Spy1, a unique cell cycle regulator, alters viability in ALS motor neurons and cell lines in response to mutant SOD1-induced DNA damage

Wang, Xudong; Zhu, Minwei; Shan, Dan; Wang, Shuyu; Yin, Xiang; Yang, Yee‐Hong; Wang, Tianhang; Zhang, Chun‐Ting; Wang, Ying; Liang, Weiwei; Zhang, Jun; Jiang, Hai-Zhi; Dong, Guangtao; Jiang, Hongquan; Yan, Qi; Feng, Honglin

doi:10.1016/j.dnarep.2018.12.005

Cited by 15 publications

(21 citation statements)

References 73 publications

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“…We are therefore optimistic about Speedy/RINGO, a novel cell cycle regulatory protein proven to have a p53-dependent anti-apoptotic function in different cell types, including U2OS osteosarcoma cells [12] as well as calpain-induced degenerating primary hippocampal neurons [13] . In addition, Speedy/RINGO expression levels were shown to be substantially decreased in ALS motor neurons compared with wild-type controls [14] . By contrast, increased Speedy/RINGO expression enhanced cell viability and prevented the DNA damage response in ALS motor neurons.…”

Section: Resultsmentioning

confidence: 97%

“…In another recent study, Speedy/RINGO expression levels were shown to substantially decreased in ALS motor neurons compared with wild-type controls [14] . As a result of decreased Speedy/RINGO expression, reduction in cell viability and activation of the DNA damage response in SOD1 mutated cells was established.…”

Section: Speedy/ringo Protein Functions As An Anti-apoptotic Factor Imentioning

confidence: 89%

“…Speedy/RINGO has been shown to have a strong protective effect for mitotic cells exposed to extrinsic or intrinsic apoptotic factors such as UV irradiation. This anti-apoptotic function of Speedy/RINGO has also been utilized and confirmed in post-mitotic degenerating primary neurons [13] and in ALS motor neurons [14] . Speedy/RINGO performs this function by inhibiting caspase-3 activation and apoptosis in the presence of the gene regulatory protein p53 [12,13] .…”

Section: A Novel Cell Cycle Regulator Speedy/ringo As a Strong Candmentioning

confidence: 97%

“…The goal of our laboratory is to understand the pro-apoptotic mechanism of Ca 2+ deregulation and to prevent apoptosis by inhibiting the downstream effects of lethal Ca 2+ influx in neurons. To this effect, we are studying the novel cell cycle regulatory protein Speedy/RINGO due to its p53-dependent anti-apoptotic function which has previously been observed in U2OS osteosarcoma cells [12] , calpain-induced degenerating primary neurons [13] , ALS motor neurons [14] and astrocytes and microglia of spinal cord lesions [15] .…”

Section: Current Studies For the Recovery Of Scimentioning

confidence: 99%

“…Speedy/rapid inducer of G2/M progression in oocytes (Speedy/RINGO) is a cell cycle regulatory protein that increases survival of p53-positive mitotic cells by inhibiting the apoptotic machinery [12] . Moreover, this protein elicits p53-dependent anti-apoptotic effects on calpain-induced degenerating primary hippocampal neurons [13] , amyotrophic lateral sclerosis (ALS) motor neurons [14] and in astrocytes and microglia in spinal cord lesions [15] . In addition, evidence from breast and testis cancer studies strongly implicates the direct or indirect interaction of Speedy/RINGO as a p53-dependent anti-apoptotic factor for ERK/MAPK and PI3K/AKT pathways [16][17][18] .…”

Section: Introductionmentioning

confidence: 99%

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Speedy/RINGO: a molecular savior in spinal cord injury-based neurodegeneration?

Kaya¹,

Yıldız²

2019

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Endogenous or exogenous insults can cause spinal cord injury (SCI), often resulting in the loss of motor, autonomic, sensory and reflex functions. The pathogenesis of SCI comprises two stages. The primary injury stage occurs at the moment of trauma and is characterized by hemorrhage and rapid cell death. The secondary injury stage occurs due to progression of primary damage and is characterized by tissue loss and functional disorder. One of the most important cellular mechanisms underlying secondary injury is glutamate excitotoxicity, which overactivates the calpain protease via excessive Ca 2+ influx and induces neuronal apoptosis via p53 induction. Furthermore, Ca 2+ influx elicits apoptosis by inducing p53, thus negatively affecting two pathways: the mitogenic extracellular signal-regulated kinase/mitogenactivated protein kinase (ERK/MAPK) pathway and the survival phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) pathway. Speedy/rapid inducer of G2/M progression in oocytes (Speedy/RINGO) is a cell cycle regulatory protein that increases survival of p53-positive mitotic cells by inhibiting the apoptotic machinery. Moreover, this protein elicits p53dependent anti-apoptotic effects on calpain-induced degeneration of primary hippocampal neurons, amyotrophic lateral sclerosis motor neurons, and astrocytes and microglia in spinal cord lesions. The pathophysiology of SCI has not been fully elucidated and this hinders the development of powerful therapeutic strategies. This review focuses on the cellular mechanisms underlying the anti-apoptotic effects of Speedy/RINGO and discusses how this protective function can possibly be exploited to facilitate recovery from SCI. Particular attention is paid to reversal of the negative effects on the ERK/MAPK and PI3K/AKT pathways via induction of p53.

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Section: Resultsmentioning

confidence: 97%

Section: Speedy/ringo Protein Functions As An Anti-apoptotic Factor Imentioning

confidence: 89%

Section: A Novel Cell Cycle Regulator Speedy/ringo As a Strong Candmentioning

confidence: 97%

Section: Current Studies For the Recovery Of Scimentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Speedy/RINGO: a molecular savior in spinal cord injury-based neurodegeneration?

Kaya¹,

Yıldız²

2019

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DNA damage as a mechanism of neurodegeneration in ALS and a contributor to astrocyte toxicity

Kok

Palminha

Souza

et al. 2021

Cell. Mol. Life Sci.

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Increasing evidence supports the involvement of DNA damage in several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Elevated levels of DNA damage are consistently observed in both sporadic and familial forms of ALS and may also play a role in Western Pacific ALS, which is thought to have an environmental cause. The cause of DNA damage in ALS remains unclear but likely differs between genetic subgroups. Repeat expansion in the C9ORF72 gene is the most common genetic cause of familial ALS and responsible for about 10% of sporadic cases. These genetic mutations are known to cause R-loops, thus increasing genomic instability and DNA damage, and generate dipeptide repeat proteins, which have been shown to lead to DNA damage and impairment of the DNA damage response. Similarly, several genes associated with ALS including TARDBP, FUS, NEK1, SQSTM1 and SETX are known to play a role in DNA repair and the DNA damage response, and thus may contribute to neuronal death via these pathways. Another consistent feature present in both sporadic and familial ALS is the ability of astrocytes to induce motor neuron death, although the factors causing this toxicity remain largely unknown. In this review, we summarise the evidence for DNA damage playing a causative or secondary role in the pathogenesis of ALS as well as discuss the possible mechanisms involved in different genetic subtypes with particular focus on the role of astrocytes initiating or perpetuating DNA damage in neurons.

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