Pathological Process Of Parkinson's Disease Research Articles

Cell cycle regulation of DNA polymerase beta in rotenone-based Parkinson's disease models.

In Parkinson's disease (PD), neuronal cells undergo mitotic catastrophe and endoreduplication prior to cell death; however, the regulatory mechanisms remain to be defined. In this study, we investigated cell cycle regulation of DNA polymerase β (poly β) in rotenone-based dopaminergic cellular and animal models. Incubation with a low concentration (0.25 µM) of rotenone for 1.5 to 7 days resulted in a flattened cell body and decreased DNA replication during S phase, whereas a high concentration (2 µM) of rotenone exposure resulted in enlarged, multi-nucleated cells and converted the mitotic cycle into endoreduplication. Consistently, DNA poly β, which is mainly involved in DNA repair synthesis, was upregulated to a high level following exposure to 2 µM rotenone. The abrogation of DNA poly β by siRNA transfection or dideoxycytidine (DDC) treatment attenuated the rotenone-induced endoreduplication. The cell cycle was reactivated in cyclin D-expressing dopaminergic neurons from the substantia nigra (SN) of rats following stereotactic (ST) infusion of rotenone. Increased DNA poly β expression was observed in the substantia nigra pars compacta (SNc) and the substantia nigra pars reticulate (SNr) of rotenone-treated rats. Collectively, in the in vitro model of rotenone-induced mitotic catastrophe, the overexpression of DNA poly β promotes endoreduplication; in the in vivo model, the upregulation of DNA poly β and cell cycle reentry were also observed in the adult rat substantia nigra. Therefore, the cell cycle regulation of DNA poly β may be involved in the pathological processes of PD, which results in the induction of endoreduplication.

Imaging the role of amyloid in PD dementia and dementia with Lewy bodies.

Cognitive impairment and dementia are significant sequelae of Parkinson disease (PD) and comprise a key feature of dementia with Lewy bodies (DLB), a disease with similar clinical and neuropathological features. Multiple independent causes have been implicated in PD dementia (PDD) and DLB, among them the accumulation of β-amyloid, a neuropathological hallmark of Alzheimer disease. Over the last decade, PET imaging has emerged as a viable method to measure amyloid burden in the human brain and relate it to neurodegenerative diseases. This article reviews what amyloid imaging has taught us about PDD and DLB. Current data suggest that brain amyloid deposition tends to be more marked in DLB, yet contributes to cognitive impairment in both DLB and PD. These results are broadly consistent with neuropathology and CSF studies. β-Amyloid may interact synergistically with other pathological processes in PD and DLB to contribute to cognitive impairment.

The effects of unilateral 6-OHDA lesion in medial forebrain bundle on the motor, cognitive dysfunctions and vulnerability of different striatal interneuron types in rats

In this study, the motor deficit, cognition impairment and the vulnerability of different striatal interneurons to the 6-hydroxydopamine (6-OHDA)-induced excitotoxicity in unilateral medial forebrain bundle (MFB) lesion rats were analyzed by employing behavioral test, immunohistochemistry and Western blot methods. The apomorphine-induced rotation after MFB lesion was used as a valid criterion of motor deficit. The 6-OHDA damaged rats had limb rigidity with longer hang time compared to the controls in the grip strength test. Cognitive and mnemonic deficits of rats with unilateral MFB lesion were observed by the water maze task. The MFB lesion resulted in a significant loss of tyrosine hydroxylase (TH)+ cells in the contralateral striatum or substantia nigra. After dopaminergic depletion, the numbers of calretinin (Cr)+ and choline acetyltransferase (ChAT)+ interneurons were notably reduced while these of neuropeptide Y (NPY)+ were markedly increased in the striatum. No noticeable change in the number of parvalbumin (Parv)+ interneurons was found in 6-OHDA rats. In addition, the fiber densities for each individual interneuron were increased after 6-OHDA treatment, especially for the fiber densities of Parv+ and Cr+ interneurons. The Western blot analysis further confirmed the results described above. In conclusion, the MFB lesion model is suitable to mimic Parkinson's disease (PD), and our results are helpful for further understanding the underlying mechanism and the specific functions of various striatal interneurons in the pathological process of PD.

Lewy body extracts from Parkinson disease brains trigger α‐synuclein pathology and neurodegeneration in mice and monkeys

Mounting evidence suggests that α-synuclein, a major protein component of Lewy bodies (LB), may be responsible for initiating and spreading the pathological process in Parkinson disease (PD). Supporting this concept, intracerebral inoculation of synthetic recombinant α-synuclein fibrils can trigger α-synuclein pathology in mice. However, it remains uncertain whether the pathogenic effects of recombinant synthetic α-synuclein may apply to PD-linked pathological α-synuclein and occur in species closer to humans. Nigral LB-enriched fractions containing pathological α-synuclein were purified from postmortem PD brains by sucrose gradient fractionation and subsequently inoculated into the substantia nigra or striatum of wild-type mice and macaque monkeys. Control animals received non-LB fractions containing soluble α-synuclein derived from the same nigral PD tissue. In both mice and monkeys, intranigral or intrastriatal inoculations of PD-derived LB extracts resulted in progressive nigrostriatal neurodegeneration starting at striatal dopaminergic terminals. No neurodegeneration was observed in animals receiving non-LB fractions from the same patients. In LB-injected animals, exogenous human α-synuclein was quickly internalized within host neurons and triggered the pathological conversion of endogenous α-synuclein. At the onset of LB-induced degeneration, host pathological α-synuclein diffusely accumulated within nigral neurons and anatomically interconnected regions, both anterogradely and retrogradely. LB-induced pathogenic effects required both human α-synuclein present in LB extracts and host expression of α-synuclein. α-Synuclein species contained in PD-derived LB are pathogenic and have the capacity to initiate a PD-like pathological process, including intracellular and presynaptic accumulations of pathological α-synuclein in different brain areas and slowly progressive axon-initiated dopaminergic nigrostriatal neurodegeneration.

Ginkgo Biloba Extract Protects Substantia Nigral Neurons from Apoptosis in PD Rat Model

Purpose: To investigate the apoptotic mechanism during the pathological process of Parkinson disease (PD) and explore the availability of Ginkgo biloba extract (EGb) to cure PD. Methods: Followed 6-OHDA injection stereotaxically to right side of substantia nigra pars compacta(SNc), at the date of 1, 7,14 and 21, we used biochemical, immunohistochemical, TUNEL and electron microscopic techniques to evaluate the level of apoptosis (TUNEL), monitor the degree of oxidative reaction (MDA.SOD), and to observe the change of ultrastructure of substantia nigra in the experimental PD models of rats (PD group), the EGb treatment group (EGb group) and the control group. Results: Contrast to the Control group, the number of apoptotic neurons and free radical level increased in the PD group and the EGb group, but the PD group surpassed the EGb group (p<0.05).In the PD group, the ultrastructure of substantia nigra exhibited the morphological characteristics of apoptosis from 1d to 21d. Conclusions: Free radical insult contributes to the pathological process of PD in rats. EGb may ameliorate the injury of substantia nigra through expiring free radicals during the pathological process of PD in rats.

Plasma oxidative and inflammatory markers in patients with idiopathic Parkinson’s disease

Parkinson's disease (PD) is the most common neurodegenerative disorder after alzheimer's disease. Neuroinflammation and oxidative damage are implicated to be responsible for the pathogenesis of neurodegenerative diseases. However, there are a few studies showing the changes in the biomarkers for neuroinflammation and oxidative damage in neurodegenerative diseases. In our study we aimed to examine the role of the molecules that are involved in oxidative stress and inflammation in PD patients taking L: -dopa treatment. Oxidized-LDL (ox-LDL), high-sensitivity C-reactive protein (hs-CRP) and the soluble intracellular adhesion molecule (ICAM) were chosen as biomarkers for systemic inflammation and oxidative damage. The patients were classified according to the Hoehn-Yahr staging system. Forty-five idiopathic L: -dopa-given PD patients and 25 age-matched healthy controls were examined. Plasma ox-LDL and ICAM levels were significantly higher in PD patients when compared with controls (p<0.001 and p<0.05, respectively). PD patients at all stages had significantly higher plasma ox-LDL levels than controls (p<0.001). Plasma ICAM levels at stage 1 and 2 and CRP levels at stage 2 patients were significantly higher than controls (p<0.05, p<0.05, and p<0.01, respectively). We insist that further studies have to be conducted to establish neuroinflammation and oxidative damage in PD. Establishing the roles of these pathological processes in PD might be the key to effective therapy at an early stage by antioxidants and/or anti-inflammatory drugs.

Changes in Sphingomyelin Level Affect Alpha-Synuclein and ABCA5 Expression

The pathological hallmark of Parkinson's disease (PD) is the presence of aggregated α-synuclein associated with lipids. Substantial evidence now exists to indicate that α-synuclein binds and interacts with regions of membranes that are enriched in lipids (lipid rafts). Lipids are transported around the brain by a group of proteins called ATP-Binding Cassette subfamily A (ABCA) transporters and in recent years there has been mounting evidence indicating that ABCA transporters regulate a number of neurodegenerative disease processes. Only recently a genome-wide association study reported that ABCA5 was genetically associated with a reduced risk for PD. However, very little is known about the role of lipids and ABCA5 in the pathological process of PD. In this study we investigate the impact of the lipid-raft lipid sphingomyelin on α-synuclein and ABCA5 expression. We also investigate in which primary human brain cells ABCA5 is expressed and whether the expression of ABCA5 is altered in PD brain. When SK-N-SH neuronal cells were treated with sphingomyelin the expression of both α-synuclein and ABCA5 was significantly increased, indicating sphingomyelin as a potential substrate for the ABCA5 transporter. ABCA5 was strongly expressed in neurons and moderately in microglia, with only weak expression observed in astrocytes and oligodendrocytes. The expression of ABCA5 was significantly elevated in PD brains compared to age- and gender-matched control brains, possibly as a protective response to the disease. These data provide new evidence indicating that lipid is important for α-synuclein pathology in PD.

α‐Synuclein expression is induced by depolarization and cyclic AMP in enteric neurons

Accumulated evidence emphasizes the importance of α-synuclein expression levels in Parkinson's disease (PD) pathogenesis. PD is a multicentric disorder that affects the enteric nervous system (ENS), whose involvement may herald the degenerative process in the CNS. We therefore undertook the present study to investigate the mechanisms involved in the regulation of expression of α-synuclein in the ENS. The regulation of α-synuclein expression was assessed by qPCR and western blot analysis in rat primary culture of ENS treated with KCl and forskolin. A pharmacological approach was used to decipher the signaling pathways involved. Intraperitoneal injections of Bay K-8644 and forskolin were performed in mice, whose proximal colons were further analyzed for α-synuclein expression. Depolarization and forskolin increased α-synuclein mRNA and protein expression in primary cultures of ENS, although L-type calcium channel and protein kinase A, respectively. Both stimuli increased α-synuclein expression through a Ras/extracellular signal-regulated kinases pathway. An increase in α-synuclein expression was also observed in vivo in the ENS of mice injected with Bay K-8644 or forskolin. In conclusion, we have identified stimuli leading to α-synuclein over-expression in the ENS, which could be critical in the initiation of the pathological process in PD.

Coordinative and limb-specific control of bimanual movements in patients with Parkinson's disease and cerebellar degeneration

The present study examined the effects of basal ganglia and cerebellar pathology on bimanual coordination using patients with Parkinson's disease (PD) and cerebellar dysfunction (CD). Twenty patients with idiopathic PD (10 untreated early and 10 advanced PD), 10 patients with cerebellar degeneration, and 11 normal subjects were instructed to perform in-phase and anti-phase bimanual coordination movements. The results indicated that while the quality of coordinated bimanual movements in untreated early PD and CD patients was not significantly different from that of normal controls, advanced PD patients exhibited reduced synchronized coordination during the faster anti-phase mode. This suggests that the observed bimanual coordination abnormalities in PD are not an early sign of the pathophysiology of the disease, and cerebellar degeneration may have minimal consequences on synchronized coordination between the limbs. In terms of the parameterization of individual limb movements, CD patients showed a tendency for hypermetric impairments with more irregular movements, while PD patients exhibited relatively slower limb movements and lower amplitudes than normal controls. Overall, the current data provide evidence of the specific functions of different neural structures involved in the pathological process of PD and CD on bimanual coordination.

Methylphenidate for the Treatment of Parkinson Disease and Other Neurological Disorders

Methylphenidate (MPH) is a central nervous system stimulant derived from an amphetamine and acts as a potent inhibitor of catecholamine reuptake and increases dopamine levels in the brain. Methylphenidate is widely used for the treatment of children and adults with attention deficit hyperactivity disorder. Because the dopaminergic system is critical to the pathological process in Parkinson disease (PD), it has been suggested that MPH, which increases dopaminergic stimulation at the postsynaptic receptor level, may provide symptomatic relief in PD patients. This article reviews those studies that have evaluated the potential of MPH to treat the motor and cognitive aspects of PD, summarizes the evidence for clinical use in other neurological diseases, and briefly reviews the physiological mechanisms whereby MPH may bring about its therapeutic effects. Methylphenidate does seem to be useful for ameliorating cognitive, affective, and motor deficits in PD and in other neurological patients; however, additional studies are needed before MPH can be routinely prescribed as an adjunct therapy in these populations.

In vivo imaging of microglial activation with [11C](R)-PK11195 PET in idiopathic Parkinson's disease

Idiopathic Parkinson's disease (PD) is a neurodegenerative disorder associated with akinesia, tremor and rigidity. While the characteristic Lewy body pathology targets pigmented and other brainstem nuclei at post-mortem, activated microglia are found in both subcortical and cortical areas. [11C](R)-PK11195 is a positron emission tomography (PET) marker of peripheral benzodiazepine sites (PBBS), which are selectively expressed by activated microglia. We examined 18 PD patients clinically and with [11C](R)-PK11195 and [18F]-dopa PET. Compared to 11 normal controls, the PD patients showed significantly increased mean levels of [11C](R)-PK11195 binding in the pons, basal ganglia and frontal and temporal cortical regions. Eight PD patients were examined longitudinally, and their [11C](R)-PK11195 signal remained stable over 2 years. Levels of microglial activation did not correlate with clinical severity or putamen [18F]-dopa uptake. Our in vivo findings confirm that widespread microglial activation is associated with the pathological process in PD. The absence of significant longitudinal changes suggests that microglia are activated early in the disease process, and levels then remain relatively static, possibly driving the disease via cytokine release.

Upregulation of the Anti-apoptotic Protein Bcl-2 May Be an Early Event in Neurodegeneration: Studies on Parkinson's and Incidental Lewy Body Disease

Apoptosis and oxidative stress have been suggested to be involved in Parkinson's disease (PD). However, whether this is a cause or consequence of neurodegeneration is unknown. Incidental Lewy Body disease (ILBD) appears to be a presymptomatic form of Parkinson's disease where individuals are neurologically normal, but after post-mortem examination pathology similar to Parkinson's disease is present. Thus, ILBD can be used to examine the early stages of the pathological process in PD. We investigated the levels of Bcl-2, an anti-apoptotic protein known to decrease cell death induced by several mechanisms, including oxidative stress. Our data show that Bcl-2 is significantly raised in the basal ganglia regions of PD patients as compared to age-matched controls. A similar trend is also found in ILBD. We propose that Bcl-2 increases in some brain regions as an early event and that these brain regions are under a stress for perhaps many years before any symptomatic changes occur.