Accumulation of <i>α</i>-Synuclein in Cerebellar Purkinje Cells of Diabetic Rats and Its Potential Relationship with Inflammation and Oxidative Stress Markers

Solmaz, Volkan; Ozlece, Hatice Kose; Eroğlu, Hüseyin Avni; Aktuğ, Hüseyin; Erbaş, Oytun; Taşkıran, Dilek

doi:10.1155/2017/5952149

Cited by 12 publications

(15 citation statements)

References 37 publications

(40 reference statements)

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“…Consistent with methods used in the previous reports (Nagayach et al, 2014;Razi et al;Sherif, 2017;Solmaz et al, 2017), our study showed that the intraperitoneal administration of STZ caused a clear-cut increase in blood and urine glucose levels, with common signs of diabetes, including body weight loss, polyphagia, polydipsia and polyuria, which was due to the diabetogenic action of STZ, thus inducing the degeneration in pancreatic Langerhans islet beta cells (Akbarzadeh et al, 2007).…”

Section: Discussionsupporting

confidence: 91%

Cerebellar Synaptopathy in Streptozotocin-Induced Diabetic Rats

et al. 2019

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There is an increasing amount of evidence that supports the diabetic complications of the central nervous system structure and function. The cerebellum, which is one of the primary structure derived from the hindbrain, plays an important role in motor control, motor coordination, and non-motor functions, such as cognitive processing. The synapse is a critical structure that regulates neuronal communication, and well-defined afferent and efferent fibre connections in the cerebellum help in maintaining the proper working order. Thus, the present study sought to investigate the long-term effects of diabetes-induced synaptopathy in the cerebellum, using both histological and ultrastructural studies. Twenty Sprague-Dawley male rats were divided randomly into control and diabetic groups, and diabetes was then induced through a single intraperitoneal injection of streptozotocin (60 mg/kg body weight). Six month later, the rats were sacrificed and the cerebellum was removed. Light and electron microscopic examinations showed a degeneration of Purkinje cells (Neuron purkinjense) with shrunken cells, pyknotic nuclei, and synaptopathy, including the reduction in synapse density, number of synaptic vesicles, and maturation of synapses in the molecular layer of diabetic cerebellum. The disruptions in synaptic profiles, which observed in the diabetic condition, could be related to cerebellar dysfunction, thus leading to the defects in coordinated movement, balance, as well as cognitive learning and memory.

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Section: Discussionsupporting

confidence: 91%

Cerebellar Synaptopathy in Streptozotocin-Induced Diabetic Rats

et al. 2019

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“…Impaired mitochondrial biogenesis, depolarization of mitochondrial membrane potential, and increased reactive oxygen species (ROS) have been reported in neuronal cells with IR [16]. In addition, diabetic rats exhibited increased SNCA in Purkinje cells [17]. Furthermore, several anti-glycemic agents, including exenatide, a glucagon-like peptide analogue, have exerted a disease-modifying effect on PD; exenatide is presently in phase III clinical trial as a neuroprotective drug for patients with PD [18,19].…”

Section: Introductionmentioning

confidence: 99%

Insulin Resistance Promotes Parkinson’s Disease through Aberrant Expression of α-Synuclein, Mitochondrial Dysfunction, and Deregulation of the Polo-Like Kinase 2 Signaling

Hong

Chen

Wang

et al. 2020

Cells

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Background: Insulin resistance (IR), considered a hallmark of diabetes at the cellular level, is implicated in pre-diabetes, results in type 2 diabetes, and negatively affects mitochondrial function. Diabetes is increasingly associated with enhanced risk of developing Parkinson’s disease (PD); however, the underlying mechanism remains unclear. This study investigated the probable culpability of IR in the pathogenesis of PD. Methods: Using MitoPark mice in vivo models, diabetes was induced by a high-fat diet in the in vivo models, and IR was induced by protracted pulse-stimulation with 100 nM insulin treatment of neuronal cells, in vitro to determine the molecular mechanism(s) underlying altered cellular functions in PD, including mitochondrial dysfunction and α-synuclein (SNCA) aberrant expression. Findings: We observed increased SNCA expression in the dopaminergic (DA) neurons of both the wild-type and diabetic MitoPark mice, coupled with enhanced degeneration of DA neurons in the diabetic MitoPark mice. Ex vivo, in differentiated human DA neurons, IR was associated with increased SNCA and reactive oxygen species (ROS) levels, as well as mitochondrial depolarization. Moreover, we demonstrated concomitant hyperactivation of polo-like kinase-2 (PLK2), and upregulated p-SNCA (Ser129) and proteinase K-resistant SNCA proteins level in IR SH-SY5Y cells, however the inhibition of PLK2 reversed IR-related increases in phosphorylated and total SNCA. Similarly, the overexpression of peroxisome proliferator-activated receptor-γ coactivator 1-alpha (PGC)-1α suppressed ROS production, repressed PLK2 hyperactivity, and resulted in downregulation of total and Ser129-phosphorylated SNCA in the IR SH-SY5Y cells. Conclusions: These findings demonstrate that IR-associated diabetes promotes the development and progression of PD through PLK2-mediated mitochondrial dysfunction, upregulated ROS production, and enhanced SNCA signaling, suggesting the therapeutic targetability of PLK2 and/or SNCA as potential novel disease-modifying strategies in patients with PD.

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“…α-Synuclein is a pre-synaptic protein involved in the regulation of exocytotic vesicles [33,67], and its expression increases in response to brain injury [68]. Further, α-synuclein oligomerization is important in the pathogenesis of synucleinopathies [69,70], where it forms neurotoxic oligomers [70][71][72][73] that accumulate in and damage Purkinje cells [74][75][76]. When released into the extracellular space, α-Synuclein oligomers are potent inducers of neuroinflammatory M1 microglia and A1 astrocyte polarization [77,78].…”

Section: Discussionmentioning

confidence: 99%

Ablation of polyamine catabolic enzymes provokes Purkinje cell damage, neuroinflammation, and severe ataxia

Zahedi

Brooks

Barone

et al. 2020

J Neuroinflammation

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Background Polyamine catabolism plays a key role in maintaining intracellular polyamine pools, yet its physiological significance is largely unexplored. Here, we report that the disruption of polyamine catabolism leads to severe cerebellar damage and ataxia, demonstrating the fundamental role of polyamine catabolism in the maintenance of cerebellar function and integrity. Methods Mice with simultaneous deletion of the two principal polyamine catabolic enzymes, spermine oxidase and spermidine/spermine N1-acetyltransferase (Smox/Sat1-dKO), were generated by the crossbreeding of Smox-KO (Smox−/−) and Sat1-KO (Sat1−/−) animals. Development and progression of tissue injury was monitored using imaging, behavioral, and molecular analyses. Results Smox/Sat1-dKO mice are normal at birth, but develop progressive cerebellar damage and ataxia. The cerebellar injury in Smox/Sat1-dKO mice is associated with Purkinje cell loss and gliosis, leading to neuroinflammation and white matter demyelination during the latter stages of the injury. The onset of tissue damage in Smox/Sat1-dKO mice is not solely dependent on changes in polyamine levels as cerebellar injury was highly selective. RNA-seq analysis and confirmatory studies revealed clear decreases in the expression of Purkinje cell-associated proteins and significant increases in the expression of transglutaminases and markers of neurodegenerative microgliosis and astrocytosis. Further, the α-Synuclein expression, aggregation, and polyamination levels were significantly increased in the cerebellum of Smox/Sat1-dKO mice. Finally, there were clear roles of transglutaminase-2 (TGM2) in the cerebellar pathologies manifest in Smox/Sat1-dKO mice, as pharmacological inhibition of transglutaminases reduced the severity of ataxia and cerebellar injury in Smox/Sat1-dKO mice. Conclusions These results indicate that the disruption of polyamine catabolism, via coordinated alterations in tissue polyamine levels, elevated transglutaminase activity and increased expression, polyamination, and aggregation of α-Synuclein, leads to severe cerebellar damage and ataxia. These studies indicate that polyamine catabolism is necessary to Purkinje cell survival, and for sustaining the functional integrity of the cerebellum.

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Accumulation of α-Synuclein in Cerebellar Purkinje Cells of Diabetic Rats and Its Potential Relationship with Inflammation and Oxidative Stress Markers

Cited by 12 publications

References 37 publications

Cerebellar Synaptopathy in Streptozotocin-Induced Diabetic Rats

Cerebellar Synaptopathy in Streptozotocin-Induced Diabetic Rats

Insulin Resistance Promotes Parkinson’s Disease through Aberrant Expression of α-Synuclein, Mitochondrial Dysfunction, and Deregulation of the Polo-Like Kinase 2 Signaling

Ablation of polyamine catabolic enzymes provokes Purkinje cell damage, neuroinflammation, and severe ataxia

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