Role of synucleins in traumatic brain injury — An experimental in vitro and in vivo study in mice

Surgucheva, Irina; He, Shuangteng; Rich, Megan; Sharma, Ram; Ninkina, Natalia; Stahel, Philip F.; Surguchov, Andrei

doi:10.1016/j.mcn.2014.10.005

Cited by 36 publications

(28 citation statements)

References 76 publications

(89 reference statements)

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“…For example, increased α-synuclein immunoreactivity has been reported in motor neurons of rabbits after SCI (Sakurai et al, 2009). And, increased levels of α-, β- and γ-synuclein have been reported in cortical axons of mice and humans after TBI (Uryu et al, 2003; Uryu et al, 2007; Surgucheva et al, 2014). Furthermore, increased levels of α-synuclein have been observed in the brains and cerebral spinal fluid of TBI patients ranging from infants to adults (Uryu et al, 2007; Su et al, 2011; Mondello et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Reducing synuclein accumulation improves neuronal survival after spinal cord injury

Fogerson

Brummen

Busch

et al. 2016

Experimental Neurology

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Spinal cord injury causes neuronal death, limiting subsequent regeneration and recovery. Thus, there is a need to develop strategies for improving neuronal survival after injury. Relative to our understanding of axon regeneration, comparatively little is known about the mechanisms that promote the survival of damaged neurons. To address this, we took advantage of lamprey giant reticulospinal neurons whose large size permits detailed examination of post-injury molecular responses at the level of individual, identified cells. We report here that spinal cord injury caused a select subset of giant reticulospinal neurons to accumulate synuclein, a synaptic vesicle-associated protein best known for its atypical aggregation and causal role in neurodegeneration in Parkinson’s and other diseases. Post-injury synuclein accumulation took the form of punctate aggregates throughout the somata and occurred selectively in dying neurons, but not in those that survived. In contrast, another synaptic vesicle protein, synaptotagmin, did not accumulate in response to injury. We further show that the post-injury synuclein accumulation was greatly attenuated after single dose application of either the “molecular tweezer” inhibitor, CLR01, or a translation-blocking synuclein morpholino. Consequently, reduction of synuclein accumulation not only improved neuronal survival, but also increased the number of axons in the spinal cord proximal and distal to the lesion. This study is the first to reveal that reducing synuclein accumulation is a novel strategy for improving neuronal survival after spinal cord injury.

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Section: Discussionmentioning

confidence: 99%

Reducing synuclein accumulation improves neuronal survival after spinal cord injury

Fogerson

Brummen

Busch

et al. 2016

Experimental Neurology

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“…Site-specific acetylation of RelA at the Lys 310 residue was necessary to switch anti-apoptotic p50/RelA, activated after a brief preconditioning ischemia and leading to brain tolerance toward the pro-apoptotic p50/RelA activated after a prolonged harmful brain ischemia (Blondeau et al, 2001;Lanzillotta et al, 2010). In this regard, studies showing that post-stroke induction of α-syn mediates ischemic brain damage (Ishimaru et al, 1998;Hu et al, 2006;Yoon et al, 2006;Unal-Cevik et al, 2011;Surgucheva et al, 2014;Kim T. et al, 2016) and that the levels of oligomeric form of α-syn of red blood cells in ischemic stroke and PD patients are both significantly higher than in controls (Zhao et al, 2016), seem to shed light on a possible link between NF-κB dysregulation and α-syn accumulation that deserves to be addressed by ad hoc studies.…”

Section: Nf-κb Factors: Transcriptional Regulators Governing Neuroinfmentioning

confidence: 99%

Nuclear Factor-κB Dysregulation and α-Synuclein Pathology: Critical Interplay in the Pathogenesis of Parkinson’s Disease

Bellucci

Bubacco

Longhena

et al. 2020

Front. Aging Neurosci.

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The loss of dopaminergic neurons of the nigrostriatal system underlies the onset of the typical motor symptoms of Parkinson's disease (PD). Lewy bodies (LB) and Lewy neurites (LN), proteinaceous inclusions mainly composed of insoluble α-synuclein (α-syn) fibrils are key neuropathological hallmarks of the brain of affected patients. Compelling evidence supports that in the early prodromal phases of PD, synaptic terminal and axonal alterations initiate and drive a retrograde degeneration process culminating with the loss of nigral dopaminergic neurons. This notwithstanding, the molecular triggers remain to be fully elucidated. Although it has been shown that α-syn fibrillary aggregation can induce early synaptic and axonal impairment and cause nigrostriatal degeneration, we still ignore how and why α-syn fibrillation begins. Nuclear factor-κB (NF-κB) transcription factors, key regulators of inflammation and apoptosis, are involved in the brain programming of systemic aging as well as in the pathogenesis of several neurodegenerative diseases. The NF-κB family of factors consists of five different subunits (c-Rel, p65/RelA, p50, RelB, and p52), which combine to form transcriptionally active dimers. Different findings point out a role of RelA in PD. Interestingly, the nuclear content of RelA is abnormally increased in nigral dopamine (DA) neurons and glial cells of PD patients. Inhibition of RelA exert neuroprotection against (1-methyl-4-phenyl-1,2,3,6tetrahydropyridine) MPTP and 1-methyl-4-phenylpyridinium (MPP+) toxicity, suggesting that this factor decreases neuronal resilience. Conversely, the c-Rel subunit can exert neuroprotective actions. We recently described that mice deficient for c-Rel develop a PD-like motor and non-motor phenotype characterized by progressive brain α-syn accumulation and early synaptic changes preceding the frank loss of nigrostriatal neurons. This evidence supports that dysregulations in this transcription factors may be involved in the onset of PD. This review highlights observations supporting a possible interplay between NF-κB dysregulation and α-syn pathology in PD, with the aim to disclose novel potential mechanisms involved in the pathogenesis of this disorder.

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“…The direct involvement of two other members of the synuclein family in the pathogenesis of neurodegenerative diseases has not been confirmed, although gamma-synuclein-positive inclusions were found in autopsy material obtained from almost half of patients with amyotrophic lateral sclerosis (ALS) [8], and an increased expression of gamma-synuclein in transgenic mice leads to the development of a progressive neurodegenerative disease in the animals with predominant lesion of motor neurons, reproducing the clinical picture of ALS [4,7]. In addition, data obtained in the studies of the mechanisms of secondary lesions in traumatic brain injuries, a direction of research that is rapidly developing in recent years, showed the involvement of synucleins in a cascade of molecular and cellular events with the typical post-translation modifications of gamma-synuclein and changes in its compartmentalization in neurons and astrocytes [13]. It should be noted that the level of posttraumatic induction of this protein in the brains of animal models directly correlated with their age [15].…”

mentioning

confidence: 71%

“…Patients may present a pool of antibodies that Of independent interest are data on the detection of autoantibodies against gamma-synuclein in patients with chronic cerebral ischemia and osteochondrosis of the cervical spine. Possibly, the increase in the level of gamma-synuclein and its subsequent penetration into the bloodstream was caused by the disturbance of cerebral circulation in patients with local structural and functional brain injuries, as in the experimental animals in simulation of secondary damage after traumatic brain injury [13]. However, these assumptions require additional tests in larger representative samples and with the use of animal models.…”

mentioning

confidence: 99%

Detection of autoantibodies to potentially amyloidogenic protein, gamma-synuclein, in the serum of patients with amyotrophic lateral sclerosis and cerebral circulatory disorders

Roman

Ковражкина

Razinskaya

et al. 2017

Dokl Biochem Biophys

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In this study, we analyzed serum for the presence of antibodies to gamma-synuclein in patients with amyotrophic lateral sclerosis (ALS) compared to the control group of patients with other neurological diseases and healthy control donors. As a result, antibodies against gamma-synuclein are not an ALS-specific feature and have been identified in patients with ALS as well as in the control group patients. Patients with the impaired cerebral circulation showed increased incidence of autoantibodies to gamma-synuclein, yet the difference lacks statistical representativeness due to limited sample size.

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Role of synucleins in traumatic brain injury — An experimental in vitro and in vivo study in mice

Cited by 36 publications

References 76 publications

Reducing synuclein accumulation improves neuronal survival after spinal cord injury

Reducing synuclein accumulation improves neuronal survival after spinal cord injury

Nuclear Factor-κB Dysregulation and α-Synuclein Pathology: Critical Interplay in the Pathogenesis of Parkinson’s Disease

Detection of autoantibodies to potentially amyloidogenic protein, gamma-synuclein, in the serum of patients with amyotrophic lateral sclerosis and cerebral circulatory disorders

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