Disruption of axonal transport in neurodegeneration

Berth, Sarah H.; Lloyd, Thomas E.

doi:10.1172/jci168554

Cited by 27 publications

(18 citation statements)

References 195 publications

(249 reference statements)

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“…Microtubules (MT), comprised of α- and β-tubulin heterodimers, are one of the three main cytoskeleton components and serve as tracks for motor protein-based bidirectional transport of cargo [72,81]. Altered microtubule function in axons usually results in protein trafficking defects [6,13,38]. Tau pathology has been shown to affect microtubule dynamics and axonal transport due to the dissociation of Tau from microtubules [1].…”

Section: Resultsmentioning

confidence: 99%

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Loss of TMEM106B exacerbates Tau pathology and neurodegeneration in PS19 mice

Feng,

Du,

2023

Preprint

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TMEM106B, a gene encoding a lysosome membrane protein, is tightly associated with brain aging, hypomyelinating leukodystrophy, and multiple neurodegenerative diseases, including frontotemporal lobar degeneration with TDP-43 aggregates (FTLD-TDP). Recently,TMEM106Bpolymorphisms have been associated with tauopathy in chronic traumatic encephalopathy (CTE) and FTLD-TDP patients. However, how TMEM106B influences Tau pathology and its associated neurodegeneration, is unclear. Here we show that loss of TMEM106B enhances the accumulation of pathological Tau, especially in the neuronal soma in the hippocampus, resulting in severe neuronal loss in the PS19 Tau transgenic mice. Moreover,Tmem106b-/-PS19 mice develop significantly increased disruption of the neuronal cytoskeleton, autophagy-lysosomal function, and lysosomal trafficking along the axon as well as enhanced gliosis compared with PS19 andTmem106b-/-mice. Together, our findings demonstrate that loss of TMEM106B drastically exacerbates Tau pathology and its associated disease phenotypes, and provide new insights into the roles of TMEM106B in neurodegenerative diseases.

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Section: Resultsmentioning

confidence: 99%

“…Mutations in the Tau-encoding gene MAPT cause approximately 5% of FTLD cases [34]. Hyperphosphorylated and aggregated Tau due to mutation in the MAPT gene leads to microtubule disruption, axonal transport defects, neuroinflammation, neuronal loss, and cognitive deficits [1][2][3]6,12,16,18,78].…”

Section: Introductionmentioning

confidence: 99%

Loss of TMEM106B exacerbates Tau pathology and neurodegeneration in PS19 mice

Feng,

Du,

2023

Preprint

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“…Dysfunctional intracellular trafficking resulting from tubulin hyperacetylation provides a plausible mechanism contributing to the neurodegenerative effects of CNTNAP5 knockdown. Axonal transport defects are linked to several neurodegenerative diseases 36,37 .…”

Section: Discussionmentioning

confidence: 99%

Post-GWAS functional analyses ofCNTNAP5suggests its role in glaucomatous neurodegeneration

Chakraborty,

Sarma,

Roy

et al. 2024

Preprint

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Primary angle closure glaucoma (PACG) affects more than 20 million people worldwide, with an increased prevalence in south-east Asia. In a prior haplotype-based GWAS, we identified a novelCNTNAP5genic region, significantly associated with PACG. In the current study, we have extended our perception ofCNTNAP5involvement in glaucomatous neurodegeneration in a zebrafish model, through investigating phenotypic consequences pertinent to retinal degeneration upon knockdown of cntnap5 by translation-blocking morpholinos. While cntnap5 knockdown was successfully validated using an antibody, immunofluorescence followed by western blot analyses in cntnap5-morphant (MO) zebrafish revealed increased expression of acetylated tubulin indicative of perturbed cytoarchitecture of retinal layers. Moreover, significant loss of Nissl substance is observed in the neuro-retinal layers of cntnap5-MO zebrafish eye, indicating neurodegeneration. Additionally, in spontaneous movement behavioural analysis, cntnap5-MO zebrafish have a significantly lower average distance traversed in light phase compared to mismatch-controls, whereas no significant difference was observed in the dark phase, corroborating with vision loss in the cntnap5-MO zebrafish. This study provides the first direct functional evidence of a putative role ofCNTNAP5in visual neurodegeneration.

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“…This result is interesting as it shows that the decline in mitochondrial motility during ageing can be partly reversed in mammalian neurons, as demonstrated previously in ageing Drosophila neurons (Vagnoni & Bullock, 2018). Understanding the mechanisms behind the transport upregulation in older neurons might therefore be of therapeutic interest for age-dependent neurodegeneration when decline in cargo trafficking can play an important role in disease progression (Berth & Lloyd, 2023; Sleigh et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

Age-specific and compartment-dependent changes in mitochondrial homeostasis and cytoplasmic viscosity in mouse peripheral neurons

Sleigh,

Mattedi,

Richter

et al. 2023

Preprint

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Mitochondria are dynamic bioenergetic hubs that become compromised with age. In neurons, declining mitochondrial axonal transport has been associated with reduced cellular health. However, it is still unclear to what extent the decline of mitochondrial transport and function observed during ageing are coupled, and if somal and axonal mitochondria display compartment-specific features that make them more susceptible to the ageing process. It is also not known whether the biophysical state of the cytoplasm, thought to affect many cellular functions, changes with age to impact mitochondrial trafficking and homeostasis. Focusing on the mouse peripheral nervous system, we show that age-dependent decline in mitochondrial trafficking is accompanied by reduction of mitochondrial membrane potential and intra-mitochondrial viscosity, but not calcium buffering, in both somal and axonal mitochondria. Intriguingly, we observe a specific increase in cytoplasmic viscosity in the cell body, where mitochondria are most polarised, which correlates with decreased cytoplasmic diffusiveness. Our work provides a reference for studying the relationship between neuronal mitochondrial homeostasis and the viscoelasticity of the cytoplasm in a compartment-dependent manner during ageing.

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Disruption of axonal transport in neurodegeneration

Cited by 27 publications

References 195 publications

Loss of TMEM106B exacerbates Tau pathology and neurodegeneration in PS19 mice

Loss of TMEM106B exacerbates Tau pathology and neurodegeneration in PS19 mice

Post-GWAS functional analyses ofCNTNAP5suggests its role in glaucomatous neurodegeneration

Age-specific and compartment-dependent changes in mitochondrial homeostasis and cytoplasmic viscosity in mouse peripheral neurons

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