-
[show abstract]
[hide abstract]
ABSTRACT: As autophagy is involved in cell growth, survival, development and death, impaired autophagic flux has been linked to a variety of human pathophysiological processes, including neurodegeneration, cancer, myopathy, cardiovascular and immune-mediated disorders. There is a growing need to identify and quantify the status of autophagic flux in different pathological conditions. Given that autophagy is a highly dynamic and complex process that is regulated at multiple steps, it is often assessed accurately. This perspective review article will focus on the autophagic flux defects in different human disorders and update the current methods of monitoring autophagic flux. This knowledge is essential for developing autophagy-related therapeutics for treating the diseases.
Acta Pharmacologica Sinica 03/2013; · 1.95 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Parkinson's disease (PD), the second most common neurodegenerative disorder, is characterized by the loss of dopamine (DA) neurons in the substantia nigra (SN). Currently, there are numerous therapeutic drugs for the treatment of PD; however, they are limited in efficacy and primarily target motor symptoms. Furthermore, these drugs have various adverse effects after long-term use. Usually, PD patients begin to take anti-parkinsonian drugs when they have developed obvious motor symptoms. At that time, a significant portion of the DA neurons in SN has been lost and the biology of the disease may have already been present for over a decade. This stage of PD diagnosis underscores the need for biomarkers that accurately indicate the onset of PD in order to apply disease-modifying therapies at an earlier stage of disease. However, development of disease modifying drugs has faced many setbacks, mostly due to the ways in which clinical trials are planned and executed. In this review paper, we summarize the recent findings of genetic biomarkers such as SNCA, LRRK2, parkin, PINK1, DJ1, etc., as well as evaluate the imaging techniques such as single proton emission computed tomography and positron emission tomography for their potential in diagnosing PD at earlier stages. Clinical trial designs, along with a comprehensive analysis of neuroprotective drugs for future treatment of PD, are also reviewed.
Acta Neurovegetativa 06/2012; · 2.73 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Background: The impairment of the ubiquitin-proteasome system (UPS) is a cellular mechanism underlying the neurodegenerative process in Parkinson's disease (PD). A mouse model induced by the selective proteasome inhibitor lactacystin targeting on substantia nigra has been demonstrated to be valuable in investigating etiopathogenesis and neuroprotection for PD. Objective: In the present study, we used adeno-associated virus type 2 vector (AAV2) encoding glial cell line-derived neurotrophic factor (GDNF) injected into the striatum of this animal model to test the effectiveness and possible mechanisms of GDNF gene therapy. Results: Our results showed that AAV2-mediated GDNF gene therapy significantly attenuated lactacystin-induced loss of nigral dopamine (DA) neurons and striatal DA levels. Furthermore, we found that GDNF protein is mostly expressed in astrocytes in the subventricular zone (SVZ) and dentate gyrus (DG). AAV2-mediated GDNF therapy can induce neurogenesis in the SVZ and DG, and increase the number of nigral newborn DA neurons. Conclusion: These data indicate that AAV2-mediated GDNF gene therapy can protect the nigral DA neurons from the UPS impairment-induced degeneration, which may partly result from the nigral DA neuron regeneration in the brain, and such experimental results may have implications for the treatment of PD.
Neurodegenerative Diseases 05/2012; · 3.06 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Autophagy is an intracellular lysosomal degradation process, which plays an important role in cell growth and development, and keeping cellular homeostasis in all eukaryotes. Autophagy has multiple physiological functions, including protein degradation, organelle turnover and response to stress. Emerging evidences support the notion that dysregulation of autophagy might be critical for pathogenesis of amyotrophic lateral sclerosis (ALS). The autophagy dysregulation in motor neurons of ALS may occur in different steps of the autophagic process. Recent studies have shown that two ALS associated proteins, TDP-43 and superoxide dismutase 1 (SOD1), are involved in the abnormal autophagy regulation. Furthermore, it is reported that several genetic mutations in ALS disturb the autophagic process in the motor neurons. This review will provide new evidence of autophagy dysregulation as a critical pathogenic process leading to ALS, and will discuss the prospect of future therapeutic targets using autophagic regulation to treat this disease.
Brain Pathology 01/2012; 22(1):110-6. · 3.99 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Aberrant protein misfolding may contribute to the pathogenesis of amyotrophic lateral sclerosis (ALS) but the detailed mechanisms are largely unknown. Our previous study has shown that autophagy is altered in the mouse model of ALS. In the present study, we systematically investigated the correlation of the autophagic alteration with the motor neurons (MNs) degeneration in the ALS mice. We have demonstrated that the autophagic protein marker LC3-II is markedly and specifically increased in the spinal cord MNs of the ALS mice. Electron microscopy and immunochemistry studies have shown that autophagic vacuoles are significantly accumulated in the dystrophic axons of spinal cord MNs of the ALS mice. All these changes in the ALS mice appear at the age of 90 d when the ALS mice display modest clinical symptoms; and they become prominent at the age of 120 d. The clinical symptoms are correlated with the progression of MNs degeneration. Moreover, we have found that p62/SQSTM1 is accumulated progressively in the spinal cord, indicating that the possibility of impaired autophagic flux in the SOD1(G93A) mice. Furthermore, to our surprise, we have found that treatment with autophagy enhancer rapamycin accelerates the MNs degeneration, shortens the life span of the ALS mice, and has no obvious effects on the accumulation of SOD1 aggregates. In addition, we have demonstrated that rapamycin treatment in the ALS mice causes more severe mitochondrial impairment, higher Bax levels and greater caspase-3 activation. These findings suggest that selective degeneration of MNs is associated with the impairment of the autophagy pathway and that rapamycin treatment may exacerbate the pathological processing through apoptosis and other mechanisms in the ALS mice.
Autophagy 04/2011; 7(4):412-25. · 7.45 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The causes of amyotrophic lateral sclerosis (ALS) are largely unknown. Oxidative stress is considered to play a major role in motor neuron degeneration associated with iron homeostasis disturbance.
Iron chelation treatment might be a potential therapeutic approach on the basis of its ability to reduce the oxygen free radical generation caused by iron accumulation.
In the present study, we applied the brain-permeable iron chelators VK-28 and M30 in a G93A mutant superoxide dismutase 1 transgenic (SOD1(G93A)) mouse model of ALS and found that VK-28 and M30 significantly delayed disease onset, extended the life span and reduced spinal cord motor neuron loss. Furthermore, we documented that both iron chelators significantly attenuated the elevated iron level and transferrin receptor expression, decreased oxygen free radicals and suppressed microglial and astrocytic activation in the spinal cords of the SOD1(G93A) mice. Moreover, we demonstrated that both iron chelators were able to decrease TDP-43 protein aggregation and the proapoptotic molecule Bax, and to enhance antiapoptotic protein Bcl-2 expression, in the ALS mice.
These results provide evidence that iron is involved in the pathogenesis of ALS and iron chelation therapy may have the potential for the prevention and treatment of ALS.
Neurodegenerative Diseases 02/2011; 8(5):310-21. · 3.06 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: New strategies for the treatment of Parkinson's disease (PD) are shifted from dopamine (DA) replacement to regeneration or restoration of the nigro-striatal system. A cell therapy using human retinal pigment epithelial (RPE) cells as substitution for degenerated dopaminergic (DAergic) neurons has been developed and showed promising prospect in clinical treatment of PD, but the exact mechanism underlying this therapy is not fully elucidated. In the present study, we investigated whether the beneficial effects of this therapy are related to the trophic properties of RPE cells and their ability to synthesize DA.
We evaluated the protective effects of conditioned medium (CM) from cultured RPE cells on the DAergic cells against 6-hydroxydopamine (6-OHDA)- and rotenone-induced neurotoxicity and determined the levels of glial cell derived neurotrophic factor (GDNF) and brain derived neurotrophic factor (BDNF) released by RPE cells. We also measured the DA synthesis and release. Finally we transplanted microcarriers-RPE cells into 6-OHDA lesioned rats and observed the improvement in apomorphine-induced rotations (AIR).
We report here: (1) CM from RPE cells can secret trophic factors GDNF and BDNF, and protect DAergic neurons against the 6-OHDA- and rotenone-induced cell injury; (2) cultured RPE cells express L-dopa decarboxylase (DDC) and synthesize DA; (3) RPE cells attached to microcarriers can survive in the host striatum and improve the AIR in 6-OHDA-lesioned animal model of PD; (4) GDNF and BDNF levels are found significantly higher in the RPE cell-grafted tissues.
These findings indicate the RPE cells have the ability to secret GDNF and BDNF, and synthesize DA, which probably contribute to the therapeutic effects of RPE cell transplantation in PD.
Journal of Translational Medicine 07/2009; 7:53. · 3.41 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The transcription factor Pitx3 is crucial for the development and differentiation of dopamine (DA) neurons. Our previous work has shown the Pitx3 can up-regulate the expression of brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) in neuroblastoma cell line SH-SY5Y. Primary astrocytes are the major nonneuronal cells and can be easily modified genetically to deliver therapeutic molecules into the brain, so we investigated whether Pitx3 can increase the expression and secretion of BDNF and GDNF in primary astrocytes. We first transfected Pitx3 plasmid in purified rat astrocytes and collected the conditioned medium (CM) from the Pitx3-transfected cultures, and then we measured the BDNF and GDNF levels from the CM and tested the protective effect of the CM against rotenone-induced DA neuron injury in ventral mesencephalon (VM) cultures. We found that the BDNF and GDNF levels were 1.4-fold and 1.5-fold higher in the CM from Pitx3-transfected astrocytes than empty vectors-transfected controls. Incubation with the CM from Pitx3-transfected astrocytes significantly attenuated the rotenone-induced DA neuron injury, and such protection can be significantly blocked by preincubation with antibodies against either BDNF or GDNF, whereas preincubation with purified BDNF or GDNF replicated the neuroprotection against rotenone-induced injury in VM cultures. These results demonstrate that Pitx3-transfection in astrocytes can up-regulate BDNF and GDNF expression and produce protective benefit to DA neurons, which might be a potential therapeutic alternative for Parkinson's disease.
Journal of Neuroscience Research 11/2008; 86(15):3393-400. · 2.74 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease caused by selective degeneration of motor neurons. Mutations in copper/zinc superoxide dismutase (SOD1) account for 20% cases of familial ALS (fALS), but the underlying pathogenetic mechanisms are largely unknown. Using SOD1(G93A) mice model of ALS, we demonstrated that mutation in SOD1 caused a significant increase in the level of plasma homocysteine (Hcy). To investigate whether Hcy-lowering therapy is beneficial to this disease, we applied folic acid (FA) and vitamin B12 which are important factors involved in the Hcy metabolism to assess the neuroprotective effect of FA and B12 in the SOD1(G93A) mice. Our results showed FA or FA+B12 treatment significantly delayed the disease onset and prolonged the lifespan, accompanied by the significant reduction of motor neuron loss. Furthermore, we found that FA or FA+B12 treatment significantly attenuated the plasma Hcy level, suppressed the activation of microglia and astrocytes, and inhibited the expression of inducible nitric oxide synthase (iNOS) and tumor necrosis factor-alpha (TNF-alpha) in spinal cord. Moreover, FA or FA+B12 treatment decreased the levels of cleaved caspase-3 and poly(ADP-ribose)polymerase (PARP) but up-regulated the level of anti-apoptotic protein Bcl-2. However, B12 treatment alone did not show any significant benefit to this disease. These results provide evidence to demonstrate that elevated Hcy is involved in the pathogenesis of fALS and FA therapy may have therapeutic potential for the treatment of the disease.
Neuropharmacology 07/2008; 54(7):1112-9. · 4.81 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Ropinirole, a D2/D3 receptor agonist has been reported to have neuroprotective effects. We showed that ropinirole can prevent rotenone-induced apoptosis in dopaminergic cell line SH-SY5Y through D3 receptor. We found that ropinirole can block the rotenone-induced phosphorylation of JNK, P38 and p-c-Jun, but promote the phosphorylation of ERK1/2. Furthermore, we demonstrated that ropinirole can reduce the rotenone-induced cleavages of caspase 9, caspase 3 and PARP and elevate the expression of anti-apoptotic proteins of p-Akt and bcl-2. These results provide a basis for neuroprotection by this drug for the treatment of Parkinson disease.
FEBS Letters 04/2008; 582(5):603-10. · 3.54 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Parkinson's disease is one of the most common neurodegenerative diseases caused by the loss of dopaminergic neurons in the substantia nigra pars compacta. Pharmacological therapies are valuable but suffer from two main drawbacks: side effects and loss of efficacy with disease progression. Surgical treatment is no better than drugs. Transplantation of embryonic mesencephalic tissue has emerged as a therapeutic alternative, but the unstable efficiency and the shortage of embryonic donors limit its clinical application. Recent advances in stem cell research inspire our hope that stem cell transplantation to replace degenerated neurons may be a promising therapy for Parkinson's disease. There are three sources of stem cells currently in testing: embryonic stem cells, neural stem cells, and mesenchymal stem cells. The stem cell transplantation in the animal model of Parkinson's disease proves that it is capable of relieving symptoms and restoring damaged brain function. Future stem cell research should focus not only on ameliorating the symptoms of Parkinson's disease but also on neuroprotection or neurorescue that can favorably modify the natural course and slow the progression of the disease.
Journal of Neuroimmune Pharmacology 10/2007; 2(3):243-50. · 4.57 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: In the past decade, enormous efforts have been devoted to understand the genetics and molecular pathogenesis of Alzheimer's disease (AD), which has been transferred into extensive experimental approaches aimed at reversing disease progression. The trend in future AD therapy has been shifted from traditional anti-acetylcholinesterase treatment to multiple mechanisms-based therapy targeting amyloid plaques formation and amyloid peptides (Abeta)-mediated cytotoxicity, and neurofibrillary tangles generation. This review will cover current experimental studies with the focus on secretases-based drug development, immunotherapy, and anti-neurofibrillary tangles intervention. The outcome of these on-going studies may provide high hope that AD can be cured in the future.
Current Neuropharmacology 07/2007; 5(2):127-34. · 2.85 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Heat shock proteins (HSPs), known as molecular chaperone to assist protein folding, have recently become a research focus in Parkinson's disease (PD) because the pathogenesis of this disease is highlighted by the intracellular protein misfolding and inclusion body formation. The present review will focus on the functions of different HSPs and their protective roles in PD. It is postulated that HSPs may serve as protein folding machinery and work together with ubiquitin-proteasome system (UPS) to assist in decomposing aberrant proteins. Failure of UPS is thought to play a key role in the pathogenesis of PD. In addition, HSPs may possess anti-apoptotic effects and keep the homeostasis of dopaminergic neurons against stress conditions. The critical role of HSPs and recent discovery of some novel HSPs inducers suggest that HSPs may be potential therapeutic targets for PD and other neurodegenerative disorders.
International journal of biological sciences 02/2007; 3(1):20-6. · 2.70 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The purpose of this study is to evaluate neuroprotective effects of (-)-Epigallocatechin-3-gallate (EGCG) in a transgenic mouse model of Amyotrophic lateral sclerosis (ALS). SOD1-G93A transgenic mice and wild-type mice were randomly divided into EGCG-treated groups (10 mg/kg, p.o) and vehicle-treated control groups. Rotarod measurement was performed to assess the motor function of mice starting at the age of 70 days. Nissl staining to examine the number of motor neurons and CD11b immunohistochemical staining to evaluate activation of microglia in the lumbar spinal cords were conducted at the age of 120 days. In addition, for further observation of regulation of cell signaling pathways by EGCG, we used immunohistochemical analysis for nuclear factor kappa B (NF-kappaB) and cleaved caspase-3 as well as western blot analysis to determine the expression of nitric oxide synthase (iNOS) and NF-kappaB in the spinal cord. This study demonstrated that oral administration of EGCG beginning from a pre-symptomatic stage significantly delayed the onset of disease, and extended life span. Furthermore, EGCG-treated transgenic mice showed increased number of motor neurons, diminished microglial activation, reduced immunohistochemical reaction of NF-kappaB and cleaved caspase-3 as well as reduced protein level of iNOS and NF-kappaB in the spinal cords. In conclusion, this study provides further evidences that EGCG has multifunctional therapeutic effects in the mouse model of ALS.
Neurochemical Research 11/2006; 31(10):1263-9. · 2.24 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: During the past decade, there has been a remarkable progress in our understanding of the biology of Parkinson disease (PD), which has been translated into searching for novel therapy for PD. Much focus is shifted from the development of drugs that only relieve PD symptoms to new generation of remedies that can potentially protect dopaminergic neurons and modify the disease course. Several novel therapeutic approaches have been tested in preclinical experiments and in clinical trials, including molecules targeting on genes involved in the pathogenesis of the disease, neurotrophic factors critical for dopaminergic neuron survival and function, new generation of dopamine receptor agonists that may possess neuroprotective effects, and agents of antioxidation, antiinflammation, and antiapoptosis. The results of these studies will shed new light to our hope that PD can be cured in the future.
American Journal of Therapeutics 13(5):445-57. · 1.49 Impact Factor
