Christos Koros

Motor and Nonmotor Features of Carriers of the p.A53T Alpha-Synuclein Mutation: A Longitudinal Study

G209A SNCA mutation carriers represent an important group of genetic PD. We describe motor and nonmotor features of G209A SNCA mutation carriers.

Fat diet affects leptin receptor levels in the rat cerebellum

OBJECTIVE The role of leptin receptors (Ob-Rs) within the hypothalamus in the control of energy expenditure has well been established. However, their role and regulation in other brain areas, including the cerebellum, is largely unexplored. In the present study we examined whether Ob-R levels in the rat cerebellum are influenced by a high-fat diet and if these changes are sexually divergent during adolescence. METHODS The fat diet (45% energy from fat) was applied from weaning to puberty (postnatal days [P] 22-42), from weaning to adulthood (P22-90), and from puberty to adulthood (P42-90) in female and male Wistar rats. Ob-R levels were detected by western blotting and the data from pubertal and adult rats were analyzed by two-way analysis of variance for the effects of diet and sex. RESULTS The fat diet affected Ob-R long isoform levels in a sexually dimorphic manner. In the cerebellum of all fat-fed male groups, Ob-R levels were reduced compared with their chow-fed counterparts (P < 0.05). In contrast, in female rat Ob-R levels were reduced only in the adult P22-90 group. CONCLUSION Our data show for the first time that Ob-R levels in the rat cerebellum are subject to diet-induced alterations and that these changes are sexually dimorphic.

Lysosomal alterations in peripheral blood mononuclear cells of Parkinson's disease patients

Reduced expression of lysosomal‐associated membrane protein 2a and heatshock‐cognate 70 proteins, involved in chaperone‐mediated autophagy and of glucocerebrosidase, is reported in PD brains. The aim of this study was to identify systemic alterations in lysosomal‐associated membrane protein 2a, heatshock cognate‐70, and glucocerebrosidase levels/activity in peripheral blood mononuclear cells from PD patients.

Frontotemporal dementia as the presenting phenotype of p.A53T mutation carriers in the alpha-synuclein gene

INTRODUCTION The p.A53T point mutation in SNCA, the alpha-synuclein gene, has been linked to a rare dominant form of Parkinsons disease (PD). METHODS Here, we describe two apparently unrelated cases of p.A53T (G209A) SNCA mutation carriers with an atypical initial manifestation and disease course. Moreover, cerebrospinal fluid (CSF) levels of tau, p-tau and amyloid Aβ42 were measured in these patients and in an additional cohort of 5 symptomatic and 2 asymptomatic p.A53T carriers without an initial manifestation of dementia. RESULTS Both patients exhibited an early onset frontal-dysexecutive dysfunction with apathy and emotional blunting resembling frontotemporal dementia (FTD). Motor symptoms typical of Parkinsons disease appeared only later in the disease course and were less prominent than cognitive ones, which included language impairment. Autonomic dysfunction and myoclonus also emerged in a more advanced disease stage. In both patients, Brain Magnetic Resonance Imaging showed fronto-temporo-parietal atrophy, and CSF analysis showed elevated tau protein levels. In contrast, tau protein levels were normal in a cohort of 7 other p.A53T mutation carriers (5 symptomatic/2 asymptomatic). A screen of Greek patients presenting with frontotemporal dementia failed to identify any additional subjects with the p.A53T SNCA mutation. CONCLUSION Although cognitive decline has been recognized as a feature of the full-blown clinical picture of p.A53T related parkinsonism, a predominant frontotemporal dementia-like phenotype at presentation has not been previously described. This may represent a subtype of this disorder, with distinctive clinical, imaging and CSF biochemical characteristics, in which additional genetic or epigenetic factors may play a role.

Interventions in progressive supranuclear palsy.

Progressive supranuclear palsy (PSP) an atypical parkinsonian with a common phenotype comprising early falls, the characteristic slowing of vertical saccades and a frontal syndrome with marked apathy (Richardsons syndrome). Currently, no effective symptomatic or neuroprotective treatment is available for PSP. Current medical have a limited role in PSP. Novel experimental treatments include davunetide or tideglusib, both inhibitors of glycogen synthase kinase-3 (GSK-3) that failed to improve the clinical outcome of PSP patients in two recent studies. Future interventions aiming at tau dysfunction and passive or active immunization are ongoing or underway.

Chapter Eight - Genetics of Parkinson's Disease: Genotype–Phenotype Correlations

Since the first discovery of a specific genetic defect in the SNCA gene, encoding for α-synuclein, as a causative factor for Parkinsons disease 20 years ago, a multitude of other genes have been linked to this disease in rare cases with Mendelian inheritance. Furthermore, the genetic contribution to the much more common sporadic disease has been demonstrated through case control association studies and, more recently, genome-wide association studies. Interestingly, some of the genes with Mendelian inheritance, such as SNCA, are also relevant to the sporadic disease, suggesting common pathogenetic mechanisms. In this review, we place an emphasis on Mendelian forms, and in particular genetic defects which present predominantly with Parkinsonism. We provide details into the particular phenotypes associated with each genetic defect, with a particular emphasis on nonmotor symptoms. For genetic defects for whom a sufficient number of patients has been assessed, there are evident genotype-phenotype correlations. However, it should be noted that patients with the same causative mutation may present with distinctly divergent phenotypes. This phenotypic variability may be due to genetic, epigenetic or environmental factors. From a clinical and genetic point of view, it will be especially interesting in the future to identify genetic factors that modify disease penetrance, the age of onset or other specific phenotypic features.

Alpha-synuclein dimerization in erythrocytes of patients with genetic and non-genetic forms of Parkinson’s Disease

BACKGROUND Variations of α-synuclein levels or species have been reported in Parkinsons Disease (PD). There has been little systematic examination of erythrocytes, a rich source of α-synuclein. METHODS Erythrocyte membranes were obtained from PD patients (mutation carriers in the α-synuclein gene (A53T-PD) and glucocerebrosidase gene (GBA-PD) (n=18 each), and patients without known mutations (GU-PD, n=56)), and age-/sex-matched controls (n=56). Levels of monomeric and dimeric α-synuclein were assessed using Western immunoblotting. RESULTS A statistically significant increase of α-synuclein dimer and dimer to monomer ratio was found in GBA-PD and GU-PD. In contrast, dimer levels of A53T-PD were not different from controls. No difference was found in α-synuclein monomer levels. CONCLUSIONS The increased α-synuclein dimer in GBA-PD and GU-PD is suggestive of an apparent systemic dysfunction causing the dimerization, and potentially oligomerization, of α-synuclein. These results may have implications for PD pathogenesis and biomarker development.

Central Nervous System Demyelination in a Charcot-Marie-Tooth Type 1A Patient

Introduction. Central nervous system involvement, either clinical or subclinical, has been reported mainly in X-linked Charcot-Marie-Tooth (CMT-X) patients. Case Presentation. We present the case of a 31-year-old man with a genetically confirmed history of CMT1A who developed CNS involvement mimicking multiple sclerosis (MS). Clinical, imaging, and laboratory findings suggested an autoimmune CNS demyelination. Discussion. Although the simultaneous existence of CMT1A and MS could be coincidental we postulate that overexpression of PMP22, the target protein in CMT1A, might influence the immunological self-tolerance to CNS proteins via molecular mimicry, leading to a CNS autoimmune demyelinating disorder.

Genetics of Parkinson's Disease: Genotype–Phenotype Correlations

Since the first discovery of a specific genetic defect in the SNCA gene, encoding for α-synuclein, as a causative factor for Parkinsons disease 20 years ago, a multitude of other genes have been linked to this disease in rare cases with Mendelian inheritance. Furthermore, the genetic contribution to the much more common sporadic disease has been demonstrated through case control association studies and, more recently, genome-wide association studies. Interestingly, some of the genes with Mendelian inheritance, such as SNCA, are also relevant to the sporadic disease, suggesting common pathogenetic mechanisms. In this review, we place an emphasis on Mendelian forms, and in particular genetic defects which present predominantly with Parkinsonism. We provide details into the particular phenotypes associated with each genetic defect, with a particular emphasis on nonmotor symptoms. For genetic defects for whom a sufficient number of patients has been assessed, there are evident genotype-phenotype correlations. However, it should be noted that patients with the same causative mutation may present with distinctly divergent phenotypes. This phenotypic variability may be due to genetic, epigenetic or environmental factors. From a clinical and genetic point of view, it will be especially interesting in the future to identify genetic factors that modify disease penetrance, the age of onset or other specific phenotypic features.

Effect of cytosine arabinoside on cerebellar neurofilaments during development: A sexual dimorphism

Previous reports suggest that the resistance of neuronal cytoskeleton to drug toxicity may vary with age and gender. The aim of the present study was to assess the impact of cytosine arabinoside (AraC) treatment on neurofilament (NF) levels and phosphorylation status in the developing cerebellum of male, female and testosterone propionate (1.25 mg/rat)-androgenized female rats. AraC (200 mg/kg bw) was administered from postnatal day (PND) 14–16 and changes in the level and phosphorylation of NFs were detected at PND 16 by Western blot analysis. The drug had no effect in male pups, while it increased the non-phosphorylated NF subunits of medium and low molecular weight in females. Androgenization of females prevented the AraC-induced increase in NF subunits. The levels of estrogen receptor beta (ER-β), known to mediate neuroprotective actions of estrogens in the brain, were significantly higher in the developing female cerebellum, as compared to males and androgenized females. These data show that the neurofilament cytoskeleton in the developing rat cerebellum exhibits resistance to AraC that appears sexually dimorphic. In young males the resistance is exemplified by a lack of responsiveness, whereas in juvenile females it is presented by an androgenization-sensitive NF upregulation.