Emerging nexus between RAB GTPases, autophagy and neurodegeneration

Jain, Navodita; Ganesh, Subramaniam

doi:10.1080/15548627.2016.1147673

Cited by 16 publications

(12 citation statements)

References 34 publications

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“…For instance, a form of hereditary spastic paraplegia linked to mutations in TECPR2, which regulates COPII-dependent vesicle formation (Stadel et al, 2015), has recently been shown to include progressive microcephaly among its symptoms (Heimer et al, 2016;Oz-Levi et al, 2012), although it is not yet known whether this is due to neurodevelopmental or neurodegenerative processes. As mentioned previously, several other ER/Golgi-associated RAB proteins such as RAB1, RAB11 and RAB24, are also involved in the regulation of autophagy, further highlighting the crosstalk, if not the overlap, between Golgi membrane trafficking and autophagy pathways (Jain and Ganesh, 2016) (Table I).…”

Section: Possible Mechanisms Underlying Postnatal Microcephalysupporting

confidence: 54%

“…Interestingly, the myelin membrane protein TPO1, which has also been proposed to activate Fyn, is highly enriched both in the Golgi and in the Fyn-positive sheets of myelinating oligodendrocytes (Fukazawa et al, 2006;Jain and Ganesh, 2016). Thus, the fine regulation of myelin formation and maintenance appear to depend on trafficking through the Golgidependent secretory pathway and microtubule network and signaling pathways in both oligodendrocytes and the neurons, and on their functional interactions at specific sites.…”

Section: Role Of the Golgi Apparatus Inmentioning

confidence: 99%

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Golgi trafficking defects in postnatal microcephaly: The evidence for “Golgipathies”

Passemard

Perez

Colin-Lemesre

et al. 2017

Progress in Neurobiology

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The Golgi apparatus plays a central role in cell homeostasis, not only in processing and maturing newly synthesized proteins and lipids but also in orchestrating their sorting, packing, routing and recycling on the way to their final destination. These multiple secretory pathways require a complex ballet of vesicular and tubular carriers that continuously bud off from donor membranes and fuse to acceptor membranes. Membrane trafficking is particularly prominent in axons, where cargo molecules have a long way to travel before they reach the synapse, and in oligodendrocytes, which require an immense increase in membrane surface in order to sheathe axons in myelin. Interestingly, in recent years, genes encoding Golgi-associated proteins with a role in membrane trafficking have been found to be defective in an increasing number of inherited disorders whose clinical manifestations include postnatal-onset microcephaly (POM), white matter defects and intellectual disability. Several of these genes encode RAB GTPases, RAB-effectors or RAB-regulating proteins, linking POM and intellectual disability to RAB-dependent Golgi trafficking pathways and suggesting that their regulation is critical to postnatal brain maturation and function. Here, we review the key roles of the Golgi apparatus in post-mitotic neurons and the oligodendrocytes that myelinate them, and provide an overview of these Golgi-associated POM-causing genes, their function in Golgi organization and trafficking and the likely mechanisms that may link dysfunctions in RAB-dependent regulatory pathways with POM.

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Section: Possible Mechanisms Underlying Postnatal Microcephalysupporting

confidence: 54%

Section: Role Of the Golgi Apparatus Inmentioning

confidence: 99%

Golgi trafficking defects in postnatal microcephaly: The evidence for “Golgipathies”

Passemard

Perez

Colin-Lemesre

et al. 2017

Progress in Neurobiology

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“…[15,70], we tentatively propose that the pre-degenerative state of crb mutant retinas is defined by reduced autophagosomal activity, which makes cells prone to degeneration upon increased light stress. Future work will reveal whether the displacement of the Arl8-positive compartments and morphological change in the Rab7-positive vesicles are associated with defects in the degradative machinery, which in turn promotes degeneration [71].…”

Section: Discussionmentioning

confidence: 99%

Changes in endolysosomal organization define a pre-degenerative state in thecrumbsmutantDrosophilaretina

Kraut

Knust

2019

Preprint

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Mutations in the epithelial polarity gene crumbs (crb) lead to retinal degeneration inDrosophila and in humans. The overall morphology of the retina and its deterioration in Drosophila crb mutants has been well-characterized, but the cell biological origin of the degeneration is not well understood. Degenerative conditions in the retina and elsewhere in the nervous system often involve defects in degradative intracellular trafficking pathways. So far, however, effects of crb on the endolysosomal system, or on the spatial organization of these compartments in photoreceptor cells have not been described. We therefore asked whether photoreceptors in crb mutants exhibit alterations in endolysosomal compartments under pre-degenerative conditions, where the retina is still morphologically intact. Data presented here show that, already well before the onset of degeneration, Arl8, Rab7, and Atg8-carrying endolysosomal and autophagosomal compartments undergo changes in morphology and positioning with respect to each other in crb mutant retinas. We propose that these changes may be early signs of the degeneration-prone condition in crb retinas.

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“…AVs including autophagosomes or autolysosmes abnormally accumulate in the affected neurons in several neurodegenerative diseases, such as Parkinson's disease (PD) (Dinter et al, 2016), Huntington's disease (HD), and Alzheimer's disease (AD) (Bucci and De Luca, 2012;Lee, 2012). More importantly, Rab7 has an indispensable role in maintaining neuronal function via its regulation of autophagy, further influencing the progress of neurodegenerative diseases (Jain and Ganesh, 2016).…”

Section: Rab7 and Neurologic Diseases Neurodegenerative Diseasesmentioning

confidence: 99%

Rab7 may be a novel therapeutic target for neurologic diseases as a key regulator in autophagy

Wen

Zhan

Chen

et al. 2017

J of Neuroscience Research

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Macroautophagy is an evolutionally conserved membrane trafficking pathway that delivers intracellular materials to lysosomes for degradation and recycling. Rab7, as a member of the Rab GTPase superfamily, has a unique role in the regulation of macroautophagy, especially in modulating autophagy flux. The functional states of Rab7 generally switch between GTP-bound and GDP-bound states under the control of guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). Activated GTP-Rab7 is capable of regulating autophagosome formation, autophagosome transportation along microtubules, endosome and autophagosome maturation, as well as lysosome biogenesis via interacting with its effector molecules. Rab7-mediated macroautophagy is closely associated with various pathological processes of several neurologic diseases, such as Parkinson's disease, Huntington's disease, Alzheimer's disease, Charcot-Marie-Tooth type 2B disease, and cerebral ischemic diseases. Considering that macroautophagy can be the prime therapeutic target in certain nervous system diseases, in-depth study of Rab7 in the regulation of macroautophagy may be helpful to identify novel strategies for the treatment of autophagy-related neurologic diseases. © 2017 Wiley Periodicals, Inc.

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Emerging nexus between RAB GTPases, autophagy and neurodegeneration

Cited by 16 publications

References 34 publications

Golgi trafficking defects in postnatal microcephaly: The evidence for “Golgipathies”

Golgi trafficking defects in postnatal microcephaly: The evidence for “Golgipathies”

Changes in endolysosomal organization define a pre-degenerative state in thecrumbsmutantDrosophilaretina

Rab7 may be a novel therapeutic target for neurologic diseases as a key regulator in autophagy

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