Normal CAG and CCG repeats in the Huntington's disease genes of Parkinson's disease patients

The clinical features of Parkinson's disease, particularly rigidity and bradykinesia and occasionally tremor, are seen in juvenile-onset Huntington's disease. Therefore, the CAG and CCG repeats in the Huntington's disease gene were investigated in 45 Parkinson's disease patients and compared to 40 control individuals. All of the Parkinson's disease chromosomes fell within the normal size ranges. In addition, the distributions of the two repeats in the Parkinson's disease patients did not differ significantly from those of the control population. Therefore, abnormalities of these trinucleotide repeats in the Huntington's disease gene are not likely to contribute to the pathogenesis of Parkinson's disease. © 1995 Wiley-Liss, Inc.     

Influence of Competing Distractors on Response Selection in Huntington's Disease and Parkinson's Disease

Current theories of the basal ganglia suggest a functional role in filtering stimuli that are competing for response selection. We hypothesised that damage to the basal ganglia, as occurs in Huntington's disease (HD) and Parkinson's disease (PD), may alter the effects of distractors on this filtering process. Fourteen HD subjects, 16 PD subjects, and age-matched healthy controls performed an ignored repetition test of negative priming. Negative priming was defined as a significant time cost in responding to a target that shared features with the distractor from the previous trial. Results indicated that whereas healthy controls and PD subjects showed normal negative priming, HD subjects failed to show negative priming. The results indicate that disruption to cells in the neostriatum, but not necessarily to cells in the substantia nigra, may affect selective attention by altering the influence of distractor stimuli competing for action.     

Mitochondria, calcium-dependent neuronal death and neurodegenerative disease

Understanding the mechanisms of neuronal dysfunction and death represents a major frontier in contemporary medicine, involving the acute cell death in stroke, and the attrition of the major neurodegenerative diseases, including Parkinson's, Alzheimer's, Huntington's and Motoneuron diseases. A growing body of evidence implicates mitochondrial dysfunction as a key step in the pathogenesis of all these diseases, with the promise that mitochondrial processes represent valuable potential therapeutic targets. Each disease is characterised by the loss of a specific vulnerable population of cells??dopaminergic neurons in Parkinson's disease, spinal motoneurons in Motoneuron disease, for example. We discuss the possible roles of cell type-specific calcium signalling mechanisms in defining the pathological phenotype of each of these major diseases and review central mechanisms of calcium-dependent mitochondrial-mediated cell death.     

Induction of heat shock protein 70 reduces the alteration of striatal electrical activity caused by mitochondrial impairment

Since mild thermal stress seems to exert neuroprotection via induction of heat-shock protein 70 kDa (hsp70), we tested whether hsp70 would preserve striatal bioelectrical activity under conditions of mitochondrial impairment. Corticostriatal slices from rats that had undergone mild thermal stress were exposed to either rotenone or 3-nitropropionic acid (3-NP), that selectively inhibits mitochondrial complex I and complex II, respectively. Rotenone is utilized to obtain an experimental model of Parkinson's disease while 3-NP replicates Huntington's disease phenotype in experimental animals. The cerebral hsp70 increase did not alter field potential amplitude of the slices but partially protected them against rotenone-induced neurotoxicity. Similarly, induction of hsp70 had also a partial neuroprotective effect on the neurotoxicity caused by 3-NP on striatal field potential. Since rotenone and 3-NP treatments mimic the mitochondrial impairment and oxidative stress that contribute to development of Parkinson's disease and Huntington's disease, these data suggest that induction of hsp70 might represent a possible neuroprotective mechanism against the pathophysiological chain of events implicated in these neurodegenerative disorders.     

Error processing in normal aging and in basal ganglia disorders

Recently it has been shown that effects of aging and pathologically induced changes of basal ganglia structures may have quite similar effects on cognitive functions mediated by the medial prefrontal cortex. The question appears, if this pattern may be assignable to other cognitive functions that are mediated via the basal ganglia and medial prefrontal brain areas. Error processing is a component of executive functions that also depends on these areas and especially on the anterior cingulate cortex (ACC). Hence we ask, if error processing functions are differentially modulated by normal aging and basal ganglia diseases. Error processing mechanisms in these groups were investigated using a cognitive event-related potential (ERP), the error negativity. Enrolling an extended sample of young and elderly controls, as well as patients with Parkinson's and Huntington's disease, we show that modulations of error processing differ between aging, different basal ganglia diseases. Despite that the examined basal ganglia disorder groups (Parkinson's and Huntington's disease) differ in their age they show similar modulations in error processing, suggesting that aging effects are overridden by pathogenic effects. The study shows that it may be valuable to compare aging not only to different forms of basal ganglia disorders in order to gain knowledge about age- and disease-related mechanisms and the effects of these on cognitive functions. Diseases of the basal ganglia may impact error processing above and beyond the effects of normal aging. Although many aging, Parkinson's disease and Huntington's disease studies on error processing functions have already been published, this study ties together several related observations across all of these groups in one experiment.     

Autophagy in neurodegenerative diseases: pathogenesis and therapy

The most prevalent pathological features of many neurodegenerative diseases are the aggregation of misfolded proteins and the loss of certain neuronal populations. Autophagy, as major intracellular machinery for degrading aggregated proteins and damaged organelles, has been reported to be involved in the occurrence of pathological changes in many neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease and amyotrophic lateral sclerosis. In this review, we summarize most recent research progress in this topic and provide a new perspective regarding autophagy regulation on the pathogenesis of neurodegenerative diseases. Finally, we discuss the signaling molecules in autophagy‐related pathways as therapeutic targets for the treatment of these diseases.     

Alterations of Hrd1 expression in various encephalic regional neurons in 6-OHDA model of Parkinson's disease

The ubiquitin-proteasome system plays a central role in regulated degradation of cellular proteins under different physiological conditions. Accumulation of misfolded proteins is involved in the pathogenesis of many neurodegenerative diseases, such as Parkinson's disease (PD), Alzheimer's disease (AD) and Huntington's disease (HD). Hrd1 is a newly identified ubiquitin ligase involved in degradation of misfolded proteins from the endoplasmic reticulum (ER), thereby protecting cells against ER stress. Increasing evidence has linked ER stress to PD pathogenesis. However, the expression of Hrd1 in PD brain remains elusive. In the present study, the expression of Hrd1 in different encephalic regions was studied in 6-OHDA model of Parkinson's disease by immunohistochemistry. The results showed that Hrd1 was up-regulated in 6-OHDA-treated mice in various encephalic regional neurons, especially those in hippocampus, substantia nigra (SN), subthalamic nucleus (STN), striatum and frontal lobe. It suggested that Hrd1 up-regulation may represent a protective response against neurodegeneration in PD.     

Autophagy in aging and neurodegenerative diseases: implications for pathogenesis and therapy

Neurodegenerative diseases, such as Alzheimer's disease Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, share a common cellular and molecular pathogenetic mechanism involving aberrant misfolded protein or peptide aggregation and deposition. Autophagy represents a major route for degradation of aggregated cellular proteins and dysfunctional organelles. Emerging studies have demonstrated that up-regulation of autophagy can lead to decreased levels of these toxic aggregate-prone proteins, and is beneficial in the context of aging and various models of neurodegenerative diseases. Understanding the signaling pathways involved in the regulation of autophagy is crucial to the development of strategies for therapy. This review will discuss the cellular and molecular mechanisms of autophagy and its important role in the pathogenesis of aging and neurodegenerative diseases, and the ongoing drug discovery strategies for therapeutic modulation.     

AMPK-mediated regulation of neuronal metabolism and function in brain diseases

The AMP-activated protein kinase (AMPK) is a serine/threonine kinase that functions as a key energy sensor in a wide variety of tissues. This kinase has been a major drug target for metabolic diseases (e.g., type 2 diabetes) and cancers. For example, metformin (an activator of AMPK) is a first-line diabetes drug that protects against cancers. Abnormal regulation of AMPK has been implicated in several brain diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and stroke. Given the emerging importance of neurodegenerative diseases in our aging societies, this review features the recent studies that have delineated the functions of AMPK in brain diseases and discusses their potential clinical implications or roles as drug targets in brain diseases.     

The immunogenetics of neurological disease

Genes encoding antigen‐presenting molecules within the human major histocompatibility complex (MHC) account for the highest component of genetic risk for many neurological diseases, such as multiple sclerosis, neuromyelitis optica, Parkinson's disease, Alzheimer's disease, schizophrenia, myasthenia gravis and amyotrophic lateral sclerosis. Myriad genetic, immunological and environmental factors may contribute to an individual's susceptibility to neurological disease. Here, we review and discuss the decades long research on the influence of genetic variation at the MHC locus and the role of immunogenetic killer cell immunoglobulin‐like receptor (KIR) loci in neurological diseases, including multiple sclerosis, neuromyelitis optica, Parkinson's disease, Alzheimer's disease, schizophrenia, myasthenia gravis and amyotrophic lateral sclerosis. The findings of immunogenetic association studies are consistent with a polygenic model of inheritance in the heterogeneous and multifactorial nature of complex traits in various neurological diseases. Future investigation is highly recommended to evaluate both coding and non‐coding variation in immunogenetic loci using high‐throughput high‐resolution next‐generation sequencing technologies in diverse ethnic groups to fully appreciate their role in neurological diseases.     

Modern approaches for modelling dystonia and Huntington's disease in vitro and in vivo

Dystonia associated with Huntington's disease, Parkinson's disease or other neurodegenerative diseases substantially affects patients’ quality of life and is a major health problem worldwide. The above‐mentioned diseases are characterized by neurodegeneration accompanied by motor and cognitive impairment and often have complex aetiology. A frequent feature of these conditions is the abnormal accumulation of protein aggregates within specific neuronal populations in the affected brain regions. Familial neurodegenerative diseases are associated with a number of genetic mutations. Identification of these mutations allowed creation of modern model systems for studying neurodegeneration, either in cultured cells or in model animals. Animal models, especially mouse models, have contributed considerably to improving our understanding of the pathophysiology of neurodegenerative diseases. These models have allowed study of the pathogenic mechanisms and development of new disease‐modifying strategies and therapeutic approaches. However, due to the complex nature of these pathologies and the irreversible damage that they cause to the neural tissue, effective therapies against neurodegeneration remain to be elaborated. In this review, we provide an overview of cellular and animal models developed for studying neurodegenerative diseases, including Huntington's disease and dystonia of different origins.     

The Epidemiology of Dementia Associated with Parkinson's Disease

Parkinson''s disease (PD) is the second most common neurodegenerative illness after Alzheimer''s disease (AD). Cognitive impairment and dementia are common features in PD and characterized by a wide range of cognitive deficits distinct from those seen in AD. Mild cognitive impairment occurs even early in PD and is associated with shorter time to dementia. The purpose of this review is to present recent findings on clinical aspects of dementia in PD and to elucidate underlying clinical and neurobiological risk factors.     

No allelic association between Parkinson's disease and dopamine D2, D3, and D4 receptor gene polymorphisms

Parkinson's disease is thought to be caused by a combination of unknown environmental, genetic, and degenerative factors. Evidence from necropsy brain samples and pharmacokinetics suggests involvement of dopamine receptors in the pathogenesis or pathophysiology of Parkinson's disease. Genetic association studies between Parkinson's disease and dopamine D2, D3 and D4 receptor gene polymorphisms were conducted. The polymorphism was examined in 71 patients with Parkinson's disease and 90 controls. There were no significant differences between two groups in allele frequencies at the D2, D3, and D4 dopamine receptor loci. Our findings do not support the hypothesis that susceptibility to Parkinson's disease is associated with the dopamine receptor polymorphisms examined. © 1994 Wiley-Liss, Inc.     

Genetic Analysis of PARK2 and PINK1 Genes in Brazilian Patients with Early-Onset Parkinson's Disease

Parkinson''s disease is the second most frequent neurodegenerative disorder in the world, affecting 1-2% of individuals over the age of 65. The etiology of Parkinson''s disease is complex, with the involvement of gene-environment interactions. Although it is considered a disease of late manifestation, early-onset forms of parkinsonism contribute to 5–10% of all cases. In the present study, we screened mutations in coding regions of PARK2 and PINK1 genes in 136 unrelated Brazilian patients with early-onset Parkinson''s disease through automatic sequencing. We identified six missense variants in PARK2 gene: one known pathogenic mutation, two variants of uncertain role, and three nonpathogenic changes. No pathogenic mutation was identified in PINK1 gene, only benign polymorphisms. All putative pathogenic variants found in this study were in heterozygous state. Our data show that PARK2 point mutations are more common in Brazilian early-onset Parkinson''s disease patients (2.9%) than PINK1 missense variants (0%), corroborating other studies worldwide.     

Verbal fluency in Alzheimer's disease, Parkinson's disease, and major depression

OBJECTIVE:

To compare verbal fluency among Alzheimer''s disease, Parkinson''s disease, and major depression and to assess the sociodemographic and clinical factors associated with the disease severity.

METHODS:

Patients from an outpatient university center with a clinical diagnosis of Alzheimer''s disease, Parkinson''s disease or major depression were studied. Severity was staged using the Hoehn & Yahr scale, the Hamilton Depression scale and the Clinical Dementia Rating for Parkinson''s disease, major depression, and Alzheimer''s disease, respectively. All subjects were tested with the Mini-Mental State Examination, the digit span test, and the verbal fluency test (animals).We fit four types of regression models for the count variable: Poisson model, negative binomial model, zero-inflated Poisson model, and zero-inflated negative binomial model.

RESULTS:

The mean digit span and verbal fluency scores were lower in patients with Alzheimer''s disease (n = 34) than in patients with major depression (n = 52) or Parkinson''s disease (n = 17) (p<0.001). The average number of words listed was much lower for Alzheimer''s disease patients (7.2 words) compared to the patients presenting with major depression (14.6 words) or Parkinson''s disease (15.7 words) (KW test = 32.4; p<0.01). Major depression and Parkinson''s disease groups listed 44% (ROM = 1.44) and 48% (ROM = 1.48) more words, respectively, compared to those patients with Alzheimer''s disease; these results were independent of age, education, disease severity and attention. Independently of diagnosis, age, and education, severe disease showed a 26% (ROM = 0.74) reduction in the number of words listed when compared to mild cases.

CONCLUSIONS:

Verbal fluency provides a better characterization of Alzheimer''s disease, major depression, and Parkinson''s disease, even at later stages.     

Symposium on neurobiology of the basal ganglia

The basal ganglia occupy a commanding place in neuroscience research, in clinical neurology and in biomedical education. The paucity of our understanding of the role of the basal ganglia in normal everyday life combined with our more extensive knowledge of their deficiencies in a variety of clinical syndromes is a potent spur to continuing investigation. That some of these neurodegenerative syndromes—such as Parkinson's disease—are already common only heightens the need for insight in the face of a population with increasing expectations of longevity. About a decade ago an explosion of information on the connectivity and immunocytochemistry of forebrain structures gave rise to concepts which have shaped the fabric of basal ganglia theory—‘patch and matrix’, ‘disinhibition’, ‘parallel circuits’. Some of these ideas seemed to facilitate an understanding of the basal ganglia, others to render them more complex and impenetrable. Perhaps unsurprisingly, the work of the last decade has tended towards consolidation and refinement. However, several new developments are receiving attention, many of them related to disorders of the basal ganglia. The realisation that some forms of Parkinson's disease have a genetic determinant is gaining strength. The molecular biology of the dopaminergic synapse on the one hand and of the production of insoluble proteins on the other will clearly influence future research into therapeutic options and neuroprotection. The importance of apoptosis, neural plasticity and free radical formation remains unresolved but these are potential areas of promise. Meanwhile, scanning techniques for brain imaging are allowing real time investigation of the working striatum in normal and disordered humans and animals. We believe that the time is opportune for a broad review of current thinking on the basal ganglia in health and disease. The following articles are based on presentations given at a Symposium on the Neurobiology of the Basal Ganglia held at Glasgow University in July 1999 as part of the Summer Meeting of the Anatomical Society of Great Britain and Ireland. The invited speakers were chosen to be wide ranging and contributions encompassed evolution, circuitry and receptors of the basal ganglia, striatal remodelling after dopamine loss, striatal functioning in humans with Huntington's disease and in primate models after midbrain fetal transplants, and the genetics of basal ganglia disorders. Short presentations and posters of current results supplemented the main presentations and some are also included amongst these reviews.     

Neuroimmunology and neuroinflammation in autoimmune,neurodegenerative and psychiatric disease

An ever‐increasing collection of neurological human diseases are becoming appreciated as encompassing a strong immunological component in pathogenesis or regulation. This derives to a large extent from genome‐wide association studies that have highlighted association with immune system genes, including those in the HLA and KIR regions. Along with the genomic findings have come insights from immune phenotyping and assays for autoimmunity. This is a group of disease processes that includes Parkinson's disease, Alzheimer's, stroke, narcolepsy, schizophrenia and psychosis. In most cases, these are diseases in which we assume that differential regulation of central nervous system inflammation may impact symptoms and severity. The specific roles played by the immune response in these disease processes is largely uncharted and will require considerable investigation.     

International workshop on the fragile X and X-linked mental retardation

The erythrocyte osmotic fragility was evaluated on 19 unmedicated subjects with Huntington's disease and 42 individuals at 50% risk, 27 children at 25% risk, and a group of 60 hematologically normal control persons. Five older subjects at 50% risk for Huntington's disease as well as 6 Alzheimer's disease individuals were also evaluated for comparison. The osmotic fragility of fresh and 24-hour incubated red cells was analyzed and a fragility index calculated for each individual. The fragility index for the Huntington's disease group was statistically lower than that of the control group (P < .001) suggesting that the Huntington's disease erythrocytes had a reduced osmotic fragility. In the 50% risk group, 45% of the subjects demonstrated decreased osmotic fragility and 55% had normal fragility. For those subjects in the 25% risk group, 22.2% had decreased fragility and 77.8% had normal fragility. Twenty-seven offspring were evaluated of the 14 persons at 50% risk for Huntington's disease with children; eight of the 14 individuals at 50% risk showed normal fragility and all 16 of their children showed fragility indices with the normal range. The remaining six persons at 50% risk for Huntington's disease had increased erythrocyte fragility and out of their 11 children, five showed normal fragility and six had decreased fragility. These data support the hypothesis of reduced erythrocyte osmotic fragility in individuals affected with and at risk for Huntington disease, and demonstrate the need of further study of the erythrocyte in this complex behavioral genetic disease.