Humans ; alpha-Synuclein/genetics* ; Parkinson Disease/pathology*

Brain ; pathology ; Genome-Wide Association Study ; Humans ; Parkinson Disease ; genetics ; Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases ; genetics ; Proto-Oncogene Proteins c-crk ; genetics

Parkinson's disease (PD) is an age-related progressive neurodegenerative disease associated with selective loss of dopaminergic neurons. The characteristic hallmark of the disease is intracytoplasmic proteinacious inclusion bodies called Lewy bodies, primarily consisting of a presynaptic protein alpha-synuclein. Oxidative stress-mediated damage to macromolecules have been shown to occur frequently in PD. Oxidative damage to DNA in the form of oxidized guanine (8-oxodG) accumulates in both the mitochondrial and nuclear DNA of dopaminergic neurons of the substantia nigra in PD. 8-oxodG-mediated transcriptional mutagenesis has been shown to have the potential to alter phenotype of cells through production of mutant pool of proteins. This review comprehensively summarizes the role of oxidative stress-mediated damage incurred during neurodegeneration, and highlights the scope of transcriptional mutagenesis event in leading to alpha-synuclein aggregation as seen in PD.
Amino Acid Sequence ; Animals ; Deoxyguanosine/*analogs & derivatives/metabolism ; Humans ; Molecular Sequence Data ; Mutagenesis ; *Oxidative Stress ; Parkinson Disease/*genetics/metabolism/pathology ; Protein Aggregation, Pathological/*genetics/metabolism/pathology ; Substantia Nigra/metabolism/*pathology ; Transcription, Genetic ; alpha-Synuclein/chemistry/*genetics

OBJECTIVETo analyze the clinical and genetic features of a family with Parkinson's disease caused by expansion of CAG triplet repeat in the ATXN2 gene.

METHODSThe CAG/CAA repeat in the ATXN2 gene was analyzed by polymerase chain reaction (PCR) and Sanger sequencing.

RESULTSMolecular testing has documented a pathological heterozygous expansion of the CAG repeat from 33 to 35 in 6 patients and other 8 family members. Two patients had pure CAG triplet repeat expansion in their ATXN2 gene, while others had CAA interruption.

CONCLUSIONExpanded CAG/CAA repeat in the ATXN2 gene is the causative mutation of the disease in this family.The 8 members with expanded CAG/CAA repeat may be asymptomatic patients. It is supposed that the number and configuration of the ATXN2 CAG/CAA repeat expansion may play an important role in the phenotypic variability of Parkinson's disease.

Aged ; Ataxin-2 ; genetics ; Base Sequence ; Family Health ; Female ; Genetic Predisposition to Disease ; genetics ; Humans ; Male ; Middle Aged ; Parkinson Disease ; genetics ; pathology ; Pedigree ; Polymerase Chain Reaction ; Sequence Analysis, DNA ; methods ; Trinucleotide Repeat Expansion ; genetics

Cholesterol is an essential component for neuronal physiology not only during development stage but also in the adult life. Cholesterol metabolism in brain is independent from that in peripheral tissues due to blood-brain barrier. The content of cholesterol in brain must be accurately maintained in order to keep brain function well. Defects in brain cholesterol metabolism has been shown to be implicated in neurodegenerative diseases, such as Alzheimer's disease (AD), Huntington's disease (HD), Parkinson's disease (PD), and some cognitive deficits typical of the old age. The brain contains large amount of cholesterol, but the cholesterol metabolism and its complex homeostasis regulation are currently poorly understood. This review will seek to integrate current knowledge about the brain cholesterol metabolism with molecular mechanisms.
ATP-Binding Cassette Transporters ; genetics ; metabolism ; Alzheimer Disease ; genetics ; metabolism ; pathology ; Blood-Brain Barrier ; Brain ; metabolism ; pathology ; Cholesterol ; metabolism ; Gene Expression Regulation ; Homeostasis ; Humans ; Huntington Disease ; genetics ; metabolism ; pathology ; Hydroxycholesterols ; metabolism ; Lipid Metabolism ; genetics ; Neurons ; metabolism ; pathology ; Parkinson Disease ; genetics ; metabolism ; pathology ; Receptors, Lipoprotein ; genetics ; metabolism

Mutations in LR RK2 (Leucine rich repeat kinase 2) are a major cause of Parkinson's disease (PD). We and others reported recently that expression of the pathogenic gainof-function mutant form of LRRK2, LRRK2 G2019S, induces mitochondrial fission in neurons through DLP1. Here we provide evidence that expression of LRRK2 G2019S stimulates mitochondria loss or mitophagy. We have characterized several LRRK2 interacting proteins and found that LRRK2 interacts with ULK1 which plays an essential role in autophagy. Knockdown of either ULK1 or DLP1 expression with shRNAs suppresses LRRK2 G2019S expression-induced mitochondrial clearance, suggesting that LRRK2 G2019S expression induces mitochondrial fission through DLP1 followed by mitophagy via an ULK1 dependent pathway. In addition to ULK1, we found that LRRK2 interacts with the endogenous MKK4/7, JIP3 and coordinates with them in the activation of JNK signaling. Interestingly, LRRK2 G2019S-induced loss of mitochondria can also be suppressed by 3 different JNK inhibitors, implying the involvement of the JNK pathway in the pathogenic mechanism of mutated LRRK2. Thus our findings may provide an insight into the complicated pathogenesis of PD as well as some clues to the development of novel therapeutic strategies.
Amino Acid Substitution ; Autophagosomes ; metabolism ; pathology ; Autophagy-Related Protein-1 Homolog ; chemistry ; genetics ; metabolism ; GTP Phosphohydrolases ; antagonists & inhibitors ; genetics ; metabolism ; Gene Knockdown Techniques ; HeLa Cells ; Humans ; Intracellular Signaling Peptides and Proteins ; chemistry ; genetics ; metabolism ; Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 ; chemistry ; genetics ; metabolism ; MAP Kinase Signaling System ; Microtubule-Associated Proteins ; antagonists & inhibitors ; genetics ; metabolism ; Mitochondrial Degradation ; genetics ; physiology ; Mitochondrial Proteins ; antagonists & inhibitors ; genetics ; metabolism ; Mutant Proteins ; chemistry ; genetics ; metabolism ; Mutation ; Parkinson Disease ; genetics ; metabolism ; pathology ; Protein Interaction Domains and Motifs ; Recombinant Proteins ; chemistry ; genetics ; metabolism

The generation of disease-specific induced pluripotent stem cell (iPSC) lines from patients with incurable diseases is a promising approach for studying disease mechanisms and drug screening. Such innovation enables to obtain autologous cell sources in regenerative medicine. Herein, we report the generation and characterization of iPSCs from fibroblasts of patients with sporadic or familial diseases, including Parkinson's disease (PD), Alzheimer's disease (AD), juvenile-onset, type I diabetes mellitus (JDM), and Duchenne type muscular dystrophy (DMD), as well as from normal human fibroblasts (WT). As an example to modeling disease using disease-specific iPSCs, we also discuss the previously established childhood cerebral adrenoleukodystrophy (CCALD)- and adrenomyeloneuropathy (AMN)-iPSCs by our group. Through DNA fingerprinting analysis, the origins of generated disease-specific iPSC lines were identified. Each iPSC line exhibited an intense alkaline phosphatase activity, expression of pluripotent markers, and the potential to differentiate into all three embryonic germ layers: the ectoderm, endoderm, and mesoderm. Expression of endogenous pluripotent markers and downregulation of retrovirus-delivered transgenes [OCT4 (POU5F1), SOX2, KLF4, and c-MYC] were observed in the generated iPSCs. Collectively, our results demonstrated that disease-specific iPSC lines characteristically resembled hESC lines. Furthermore, we were able to differentiate PD-iPSCs, one of the disease-specific-iPSC lines we generated, into dopaminergic (DA) neurons, the cell type mostly affected by PD. These PD-specific DA neurons along with other examples of cell models derived from disease-specific iPSCs would provide a powerful platform for examining the pathophysiology of relevant diseases at the cellular and molecular levels and for developing new drugs and therapeutic regimens.
Alzheimer Disease/genetics/*pathology ; Cell Differentiation ; Cells, Cultured ; Diabetes Mellitus, Type 1/genetics/*pathology ; Drug Discovery/*methods ; Fibroblasts/cytology/metabolism/pathology ; Gene Expression ; Humans ; Induced Pluripotent Stem Cells/cytology/metabolism/*pathology ; Muscular Dystrophy, Duchenne/genetics/*pathology ; Parkinson Disease/genetics/*pathology

OBJECTIVETo explore the effect of Bushen Huoxue Decoction (BHD) on the orphan receptor (Nurr1) and tyrosine hydroxylase (TH) in the brain of rats with Parkinson's disease (PD).

METHODSOne hundred and twenty SD rats were divided into 100 in the model group and 20 in the normal control group, fifty-eight SD rats from the model group, established into PD model successfully by injuring their substantia nigra (SSN) with 6-hydroxydopamine, were divided equally into the model group and the test group, and they were treated with saline and BHD, respectively, for eight successive weeks. The change in the rats' behavior before and after treatment was observed by counting the cycles of rotation induced by apomorphine injection; the pathology of neurons, level of Nurr1 mRNA expression, and amount of TH positive cells in SSN were observed after treatment.

RESULTSThe rats' behavior was improved in the tested group significantly, the rotation cycle after treatment being 84.0 ± 20.0 cycles/40 min, which was significantly lower than that in the model group (377.0 ± 62.3 cycles/40 min, P<0.01). Besides, the Nurr1 mRNA expression and TH positive cell in the test group were 0.97 ± 0.15 and 49.40 ± 14.72, respectively, which were significantly higher than those in the model group, 0.22 ± 0.03 and 5.45 ± 2.58, respectively (all P<0.01).

CONCLUSIONBHD could treat PD by enhancing the Nurr1 mRNA expression, increasing the TH content in brain, and promoting the repairing of injured neuron in cerebral SSN.

Animals ; Behavior, Animal ; drug effects ; Brain ; drug effects ; enzymology ; pathology ; Drugs, Chinese Herbal ; pharmacology ; therapeutic use ; Female ; Gene Expression Regulation ; drug effects ; Neurons ; drug effects ; enzymology ; pathology ; Nuclear Receptor Subfamily 4, Group A, Member 2 ; genetics ; metabolism ; Parkinson Disease ; drug therapy ; enzymology ; pathology ; RNA, Messenger ; genetics ; metabolism ; Rats ; Rats, Sprague-Dawley ; Substantia Nigra ; drug effects ; metabolism ; pathology ; Tyrosine 3-Monooxygenase ; metabolism

Genetic Markers ; Genome-Wide Association Study ; HLA-DQ Antigens ; genetics ; HLA-DR Antigens ; genetics ; Humans ; Inflammation ; complications ; genetics ; pathology ; Parkinson Disease ; diagnosis ; genetics ; pathology ; Risk Factors ; Time Factors

Many major neurodegenerative diseases are associated with proteins misfolding and aggregation, which are also called "neurodegenerative conformational disease". The interaction of gene mutation and environmental factors are probably primary events resulting in oligomer and aggregate formations of proteins. Moreover, the dysfunctions of protein control systems, i.e. the ubiquitin-proteasome system and autophagy-lysosomal system, also contribute to the neurodegenerative process. The present review mainly summarizes protein misfolding and aggregation in the development of neurodegenerative conformational disease and the underling mechanisms, as well as upregulation of heatshock proteins as a promising treatment method for this kind of disease.
Alzheimer Disease ; drug therapy ; genetics ; metabolism ; pathology ; Animals ; Annona ; chemistry ; Autophagy ; Benzeneacetamides ; isolation & purification ; therapeutic use ; Heat-Shock Proteins ; metabolism ; physiology ; Humans ; Mutation ; Neurodegenerative Diseases ; drug therapy ; genetics ; metabolism ; pathology ; Parkinson Disease ; drug therapy ; genetics ; metabolism ; pathology ; Phenols ; isolation & purification ; therapeutic use ; Plants, Medicinal ; chemistry ; Proteasome Endopeptidase Complex ; metabolism ; Protein Folding ; Ubiquitin ; metabolism