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Critical role of calpain in spinal cord degeneration in Parkinson's disease.

ABSTRACT: While multiple molecular mechanisms contribute to midbrain nigrostriatal dopaminergic degeneration in Parkinson's disease (PD), the mechanism of damage in non-dopaminergic sites within the central nervous system, including the spinal cord, is not well-understood. Thus, to understand the comprehensive pathophysiology underlying this devastating disease, postmortem spinal cord tissue samples (cervical, thoracic, and lumbar segments) from patients with PD were analyzed compared to age-matched normal subjects or Alzheimer's disease for selective molecular markers of neurodegeneration and inflammation. Distal axonal degeneration, relative abundance of both sensory and motor neuron death, selective loss of ChAT(+) motoneurons, reactive astrogliosis, microgliosis, increased cycloxygenase-2 (Cox-2) expression, and infiltration of T cells were observed in spinal cord of PD patients compared to normal subjects. Biochemical analyses of spinal cord tissues revealed associated inflammatory and proteolytic events (elevated levels of Cox-2, expression and activity of ?- and m-calpain, degradation of axonal neurofilament protein, and concomitantly low levels of endogenous inhibitor - calpastatin) in spinal cord of PD patients. Thus, pathologically upregulated calpain activity in spinal cords of patients with PD may contribute to inflammatory response-mediated neuronal death, leading to motor dysfunction. We proposed calpain over-activation and calpain-calpastatin dysregulation driving in a cascade of inflammatory responses (microglial activation and T cell infiltration) and degenerative pathways culminating in axonal degeneration and neuronal death in spinal cord of Parkinson's disease patients. This may be one of the crucial mechanisms in the degenerative process.

SUBMITTER: Samantaray S

PROVIDER: S-EPMC3859802 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature

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Critical role of calpain in spinal cord degeneration in Parkinson's disease.

Samantaray Supriti S Knaryan Varduhi H VH Shields Donald C DC Banik Naren L NL

Journal of neurochemistry 20130820 6

While multiple molecular mechanisms contribute to midbrain nigrostriatal dopaminergic degeneration in Parkinson's disease (PD), the mechanism of damage in non-dopaminergic sites within the central nervous system, including the spinal cord, is not well-understood. Thus, to understand the comprehensive pathophysiology underlying this devastating disease, postmortem spinal cord tissue samples (cervical, thoracic, and lumbar segments) from patients with PD were analyzed compared to age-matched norma ...[more]

PMID: 23875735

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Project description:BACKGROUND:Spinal cord injury (SCI) is one of the leading causes of disability and chronic pain. In SCI-induced pathology, homeostasis of the nitric oxide (NO) metabolome is lost. Major NO metabolites such as S-nitrosoglutathione (GSNO) and peroxynitrite are reported to play pivotal roles in regulating the activities of key cysteine proteases, calpains. While peroxynitrite (a metabolite of NO and superoxide) up regulates the activities of calpains leading to neurodegeneration, GSNO (a metabolite of NO and glutathione) down regulates the activities of calpains leading to neuroprotection. In this study, effect of GSNO on locomotor function and pain threshold and their relationship with the levels of peroxynitrite and the activity of calpain in the injured spinal cord were investigated using a 2-week rat model of contusion SCI. RESULTS:SCI animals were initially treated with GSNO at 2 h after the injury followed by a once daily dose of GSNO for 14 days. Locomotor function was evaluated by "Basso Beattie and Bresnahan (BBB) locomotor rating scale" and pain by mechanical allodynia. Peroxynitrite level, as expression of 3-nitrotyrosine (3-NT), calpain activity, as the degradation products of calpain substrate alpha II spectrin, and nNOS activity, as the expression phospho nNOS, were measured by western blot analysis. Treatment with GSNO improved locomotor function and mitigated pain. The treatment also reduced the levels of peroxynitrite (3-NT) and decreased activity of calpains. Reduced levels of peroxynitrite resulted from the GSNO-mediated inhibition of aberrant activity of neuronal nitric oxide synthase (nNOS). CONCLUSIONS:The data indicates that higher levels of 3-NT and aberrant activities of nNOS and calpains correlated with SCI pathology and functional deficits. Treatment with GSNO improved locomotor function and mitigated mechanical allodynia acutely post-injury. Because GSNO shows potential to ameliorate experimental SCI, we discuss implications for GSNO therapy in clinical SCI research.

Project description:Background: Parkinson's disease (PD) is the most common movement disorder affecting up to 1% of the population above the age of 60 and 4-5% of those above the age of 85. Little progress has been made on efforts to prevent disease development or halt disease progression. Diet has emerged as a potential factor that may prevent the development or slow the progression of PD. In this review, we discuss evidence for a role for the intestinal microbiome in PD and how diet-associated changes in the microbiome may be a viable approach to prevent or modify disease progression. Methods: We reviewed studies demonstrating that dietary components/foods were related to risk for PD. We reviewed evidence for the dysregulated intestinal microbiome in PD patients including abnormal shifts in the intestinal microbiota composition (i.e., dysbiosis) characterized by a loss of short chain fatty acid (SCFA) bacteria and increased lipopolysaccharide (LPS) bacteria. We also examined several candidate mechanisms by which the microbiota can influence PD including the NLRP3 inflammasome, insulin resistance, mitochondrial function, vagal nerve signaling. Results: The PD-associated microbiome is associated with decreased production of SCFA and increased LPS and it is believed that these changes may contribute to the development or exacerbation of PD. Diet robustly impacts the intestinal microbiome and the Western diet is associated with increased risk for PD whereas the Mediterranean diet (including high intake of dietary fiber) decreases PD risk. Mechanistically this may be the consequence of changes in the relative abundance of SCFA-producing or LPS-containing bacteria in the intestinal microbiome with effects on intestinal barrier function, endotoxemia (i.e., systemic LPS), NLRP3 inflammasome activation, insulin resistance, and mitochondrial dysfunction, and the production of factors such as glucagon like peptide 1 (GLP-1) and brain derived neurotrophic factor (BDNF) as well as intestinal gluconeogenesis. Conclusions: This review summarizes a model of microbiota-gut-brain-axis regulation of neuroinflammation in PD including several new mechanisms. We conclude with the need for clinical trials in PD patients to test this model for beneficial effects of Mediterranean based high fiber diets.

Project description:Background:Spinal cord stimulation (SCS) exerts neuroprotective effects in animal models of Parkinson's disease (PD). Conventional stimulation techniques entail limited stimulation time and restricted movement of animals, warranting the need for optimizing the SCS regimen to address the progressive nature of the disease and to improve its clinical translation to PD patients. Objective:Recognizing the limitations of conventional stimulation, we now investigated the effects of continuous SCS in freely moving parkinsonian rats. Methods:We developed a small device that could deliver continuous SCS. At the start of the experiment, thirty female Sprague-Dawley rats received the dopamine (DA)-depleting neurotoxin, 6-hydroxydopamine, into the right striatum. The SCS device was fixed below the shoulder area of the back of the animal, and a line from this device was passed under the skin to an electrode that was then implanted epidurally over the dorsal column. The rats were divided into three groups: control, 8-h stimulation, and 24-h stimulation, and behaviorally tested then euthanized for immunohistochemical analysis. Results:The 8- and 24-h stimulation groups displayed significant behavioral improvement compared to the control group. Both SCS-stimulated groups exhibited significantly preserved tyrosine hydroxylase (TH)-positive fibers and neurons in the striatum and substantia nigra pars compacta (SNc), respectively, compared to the control group. Notably, the 24-h stimulation group showed significantly pronounced preservation of the striatal TH-positive fibers compared to the 8-h stimulation group. Moreover, the 24-h group demonstrated significantly reduced number of microglia in the striatum and SNc and increased laminin-positive area of the cerebral cortex compared to the control group. Conclusions:This study demonstrated the behavioral and histological benefits of continuous SCS in a time-dependent manner in freely moving PD animals, possibly mediated by anti-inflammatory and angiogenic mechanisms.

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Critical role of calpain in spinal cord degeneration in Parkinson's disease.

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Critical role of calpain in spinal cord degeneration in Parkinson's disease.

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