Abnormal Golgi morphology and decreased COPI function in cells with low levels of SMN

Custer, Sara K.; Foster, J.N.; Astroski, Jacob W.; Androphy, Elliot J.

doi:10.1016/j.brainres.2018.11.005

Cited by 14 publications

(8 citation statements)

References 48 publications

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“…We believe that expression of α-COP is redistributing the low levels of SMN protein available and directing its ability to support motor neuron function. We recently showed that in motor neuron-like NSC-34 cells, SMN protein is absent from the growth cone following depletion of α-COP, indicating that α-COP expression is required for normal distribution of SMN, and echoing finding from a previous publication which reported that a portion of the SMN protein was sequestered in the trans-Golgi network following knockdown of α-COP [23,26].…”

Section: Discussionsupporting

confidence: 67%

“…In a zebrafish model of SMA, expression of these dilysine mutants was unable to restore normal motor neuron morphology [17]. However, not all SMN function is affected by this mutation as SMN with lysines 76, 77, 82 and 83 mutated to alanine (referred to as SMN ΔΔ) was able to restore Golgi morphology to normal in SMA patient fibroblasts despite its inability to bind α-COP [23]. To determine whether the dilysine motif was required the human SMN rescue of SMA disease pathology in the 5058 mouse model, we used site-directed mutagenesis to convert either lysine 76 and 77 (Δ76), lysine 82 and 83 (Δ82) or all four lysines to alanines SMN ΔΔ.…”

Section: Lentiviral-mediated Transgenic Expression Of Dilysine Mutantmentioning

confidence: 99%

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Interaction between alpha-COP and SMN ameliorates disease phenotype in a mouse model of spinal muscular atrophy

Custer

Astroski

et al. 2019

Biochemical and Biophysical Research Communications

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We report that expression of the α-COP protein rescues disease phenotype in a severe mouse model of Spinal Muscular Atrophy (SMA).. Lentiviral particles expressing α-COP were injected directly into the testes of genetically pure mouse strain of interest resulting in infection of the spermatagonial stem cells. α-COP was stably expressed in brain, skeletal muscle, and spinal cord without altering SMN protein levels. SMA mice transgenic for α-COP live significantly longer than their non-transgenic littermates, and showed increased body mass and normal muscle morphology at postnatal day 15. We previously reported that binding between SMN and α-COP is required for restoration of neurite outgrowth in cells lacking SMN, and we report similar finding here. Lentiviral-mediated transgenic expression of SMN where the dilysine domain in exon 2b was mutated was not able to rescue the SMA phenotype despite robust expression of the mutant SMN protein in brain, muscle and spinal cord. These results demonstrate that α-COP is a validated modifier of SMA disease phenotype in a mammalian, vertebrate model and is a potential target for development of future SMN-independent therapeutic interventions.

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Section: Discussionsupporting

confidence: 67%

Section: Lentiviral-mediated Transgenic Expression Of Dilysine Mutantmentioning

confidence: 99%

Interaction between alpha-COP and SMN ameliorates disease phenotype in a mouse model of spinal muscular atrophy

Custer

Astroski

et al. 2019

Biochemical and Biophysical Research Communications

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“…SMN (survival of motor neurons) proteins are ubiquitously expressed and have been involved in different functions, including snRNP transport, nuclear RNA splicing and profilin and actin-dependent axonal transport [142]. Interestingly, SMN proteins bind the coatomer subunit α-COP [143] and low levels of SMN proteins affect COPI-dependent ER-Golgi transport [144]. Fibroblasts from SMA patients have an altered Golgi, a morphology that can be rescued by over-expression of α-COP or SMN proteins [144].…”

Section: Lessons From Other Neurodegenerative Diseasesmentioning

confidence: 99%

“…Interestingly, SMN proteins bind the coatomer subunit α-COP [143] and low levels of SMN proteins affect COPI-dependent ER-Golgi transport [144]. Fibroblasts from SMA patients have an altered Golgi, a morphology that can be rescued by over-expression of α-COP or SMN proteins [144]. Thus, Golgi alteration in SMA samples could be due to suboptimal α-COP functioning.…”

Section: Lessons From Other Neurodegenerative Diseasesmentioning

confidence: 99%

Golgi Fragmentation in Neurodegenerative Diseases: Is There a Common Cause?

Martı́nez-Menárguez

Tomàs

Martínez-Martínez

et al. 2019

Cells

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In most mammalian cells, the Golgi complex forms a continuous ribbon. In neurodegenerative diseases, the Golgi ribbon of a specific group of neurons is typically broken into isolated elements, a very early event which happens before clinical and other pathological symptoms become evident. It is not known whether this phenomenon is caused by mechanisms associated with cell death or if, conversely, it triggers apoptosis. When the phenomenon was studied in diseases such as Parkinson’s and Alzheimer’s or amyotrophic lateral sclerosis, it was attributed to a variety of causes, including the presence of cytoplasmatic protein aggregates, malfunctioning of intracellular traffic and/or alterations in the cytoskeleton. In the present review, we summarize the current findings related to these and other neurodegenerative diseases and try to search for clues on putative common causes.

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“…Additionally, COPI, through its subunit α-COP, binds with survival motor neuron protein (SMN), which is deficient in spinal muscular atrophy (SMA) and is involved in its axonal transport [59]. Furthermore, SMA patients show abnormal Golgi apparatus morphology which can be corrected by overexpression of α-COP [60].…”

Section: Discussionmentioning

confidence: 99%

Biallelic variants in COPB1 cause a novel, severe intellectual disability syndrome with cataracts and variable microcephaly

et al. 2021

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Background Coat protein complex 1 (COPI) is integral in the sorting and retrograde trafficking of proteins and lipids from the Golgi apparatus to the endoplasmic reticulum (ER). In recent years, coat proteins have been implicated in human diseases known collectively as “coatopathies”. Methods Whole exome or genome sequencing of two families with a neuro-developmental syndrome, variable microcephaly and cataracts revealed biallelic variants in COPB1, which encodes the beta-subunit of COPI (β-COP). To investigate Family 1’s splice donor site variant, we undertook patient blood RNA studies and CRISPR/Cas9 modelling of this variant in a homologous region of the Xenopus tropicalis genome. To investigate Family 2’s missense variant, we studied cellular phenotypes of human retinal epithelium and embryonic kidney cell lines transfected with a COPB1 expression vector into which we had introduced Family 2’s mutation. Results We present a new recessive coatopathy typified by severe developmental delay and cataracts and variable microcephaly. A homozygous splice donor site variant in Family 1 results in two aberrant transcripts, one of which causes skipping of exon 8 in COPB1 pre-mRNA, and a 36 amino acid in-frame deletion, resulting in the loss of a motif at a small interaction interface between β-COP and β’-COP. Xenopus tropicalis animals with a homologous mutation, introduced by CRISPR/Cas9 genome editing, recapitulate features of the human syndrome including microcephaly and cataracts. In vitro modelling of the COPB1 c.1651T>G p.Phe551Val variant in Family 2 identifies defective Golgi to ER recycling of this mutant β-COP, with the mutant protein being retarded in the Golgi. Conclusions This adds to the growing body of evidence that COPI subunits are essential in brain development and human health and underlines the utility of exome and genome sequencing coupled with Xenopus tropicalis CRISPR/Cas modelling for the identification and characterisation of novel rare disease genes.

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Abnormal Golgi morphology and decreased COPI function in cells with low levels of SMN

Cited by 14 publications

References 48 publications

Interaction between alpha-COP and SMN ameliorates disease phenotype in a mouse model of spinal muscular atrophy

Interaction between alpha-COP and SMN ameliorates disease phenotype in a mouse model of spinal muscular atrophy

Golgi Fragmentation in Neurodegenerative Diseases: Is There a Common Cause?

Biallelic variants in COPB1 cause a novel, severe intellectual disability syndrome with cataracts and variable microcephaly

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