Cell Cycle Regulators in the Neuronal Death Pathway of Amyotrophic Lateral Sclerosis Caused by Mutant Superoxide Dismutase 1

Nguyen, Minh Dang; Boudreau, Mathieu; Križ, Jasna; Couillard‐Després, Sébastien; Kaplan, David R.; Julien, Jean‐Pierre

doi:10.1523/jneurosci.23-06-02131.2003

Cited by 150 publications

(128 citation statements)

References 71 publications

Supporting

Mentioning

120

Contrasting

Unclassified

Order By: Relevance

“…In vivo studies of cortical or spinal cord neurons after ischemia or excitotoxic-mediated DNA damage have shown the occurrence of apoptotic cell death associated with cyclin D1-cdk4, cyclin G, PCNA, or Rb͞E2F protein and mRNA overexpression (21)(22)(23)(24)(25). Inhibition of neuronal death, and improvement of functional recovery with flavopiridol treatment has been reported after brain ischemia in rats, although effects on glial and microglial cells were not addressed (39,40).…”

Section: Discussionmentioning

confidence: 99%

“…Cell cycle induction leading to apoptotic neuronal death has been described in vitro (15)(16)(17)(18)(19)(20) and in vivo, including animal models of stroke, amyotrophic lateral sclerosis, and Alzheimer's disease (12,(21)(22)(23)(24)(25). Although aberrant cell cycle activation can lead to apoptosis in postmitotic cells, cell cycle transition can also induce proliferation in mitotic cells such as astrocytes and microglia after brain ischemia (26,27).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Cell cycle inhibition provides neuroprotection and reduces glial proliferation and scar formation after traumatic brain injury

Giovanni

Movsesyan²,

Ahmed³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

350

311

View full text Add to dashboard Cite

Traumatic brain injury (TBI) causes neuronal apoptosis, inflammation, and reactive astrogliosis, which contribute to secondary tissue loss, impaired regeneration, and associated functional disabilities. Here, we show that up-regulation of cell cycle components is associated with caspase-mediated neuronal apoptosis and glial proliferation after TBI in rats. In primary neuronal and astrocyte cultures, cell cycle inhibition (including the cyclin-dependent kinase inhibitors flavopiridol, roscovitine, and olomoucine) reduced upregulation of cell cycle proteins, limited neuronal cell death after etoposide-induced DNA damage, and attenuated astrocyte proliferation. After TBI in rats, flavopiridol reduced cyclin D1 expression in neurons and glia in ipsilateral cortex and hippocampus. Treatment also decreased neuronal cell death and lesion volume, reduced astroglial scar formation and microglial activation, and improved motor and cognitive recovery. The ability of cell cycle inhibition to decrease both neuronal cell death and reactive gliosis after experimental TBI suggests that this treatment approach may be useful clinically.flavopiridol ͉ glial scar ͉ neuron ͉ trauma

show abstract

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Cell cycle inhibition provides neuroprotection and reduces glial proliferation and scar formation after traumatic brain injury

Giovanni

Movsesyan²,

Ahmed³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

350

311

View full text Add to dashboard Cite

show abstract

“…4.8 software, t nom is the nominal section thickness (of 30 mm in this study) and ssf is the fraction of the sections sampled or section sampling fraction (of 1/6 in this study). The volumes are reported as mm 3 . The subfield areas were delineated with a 2.5 Â objective lens.…”

Section: Methodsmentioning

confidence: 99%

“…1 In post-mitotic neurons, some pathological conditions upregulate cyclin D1/CDK4 complex expression to induce activation of E2F members that contributes to increased transcription of proapoptotic molecules. 2,3 However, it is unclear whether cyclin D1 expression directly induces neuronal death for a number of following reasons. First, due to a time lag between cyclin D1/CDK4 expression and the onset of DNA fragmentation, most cyclin D1-positive neurons show TUNEL negativity.…”

mentioning

confidence: 99%

LIM kinase-2 induces programmed necrotic neuronal death via dysfunction of DRP1-mediated mitochondrial fission

et al. 2014

View full text Add to dashboard Cite

Although the aberrant activation of cell cycle proteins has a critical role in neuronal death, effectors or mediators of cyclin D1/ cyclin-dependent kinase 4 (CDK4)-mediated death signal are still unknown. Here, we describe a previously unsuspected role of LIM kinase 2 (LIMK2) in programmed necrotic neuronal death. Downregulation of p27 Kip1 expression by Rho kinase (ROCK) activation induced cyclin D1/CDK4 expression levels in neurons vulnerable to status epilepticus (SE). Cyclin D1/CDK4 complex subsequently increased LIMK2 expression independent of caspase-3 and receptor interacting protein kinase 1 activity. In turn, upregulated LIMK2 impaired dynamic-related protein-1 (DRP1)-mediated mitochondrial fission without alterations in cofilin phosphorylation/expression and finally resulted in necrotic neuronal death. Inhibition of LIMK2 expression and rescue of DRP1 function attenuated this programmed necrotic neuronal death induced by SE. Therefore, we suggest that the ROCK-p27 Kip1 -cyclin D1/CDK4-LIMK2-DRP1-mediated programmed necrosis may be new therapeutic targets for neuronal death. The cell cycle is essential for a vital process, including proliferation, differentiation and survival of various cells. Cell cycle progression is regulated by two classes of proteins, the cyclins and the cyclin-dependent kinases (CDKs). Among them, cyclin D1 forms a complex with CDK4 and inactivates retinoblastoma protein (Rb) through phosphorylation resulting in activating E2 promoter-binding factor (E2F) family of transcription factors. Active E2F induces various gene transcriptions involving the cell cycle. 1 In post-mitotic neurons, some pathological conditions upregulate cyclin D1/CDK4 complex expression to induce activation of E2F members that contributes to increased transcription of proapoptotic molecules. 2,3 However, it is unclear whether cyclin D1 expression directly induces neuronal death for a number of following reasons. First, due to a time lag between cyclin D1/CDK4 expression and the onset of DNA fragmentation, most cyclin D1-positive neurons show TUNEL negativity. 4,5 Second, cyclin D1 level is unaltered in cultured embryonic neurons following apoptosis induction. 6 Third, Rb phosphorylation is rarely observed in vivo, 4 although cyclin D1/CDK4 complex phosphorylates Rb protein in apoptotic cultured neurons. 6 Fourth, cyclin D1 induction following ischemia is associated with regeneration and resistance to apoptosis rather than a mediator of apoptosis. 5,7,8 Fifth, effectors or mediators of cyclin D1/CDK4-mediated death signal are still unknown. Finally, neuronal death induced by various insults is morphologically necrotic rather than apoptotic. 9-12 Therefore, it is likely that some essential factors are missing in the cyclin D/CDK4-mediated neuronal death pathway.LIM kinases (LIMK1 and LIMK2) phosphorylate cofilin that is a stimulus-responsive mediator of actin dynamics. [13][14][15] Interestingly, non-phosphorylated cofilin targets mitochondrial membranes in response to apoptotic stimuli for cytochrome c releas...

show abstract

“…In those studies, it was suggested that cell cycle signaling may affect the neuronal death pathway (25,33). Thus we hypothesized that the cell cycle might be affected by mutated Cu,Zn-SOD in FALS.…”

mentioning

confidence: 93%

Overexpression of mutated Cu,Zn-SOD in neuroblastoma cells results in cytoskeletal change

Takamiya

Takahashi²,

Park³

et al. 2005

American Journal of Physiology-Cell Physiology

View full text Add to dashboard Cite

Amyotrophic lateral sclerosis (ALS) involves the progressive degeneration of motor neurons in the spinal cord and the motor cortex. It has been shown that 15–20% of patients with familial ALS (FALS) have defects in the Sod1 gene, which encodes Cu,Zn-superoxide dismutase (SOD). To elucidate the pathological role of mutated Cu,Zn-SOD, we examined the issue of whether mutated Cu,Zn-SOD affects the cell cycle. Mouse neuroblastoma Neuro-2a cells were transfected with human wild-type or mutated (G37R, G93A) Cu,Zn-SOD. Mutated, Cu,Zn-SOD-transfected cells exhibited marked retardation in cell growth and G2/M arrest. They also displayed lower reactivity to phalloidin, indicating that the cytoskeleton was disrupted. Immunoprecipitation, two-dimensional gel electrophoresis, and Western blot analysis indicated that mutated Cu,Zn-SOD associates with actin. Similar results were obtained by in vitro incubation experiments with purified actin and mutated Cu,Zn-SOD (G93A). These results suggest that mutated Cu,Zn-SOD in FALS causes cytoskeletal changes by associating with actin, which subsequently causes G2/M arrest and growth retardation.

show abstract

Cell Cycle Regulators in the Neuronal Death Pathway of Amyotrophic Lateral Sclerosis Caused by Mutant Superoxide Dismutase 1

Cited by 150 publications

References 71 publications

Cell cycle inhibition provides neuroprotection and reduces glial proliferation and scar formation after traumatic brain injury

Cell cycle inhibition provides neuroprotection and reduces glial proliferation and scar formation after traumatic brain injury

LIM kinase-2 induces programmed necrotic neuronal death via dysfunction of DRP1-mediated mitochondrial fission

Overexpression of mutated Cu,Zn-SOD in neuroblastoma cells results in cytoskeletal change

Contact Info

Product

Resources

About