Understanding how kinesin motor proteins regulate postsynaptic function in neuron

Fan, Ruolin; Lai, Kwok-On

doi:10.1111/febs.16285

Cited by 23 publications

(17 citation statements)

References 136 publications

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“…However, we posit that cytoplasmic SFPQ aggregates are likely to perturb the trafficking of GluA1-containing AMPARs in primary neurons. Our hypothesis is supported by the fact that SFPQ is present in AMPAR-containing vesicles purified from mouse whole brain lysates [ 43 ], and the demonstration that it also interacts with the motor protein KIF5 [ 18 ], which has previously been shown to regulate the dendritic transport of such vesicles [ 44 – 47 ]. Importantly, mutations in the KIF5A C-terminal cargo binding domain are associated with fALS [ 48 , 49 ].…”

Section: Discussionmentioning

confidence: 72%

Familial ALS-associated SFPQ variants promote the formation of SFPQ cytoplasmic aggregates in primary neurons

et al. 2022

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Splicing factor proline- and glutamine-rich (SFPQ) is a nuclear RNA-binding protein that is involved in a wide range of physiological processes including neuronal development and homeostasis. However, the mislocalization and cytoplasmic aggregation of SFPQ are associated with the pathophysiology of amyotrophic lateral sclerosis (ALS). We have previously reported that zinc mediates SFPQ polymerization and promotes the formation of cytoplasmic aggregates in neurons. Here we characterize two familial ALS (fALS)-associated SFPQ variants, which cause amino acid substitutions in the proximity of the SFPQ zinc-coordinating centre (N533H and L534I). Both mutants display increased zinc-binding affinities, which can be explained by the presence of a second zinc-binding site revealed by the 1.83 Å crystal structure of the human SFPQ L534I mutant. Overexpression of these fALS-associated mutants significantly increases the number of SFPQ cytoplasmic aggregates in primary neurons. Although they do not affect the density of dendritic spines, the presence of SFPQ cytoplasmic aggregates causes a marked reduction in the levels of the GluA1, but not the GluA2 subunit of AMPA-type glutamate receptors on the neuronal surface. Taken together, our data demonstrate that fALS-associated mutations enhance the propensity of SFPQ to bind zinc and form aggregates, leading to the dysregulation of AMPA receptor subunit composition, which may contribute to neuronal dysfunction in ALS.

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Section: Discussionmentioning

confidence: 72%

Familial ALS-associated SFPQ variants promote the formation of SFPQ cytoplasmic aggregates in primary neurons

et al. 2022

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“…However, we posit that cytoplasmic SFPQ aggregates are likely to perturb the trafficking of GluA1-containing AMPARs in primary neurons. Our hypothesis is supported by the fact that SFPQ is present in AMPAR-containing vesicles purified from mouse whole brain lysates [53], and the demonstration that it also interacts with the motor protein KIF5 [11], which has previously been shown to regulate the dendritic transport of such vesicles [54-57]. Importantly, mutations in the KIF5A C-terminal cargo binding domain are associated with fALS [58, 59].…”

Section: Discussionmentioning

confidence: 72%

Familial ALS-associated SFPQ variants promote the formation of SFPQ cytoplasmic aggregates that reduce surface AMPA receptor expression in primary neurons

Widagdo

Udagedara

Bhembre

et al. 2022

Preprint

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SFPQ is a nuclear RNA-binding protein that is involved in a wide range of physiological processes including neuronal development and homeostasis. However, the mislocalization and cytoplasmic aggregation of SFPQ are associated with the pathophysiology of amyotrophic lateral sclerosis (ALS). We have previously reported that zinc mediates SFPQ polymerization and promotes the formation of cytoplasmic aggregates in neurons. Here we characterize two familial ALS (fALS)-associated SFPQ variants, which cause amino acid substitutions in the proximity of the SFPQ zinc-coordinating center (N533H and L534I). Both mutants display increased zinc-binding affinities, which can be explained by the presence of a secondary zinc-binding site revealed by the 1.83Å crystal structure of the human SFPQ L534I mutant. Overexpression of these fALS-associated mutants significantly increases the number of SFPQ cytoplasmic aggregates in primary neurons. Although they do not affect the density of dendritic spines, the presence of SFPQ cytoplasmic aggregates causes a marked reduction in the levels of the GluA1, but not the GluA2 subunit of AMPA-type glutamate receptors on the neuronal surface. Taken together, our data demonstrate that fALS-associated mutations enhance the propensity of SFPQ to bind zinc and form aggregates, leading to the dysregulation of AMPA receptor subunit composition, which may contribute to neuronal dysfunction in ALS.

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“…Kinesins facilitate anterograde axonal transport of neurotransmitter receptors, mitochondria [reviewed in ( Fan and Lai, 2021 )], and also mRNAs [reviewed in ( Kanai et al, 2004 ; Turner-Bridger et al, 2020 )]. Remarkably, most kinesin mRNAs were depleted in proximal nerve segments at 24 h post-axotomy, except for members of the conventional kinesin-1 family Kif5a/b/c increased in males.…”

Section: Discussionmentioning

confidence: 99%

Sexually dimorphic transcriptional programs of early-phase response in regenerating peripheral nerves

Chernov

Shubayev

2022

Front. Mol. Neurosci.

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The convergence of transcriptional and epigenetic changes in the peripheral nervous system (PNS) reshapes the spatiotemporal gene expression landscape in response to nerve transection. The control of these molecular programs exhibits sexually dimorphic characteristics that remain not sufficiently characterized. In the present study, we recorded genome-wide and sex-dependent early-phase transcriptional changes in regenerating (proximal) sciatic nerve 24 h after axotomy. Male nerves exhibited more extensive transcriptional changes with male-dominant upregulation of cytoskeletal binding and structural protein genes. Regulation of mRNAs encoding ion and ionotropic neurotransmitter channels displayed prominent sexual dimorphism consistent with sex-specific mRNA axonal transport in an early-phase regenerative response. Protein kinases and axonal transport genes showed sexually dimorphic regulation. Genes encoding components of synaptic vesicles were at high baseline expression in females and showed post-injury induction selectively in males. Predictive bioinformatic analyses established patterns of sexually dimorphic regulation of neurotrophic and immune genes, including activation of glial cell line-derived neurotrophic factor Gfra1 receptor and immune checkpoint cyclin D1 (Ccnd1) potentially linked to X-chromosome encoded tissue inhibitor of matrix metallo proteinases 1 (Timp1). Regulatory networks involving Olig1, Pou3f3/Oct6, Myrf, and Myt1l transcription factors were linked to sex-dependent reprogramming in regenerating nerves. Differential expression patterns of non-coding RNAs motivate a model of sexually dimorphic nerve regenerative responses to injury determined by epigenetic factors. Combined with our findings in the corresponding dorsal root ganglia (DRG), unique early-phase sex-specific molecular triggers could enrich the mechanistic understanding of peripheral neuropathies.

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Understanding how kinesin motor proteins regulate postsynaptic function in neuron

Cited by 23 publications

References 136 publications

Familial ALS-associated SFPQ variants promote the formation of SFPQ cytoplasmic aggregates in primary neurons

Familial ALS-associated SFPQ variants promote the formation of SFPQ cytoplasmic aggregates in primary neurons

Familial ALS-associated SFPQ variants promote the formation of SFPQ cytoplasmic aggregates that reduce surface AMPA receptor expression in primary neurons

Sexually dimorphic transcriptional programs of early-phase response in regenerating peripheral nerves

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