HTT (huntingtin) and RAB7 co-migrate retrogradely on a signaling LAMP1-containing late endosome during axonal injury

Krzystek, Thomas J.; White, Joseph A.; Rathnayake, P. G. R. G.; Thurston, Layne; Hoffmar-Glennon, Hayley; Li, Yichen; Gunawardena, Shermali

doi:10.1080/15548627.2022.2119351

Cited by 4 publications

(4 citation statements)

References 135 publications

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“…Further, immunoblot bands in Fig. 3C and D showed that Ace Pg3G treatment significantly up-regulated the expression of LAMP1 protein (lysosome-associated membrane protein 1), a lysosomal marker protein, 55,56 indicating that it caused an increase in the number of lysosomes in L02 cells, which might increase the capacity of lysosome to degrade lipids. The degradation of macromolecules such as proteins, nucleic acids, lipids, and damaged organelles by lysosomes is dependent on the action of hydrolases, most common of which is Cathepsin D (CTSD).…”

Section: Resultsmentioning

confidence: 91%

Acetylated pelargonidin-3-O-glucoside alleviates hepatocyte lipid deposition through activating the AMPK-mediated lysosome-autophagy pathway and redox state

Xie,

Hao,

Xie

et al. 2024

Food Funct.

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Section: Resultsmentioning

confidence: 91%

Acetylated pelargonidin-3-O-glucoside alleviates hepatocyte lipid deposition through activating the AMPK-mediated lysosome-autophagy pathway and redox state

Xie,

Hao,

Xie

et al. 2024

Food Funct.

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“…Expression of pathogenic HTT ex1 in Drosophila also showed HTT accumulation [15,27], decreased locomotion of adult flies, and decreased longevity [27]. Axonal transport defects and neuronal cell death were also seen in pathogenic HTT ex1 expressing larvae [18,26,28] (Figure 2). Larval segmental nerves from HTT.72Q ex1 or HTT.103Q ex1 expressing larvae show decreased mitochondria surface areas in contrast to larvae expressing non-pathogenic HTT ex1 (p = 0.031 and p = 0.020, respectively) (Figure 1B), indicating that the expression of pathogenic HTT ex1 is sufficient to cause mitochondria fragmentation.…”

Section: Excess Pathogenic Huntingtin Causes Mitochondrial Fragmentat...mentioning

confidence: 92%

“…Expression of pathogenic caspase-cleaved HTT (HTT.138Q C ) caused HTT accumulations, decreased lifespan of adult flies, and decreased crawling ability in larvae compared to normal caspase-cleaved HTT (HTT.15Q C ) [13]. HTT.138Q C expressing larvae also contained axonal blockages in their segmental nerves and neuronal cell death in their brains [26,28] (Figure 2). Fragmented mitochondria with significant decreases in mitochondrial surface areas (p = 0.011) and diameters (p = 0.030) were also seen in HTT.138Q C larval nerves compared to HTT.15Q C larval nerves (Figure 1C).…”

Section: Excess Pathogenic Huntingtin Causes Mitochondrial Fragmentat...mentioning

confidence: 99%

PolyQ-Expansion Causes Mitochondria Fragmentation Independent of Huntingtin and Is Distinct from Traumatic Brain Injury (TBI)/Mechanical Stress-Mediated Fragmentation Which Results from Cell Death

Swinter,

Salah,

Rathnayake

et al. 2023

Cells

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Mitochondrial dysfunction has been reported in many Huntington’s disease (HD) models; however, it is unclear how these defects occur. Here, we test the hypothesis that excess pathogenic huntingtin (HTT) impairs mitochondrial homeostasis, using Drosophila genetics and pharmacological inhibitors in HD and polyQ-expansion disease models and in a mechanical stress-induced traumatic brain injury (TBI) model. Expression of pathogenic HTT caused fragmented mitochondria compared to normal HTT, but HTT did not co-localize with mitochondria under normal or pathogenic conditions. Expression of pathogenic polyQ (127Q) alone or in the context of Machado Joseph Disease (MJD) caused fragmented mitochondria. While mitochondrial fragmentation was not dependent on the cellular location of polyQ accumulations, the expression of a chaperone protein, excess of mitofusin (MFN), or depletion of dynamin-related protein 1 (DRP1) rescued fragmentation. Intriguingly, a higher concentration of nitric oxide (NO) was observed in polyQ-expressing larval brains and inhibiting NO production rescued polyQ-mediated fragmented mitochondria, postulating that DRP1 nitrosylation could contribute to excess fission. Furthermore, while excess PI3K, which suppresses polyQ-induced cell death, did not rescue polyQ-mediated fragmentation, it did rescue fragmentation caused by mechanical stress/TBI. Together, our observations suggest that pathogenic polyQ alone is sufficient to cause DRP1-dependent mitochondrial fragmentation upstream of cell death, uncovering distinct physiological mechanisms for mitochondrial dysfunction in polyQ disease and mechanical stress.

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“…In axons, Rab7 also localizes to late endosomes and autophagic vesicles, which progressively increase degradative capacity as they localize more proximally [ 52 , 53 , 54 , 55 , 56 ], though retrograde Rab7 late endosome and autophagosome maturation progress independently of one another [ 57 ]. Many studies in numerous model systems have characterized the trafficking dynamics of axonal Rab7-positive endosomes and demonstrated that they undergo long-range trafficking within axons, often with retrograde bias, which coincides with their endosomal and autophagosomal maturation [ 48 , 54 , 58 , 59 , 60 , 61 , 62 ]. Notably, Rab7-mediated retrograde traffic is also seen within sensory neurons, where Rab7 co-traffics with distally internalized axonal neurotrophin receptors [ 63 ].…”

Section: Physiologic Control Of Rab7 In Neuronal Trafficking and Trop...mentioning

confidence: 99%

Regulation of Endosomal Trafficking by Rab7 and Its Effectors in Neurons: Clues from Charcot–Marie–Tooth 2B Disease

Mulligan,

Winckler

2023

Biomolecules

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Intracellular endosomal trafficking controls the balance between protein degradation and synthesis, i.e., proteostasis, but also many of the cellular signaling pathways that emanate from activated growth factor receptors after endocytosis. Endosomal trafficking, sorting, and motility are coordinated by the activity of small GTPases, including Rab proteins, whose function as molecular switches direct activity at endosomal membranes through effector proteins. Rab7 is particularly important in the coordination of the degradative functions of the pathway. Rab7 effectors control endosomal maturation and the properties of late endosomal and lysosomal compartments, such as coordination of recycling, motility, and fusion with downstream compartments. The spatiotemporal regulation of endosomal receptor trafficking is particularly challenging in neurons because of their enormous size, their distinct intracellular domains with unique requirements (dendrites vs. axons), and their long lifespans as postmitotic, differentiated cells. In Charcot–Marie–Tooth 2B disease (CMT2B), familial missense mutations in Rab7 cause alterations in GTPase cycling and trafficking, leading to an ulcero-mutilating peripheral neuropathy. The prevailing hypothesis to account for CMT2B pathologies is that CMT2B-associated Rab7 alleles alter endocytic trafficking of the neurotrophin NGF and its receptor TrkA and, thereby, disrupt normal trophic signaling in the peripheral nervous system, but other Rab7-dependent pathways are also impacted. Here, using TrkA as a prototypical endocytic cargo, we review physiologic Rab7 effector interactions and control in neurons. Since neurons are among the largest cells in the body, we place particular emphasis on the temporal and spatial regulation of endosomal sorting and trafficking in neuronal processes. We further discuss the current findings in CMT2B mutant Rab7 models, the impact of mutations on effector interactions or balance, and how this dysregulation may confer disease.

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HTT (huntingtin) and RAB7 co-migrate retrogradely on a signaling LAMP1-containing late endosome during axonal injury

Cited by 4 publications

References 135 publications

Acetylated pelargonidin-3-O-glucoside alleviates hepatocyte lipid deposition through activating the AMPK-mediated lysosome-autophagy pathway and redox state

Acetylated pelargonidin-3-O-glucoside alleviates hepatocyte lipid deposition through activating the AMPK-mediated lysosome-autophagy pathway and redox state

PolyQ-Expansion Causes Mitochondria Fragmentation Independent of Huntingtin and Is Distinct from Traumatic Brain Injury (TBI)/Mechanical Stress-Mediated Fragmentation Which Results from Cell Death

Regulation of Endosomal Trafficking by Rab7 and Its Effectors in Neurons: Clues from Charcot–Marie–Tooth 2B Disease

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