Induced pluripotent stem cells: a tool for modeling Parkinson's disease.

Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder. Among its pathologies, progressive loss of dopaminergic (DA) neurons in the substantia nigra is characteristic and contributes to many of the most severe symptoms of PD. Recent advances in induced pluripotent stem cell (iPSC) technology have made it possible to generate patient-derived DA neuronal cell culture and organoid models of PD. These models have contributed to understanding disease mechanisms and the identification of novel targets and therapeutic candidates. Still needed are better ways to model the age-related aspects of PD, as well as a deeper understanding of the interactions among disease-modifying genes and between genetic and environmental contributions to the etiology and progression of PD.

Magnetic Resonance Imaging of Malformations of Cortical Development-A Comprehensive Review.

Malformations of cortical development (MCDs) are structural anomalies that disrupt the normal process of cortical development. These include microcephaly with simplified gyral pattern/microlissencephaly, hemimegalencephaly, focal cortical dysplasia, lissencephaly, heterotopia, polymicrogyria, and schizencephaly. They can present with intractable epilepsy, developmental delay, neurologic deficits, or cognitive impairment. Though the definitive diagnosis of MCD depends on histopathology, the pathologic tissue is rarely available; hence diagnosis begins with neuroimaging. This article shall briefly review the embryology, followed by specific magnetic resonance imaging features of MCD in an attempt to simplify the process of diagnosing these disorders with clinical and genetic correlation. A table has been included to highlight the embryologic, clinical, and genetic findings associated with various MCDs.

Mitochondrial dysfunction and oxidative stress in induced pluripotent stem cell models of Parkinson's disease.

Parkinson's disease (PD) is the second most common neurodegenerative disease. Two percent of the population above the age of 60 is affected by the disease. The pathological hallmarks of PD include loss of dopaminergic neurons and the presence of Lewy bodies. Mitochondrial dysfunction and oxidative stress are thought to play a pivotal role in both sporadic and familial forms of the disease. In this review we focus on the role of mitochondrial dysfunction and oxidative stress in induced pluripotent stem cell (IPSC) models of PD.We also provide an overview of therapeutics that have been tested and some possible new therapeutics that can be tested in IPSC models of PD.

Parkinson's Disease and Melanoma: Co-Occurrence and Mechanisms.

Parkinson's disease (PD) is a neurodegenerative disorder that is characterized by loss of dopaminergic neurons in the substantia nigra pars compacta, depletion of dopamine in the striatum and the presence of Lewy bodies. Cancer is uncontrolled growth of cells in the body and migration of these cells from their site of origin to other parts of the body. PD and cancer are two opposite diseases, one arising from cell proliferation and the other from cell degeneration. This fundamental difference is consistent with inverse comorbidity between most cancers and neurodegenerative diseases. However, a positive association of PD and melanoma has been reported which has recently become of significant interest. A link between PD and cancer has been supported by many epidemiological studies, most of which show that PD patients have a lower risk of developing most cancers than the general population. However, the mechanisms underlying this epidemiological observation are not known. In this review we focus on epidemiological studies correlating PD and melanoma and the possible mechanisms underlying the co-occurrence of the two diseases. We explore possible explanations for the important observations that more PD patients develop melanoma that would otherwise be expected and vice-versa.

Mitochondrial dysfunction in Parkinson's disease.

Parkinson's disease (PD) is the second most common neurodegenerative disease. About 2% of the population above the age of 60 is affected by the disease. The pathological hallmarks of the disease include the loss of dopaminergic neurons in the substantia nigra and the presence of Lewy bodies that are made of α-synuclein. Several theories have been suggested for the pathogenesis of PD, of which mitochondrial dysfunction plays a pivotal role in both sporadic and familial forms of the disease. Dysfunction of the mitochondria that is caused by bioenergetic defects, mutations in mitochondrial DNA, nuclear DNA gene mutations linked to mitochondria, and changes in dynamics of the mitochondria such fusion or fission, changes in size and morphology, alterations in trafficking or transport, altered movement of mitochondria, impairment of transcription, and the presence of mutated proteins associated with mitochondria are implicated in PD. In this review, we provide a detailed overview of the mechanisms that can cause mitochondrial dysfunction in PD. We bring to the forefront, new signaling pathways such as the retromer-trafficking pathway and its implication in the disease and also provide a brief overview of therapeutic strategies to improve mitochondrial defects in PD. Bioenergetic defects, mutations in mitochondrial DNA, nuclear DNA gene mutations, alterations in mitochondrial dynamics, alterations in trafficking/transport and mitochondrial movement, abnormal size and morphology, impairment of transcription and the presence of mutated proteins associated with mitochondria are implicated in PD. In this review, we focus on the mechanisms underlying mitochondrial dysfunction in PD and bring to the forefront new signaling pathways that may be involved in PD. We also provide an overview of therapeutic strategies to improve mitochondrial defects in PD. This article is part of a special issue on Parkinson disease.

Modulation of tau phosphorylation by the kinase PKR: implications in Alzheimer's disease.

Double-stranded RNA dependent kinase (PKR) is a pro-apoptotic kinase that controls protein translation. Previous studies revealed that activated PKR is increased in brains with Alzheimer's disease (AD). Glycogen Synthase Kinase Aß (GSK-3ß) is responsible for tau phosphorylation and controls several cellular functions also including apoptosis. The goal of this work was to determine if PKR could concurrently trigger GSK-3ß activation, tau phosphorylation and apoptosis. In AD brains, both activated kinases co-localize with phosphorylated tau in neurons. In SH-SY5Y cell cultures, tunicamycin and Aß(1-42) activate PKR, GSK-3ß and induce tau phosphorylation and all these processes are attenuated by PKR inhibitors or PKR siRNA. Our results demonstrate that neuronal PKR co-localizes with GSK-3ß and tau in AD brains and is able to modulate GSK-3ß activation, tau phosphorylation and apoptosis in neuroblastoma cells exposed to tunicamycin or Aß. PKR could represent a crucial signaling point relaying stress signals to neuronal pathways leading to cellular degeneration in AD.

Neuronal phosphorylated RNA-dependent protein kinase in Creutzfeldt-Jakob disease.

The mechanisms of neuronal apoptosis in Creutzfeldt-Jakob disease (CJD) and their relationship to accumulated prion protein (PrP) are unclear. A recent cell culture study showed that intracytoplasmic PrP may induce phosphorylated RNA-dependent protein kinase (PKR(p))-mediated cell stress. The double-stranded RNA protein kinase PKR is a proapoptotic and stress kinase that accumulates in degenerating neurons in Alzheimer disease. To determine whether neuronal apoptosis in human CJD is associated with activation of the PKR(p) signaling pathway, we assessed in situ end labeling and immunocytochemistry for PrP, glial fibrillary acidic protein, CD68, activated caspase 3, and phosphorylated PKR (Thr451) in samples of frontal, occipital, and temporal cortex, striatum, and cerebellum from 6 patients with sporadic CJD and 5 controls. Neuronal immunostaining for activated PKR was found in all CJD cases. The most staining was in nuclei and, in contrast to findings in Alzheimer disease, cytoplasmic labeling was not detected. Both the number and distribution of PKR(p)-positive neurons correlated closely with the extent of neuronal apoptosis, spongiosis, astrocytosis, and microglial activation and with the phenotype and disease severity. There was no correlation with the type, topography, or amount of extracellular PrP deposits. These findings suggest that neuronal apoptosis in human CJD may result from PKR(p)-mediated cell stress and are consistent with recent studies supporting a pathogenic role for intracellular or transmembrane PrP.

Protective role of exogenous polyamines on salinity-stressed rice (Oryza sativa) plants.

Salt-tolerant Pokkali rice plants accumulate higher polyamines (PAs) such as spermidine (Spd) and spermine (Spm) in response to salinity stress, while the sensitive cultivarM-1-48 is unable to maintain high titres of these PAs under similar conditions. The effects of the triamine Spd and the tetramine Spm on physiological and biochemical changes in 12-day-old rice seedlings were investigated during salinity stress to determine whether they could protect the sensitive plants from stress effects. At physiological concentrations Spd and Spm significantly prevented the leakage of electrolytes and amino acids from roots and shoots induced by salinity stress. To different degrees they also prevented chlorophyll loss, inhibition of photochemical reactions of photosynthesis as well as downregulation of chloroplast-encoded genes like psbA, psbB, psbE and rbcL, indicating a positive correlation between salt tolerance and accumulation of higher PAs in rice. The inhibitory effect of salinity stress and its reversal by exogenous PAs were more pronounced in the salt-sensitiveM-1-48 plants than in the tolerant Pokkali plants.