CHP1 reduction ameliorates spinal muscular atrophy pathology by restoring calcineurin activity and endocytosis

Janzen, Eva; Mendoza-Ferreira, Natalia; Hosseinibarkooie, Seyyedmohsen; Schneider, Svenja; Hupperich, Kristina; Tschanz, Theresa; Grysko, Vanessa; Rießland, Markus; Hammerschmidt, Matthias; Rigo, Frank; Bennett, C. Frank; Kye, Min Jeong; Torres-Benito, Laura; Wirth, Brunhilde

doi:10.1093/brain/awy167

Cited by 48 publications

(54 citation statements)

References 73 publications

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“…Elucidation of the specific cellular deficits underlying Stasimon-dependent motor circuit pathology in SMA will require greater knowledge of the full breadth of Stasimon functions. It will also need to integrate previous, seemingly unrelated, findings linking dysregulation of endocytosis (Ackermann et al, 2013;Hosseinibarkooie et al, 2016;Janzen et al, 2018;Riessland et al, 2017) and UBA1/ GARS-dependent pathways (Shorrock et al, 2018) to the loss of SMA proprioceptive synapses into a coherent model. In summary, our work identifies Stasimon as a determinant of defective synaptic connectivity and function in the SMA sensorymotor circuit as well as an upstream trigger of a signaling cascade that feeds into p53 and the motor neuron cell death pathway through p38 MAPK activation.…”

Section: Discussionmentioning

confidence: 99%

Stasimon Contributes to the Loss of Sensory Synapses and Motor Neuron Death in a Mouse Model of Spinal Muscular Atrophy

et al. 2019

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Section: Discussionmentioning

confidence: 99%

Stasimon Contributes to the Loss of Sensory Synapses and Motor Neuron Death in a Mouse Model of Spinal Muscular Atrophy

et al. 2019

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“…Elucidation of the downstream molecular mechanisms underlying dysfunction and loss of proprioceptive synapses in SMA will require greater knowledge of the full breadth of Stasimon functions. It will also need to integrate previous, seemingly unrelated findings implicating dysregulation of endocytosis (Ackermann et al, 2013;Hosseinibarkooie et al, 2016;Janzen et al, 2018;Riessland et al, 2017) and UBA1/GARS-dependent pathways (Shorrock et al, 2018) in the loss of SMA proprioceptive synapses into a coherent model.…”

Section: Discussionmentioning

confidence: 99%

Stasimon contributes to the loss of sensory synapses and motor neuron death in a mouse model of spinal muscular atrophy

Simon

Alstyne

Lotti

et al. 2019

Preprint

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Reduced expression of the SMN protein causes spinal muscular atrophy (SMA) -an inherited neurodegenerative disease characterized by multiple synaptic deficits and motor neuron loss. Here, we show that AAV9-mediated delivery of Stasimon -a gene encoding an ER-resident transmembrane protein regulated by SMN -improves motor function in a mouse model of SMA through multiple mechanisms. In proprioceptive neurons of SMA mice, Stasimon overexpression prevents the loss of afferent synapses on motor neurons and enhances sensory-motor neurotransmission. In SMA motor neurons, Stasimon suppresses the neurodegenerative process by selectively reducing phosphorylation but not upregulation of the tumor suppressor p53, both of which are converging events required to trigger neuronal death. We further show that Stasimon deficiency synergizes with SMA-related mechanisms of p53 upregulation to induce phosphorylation of p53. These findings identify Stasimon dysfunction induced by SMN deficiency as an upstream driver of cellular pathways that lead to synaptic loss and motor neuron degeneration, revealing a dual contribution of Stasimon to motor circuit pathology in SMA.

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“…The gene NCALD encoding neurocalcin delta (NCALD), which belongs to the subfamily of helix‐loop‐helix calcium‐binding proteins 8 and often plays roles in diet‐induced obesity, 9 spinal muscular atrophy, 10 neurocognitive disabilities, 11 and other diseases. The association of NCALD with cancer is obscure; few studies have implicated this gene in autophagy, the S phase of the cell cycle, transduction, apoptosis, and cell cycle progression in several cancers 12,13 .…”

Section: Introductionmentioning

confidence: 99%

NCALD affects drug resistance and prognosis by acting as a ceRNA of CX3CL1 in ovarian cancer

Dong

Yin

Zhu

et al. 2020

J of Cellular Biochemistry

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Drug resistance, an impenetrable barrier in the treatment of ovarian cancer (OC), is often associated with poor outcomes. Hence, it is urgent to discover new factors controlling drug resistance and survival. The association between neurocalcin delta (NCALD) and cancer drug resistance is poorly understood. Here, we reveal that NCALD messenger RNA expression, probably regulated by DNA methylation and microRNAs, was significantly downregulated in at least three independent microarrays covering 633 ovarian carcinomas and 16 normal controls, which includes the Cancer Genome Atlas (TCGA) ovarian cohort. In the sub‐groups of the TCGA cohort, NCALD was suppressed in 90 platinum‐resistant tissues vs in 197 sensitive tissues. It is consistent with the quantitative reverse transcription polymerase chain reaction results revealing gene downregulation in carboplatin‐resistant SKOV3 and HeyA8 OC cells as compared with that in controls. Low expression of NCALD predicted poor overall survival (OS) in sub‐groups of 1656 patients, progression‐free survival (PFS) in 1435 patients, and post‐progression survival (PPS) in 782 patients according to Kaplan‐Meier plotter covering 1815 OC patients. Comprehensive bioinformatic analyses strongly implicated NCALD in the regulation of drug resistance, probably via competing for endogenous RNA (ceRNA) interactions with CX3CL1 and tumor immune‐microenvironment. NCALD acted as a ceRNA for CX3CL1 in 21 different cancers includes OC according to Starbase. These two genes negatively correlated with tumor purity and positively correlated with infiltration levels of neutrophils and dendritic cells in OC. The combined low expression of NCALD and CX3CL1 showed better prognosis potential for OS, PFS, and PPS in the 1815 OC patients than any of the individually tested genes. In summary, NCALD acts as a ceRNA for CX3CL1, and its downregulation may affect drug resistance and prognosis in OC. Thus, NCALD could be a new therapeutic target for anticancer therapy and a new biomarker for survival prediction in OC.

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CHP1 reduction ameliorates spinal muscular atrophy pathology by restoring calcineurin activity and endocytosis

Cited by 48 publications

References 73 publications

Stasimon Contributes to the Loss of Sensory Synapses and Motor Neuron Death in a Mouse Model of Spinal Muscular Atrophy

Stasimon Contributes to the Loss of Sensory Synapses and Motor Neuron Death in a Mouse Model of Spinal Muscular Atrophy

Stasimon contributes to the loss of sensory synapses and motor neuron death in a mouse model of spinal muscular atrophy

NCALD affects drug resistance and prognosis by acting as a ceRNA of CX3CL1 in ovarian cancer

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