several neuroprotective, neurotoxic and regulatory effects on neuronal viability and neurotransmitter functions. Maintenance of the pool of mitochondrial acetyl-CoA derived from glycolytic glucose metabolism is a key factor for neuronal survival. Thus, acetyl-CoA is regarded as a direct energy precursor through the TCA cycle and respiratory chain, thereby affecting brain cell viability. It is also used for hundreds of acetylation reactions, including N-acetyl aspartate synthesis in neuronal mitochondria, acetylcholine synthesis in cholinergic neurons, as well as divergent acetylations of several proteins, peptides, histones and low-molecular-weight species in all cellular compartments. Therefore, acetyl-CoA should be considered as the central point of metabolism maintaining equilibrium between anabolic and catabolic pathways in the brain. This review presents data supporting this thesis.

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“…In innervated niches, autophagic stress caused by dysfunction of autophagosome-lysosome fusion is lethal to highly differentiated neurons ( Farfel-Becker et al, 2020 ). It is an indisputable fact that deficits in neuronal lysosome function and dysfunction of autophagy result in neurodegeneration ( Roney et al, 2022 ). Based on this, we hypothesize that blockage of the autophagy flux by chloroquine and hydroxychloroquine not only diminishes the positive effect in maintaining the innervated niche homeostasis but even leads to lethal autophagic stress.…”

Section: Drug Repurposing For Cancer Therapy: Targeting Autophagy In ...mentioning

confidence: 99%

Drug repurposing in cancer neuroscience: From the viewpoint of the autophagy-mediated innervated niche

Shi

et al. 2022

Front. Pharmacol.

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Based on the bidirectional interactions between neurology and cancer science, the burgeoning field “cancer neuroscience” has been proposed. An important node in the communications between nerves and cancer is the innervated niche, which has physical contact with the cancer parenchyma or nerve located in the proximity of the tumor. In the innervated niche, autophagy has recently been reported to be a double-edged sword that plays a significant role in maintaining homeostasis. Therefore, regulating the innervated niche by targeting the autophagy pathway may represent a novel therapeutic strategy for cancer treatment. Drug repurposing has received considerable attention for its advantages in cost-effectiveness and safety. The utilization of existing drugs that potentially regulate the innervated niche via the autophagy pathway is therefore a promising pharmacological approach for clinical practice and treatment selection in cancer neuroscience. Herein, we present the cancer neuroscience landscape with an emphasis on the crosstalk between the innervated niche and autophagy, while also summarizing the underlying mechanisms of candidate drugs in modulating the autophagy pathway. This review provides a strong rationale for drug repurposing in cancer treatment from the viewpoint of the autophagy-mediated innervated niche.

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Neuronal endolysosomal transport and lysosomal functionality in maintaining axonostasis

Cited by 47 publications

References 166 publications

Spatacsin regulates directionality of lysosome trafficking

Spatacsin regulates directionality of lysosome trafficking

Metabolic and Cellular Compartments of Acetyl-CoA in the Healthy and Diseased Brain

Drug repurposing in cancer neuroscience: From the viewpoint of the autophagy-mediated innervated niche

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