1.
Calcium ions in neuronal degeneration.
Source
Laboratory of Neurodegeneration, International Institute of Molecular and Cell Biology, Ks. Trojdena 4, 02-109 Warsaw, Poland. ulawojda@iimcb.gov.pl
Abstract
Neuronal Ca(2+) homeostasis and Ca(2+) signaling regulate multiple neuronal functions, including synaptic transmission, plasticity, and cell survival. Therefore disturbances in Ca(2+) homeostasis can affect the well-being of the neuron in different ways and to various degrees. Ca(2+) homeostasis undergoes subtle dysregulation in the physiological ageing. Products of energy metabolism accumulating with age together with oxidative stress gradually impair Ca(2+) homeostasis, making neurons more vulnerable to additional stress which, in turn, can lead to neuronal degeneration. Neurodegenerative diseases related to aging, such as Alzheimer's disease, Parkinson's disease, or Huntington's disease, develop slowly and are characterized by the positive feedback between Ca(2+) dyshomeostasis and the aggregation of disease-related proteins such as amyloid beta, alfa-synuclein, or huntingtin. Ca(2+) dyshomeostasis escalates with time eventually leading to neuronal loss. Ca(2+) dyshomeostasis in these chronic pathologies comprises mitochondrial and endoplasmic reticulum dysfunction, Ca(2+) buffering impairment, glutamate excitotoxicity and alterations in Ca(2+) entry routes into neurons. Similar changes have been described in a group of multifactorial diseases not related to ageing, such as epilepsy, schizophrenia, amyotrophic lateral sclerosis, or glaucoma. Dysregulation of Ca(2+) homeostasis caused by HIV infection or by sudden accidents, such as brain stroke or traumatic brain injury, leads to rapid neuronal death. The differences between the distinct types of Ca(2+) dyshomeostasis underlying neuronal degeneration in various types of pathologies are not clear. Questions that should be addressed concern the sequence of pathogenic events in an affected neuron and the pattern of progressive degeneration in the brain itself. Moreover, elucidation of the selective vulnerability of various types of neurons affected in the diseases described here will require identification of differences in the types of Ca(2+) homeostasis and signaling among these neurons. This information will be required for improved targeting of Ca(2+) homeostasis and signaling components in future therapeutic strategies, since no effective treatment is currently available to prevent neuronal degeneration in any of the pathologies described here.
Copyright 2008 IUBMB
Genetics of Parkinson's disease.
Source
Department of Clinical Genetics, Erasmus MC, Rotterdam, The Netherlands. v.bonifati@erasmusmc.nl
Abstract
The past few years, mutations in 5 genes (a-synuclein, parkin, DJ-1, PINK1, and LRRK2) have been firmly implicated, and additional chromosomal loci have been mapped for inherited forms of Parkinson's disease (PD). These discoveries have profound implications for both the scientific and clinical communities. First, although some of the Mendelian forms of PD are very rare (including those caused by alfa-synuclein, DJ-1, and PINK1 mutations) they are facilitating greatly the dissection of the molecular pathways that lead to death of dopaminergic neurons; these pathways might also be implicated in the pathogenesis of the common forms of PD. Second, the discoveries of Mendelian forms are challenging the concept of PD as one disease, as well as the validity of the current clinico-pathological disease definition. Last, mutations in 2 of these genes turned out to be frequent enough to have relevance in clinical practice: parkin mutations are common in early-onset familial and sporadic PD; moreover, emerging data delineate mutations in the LRRK2 gene (encoding the dardarin protein) as a frequent cause of the familial late onset PD forms, and even of few late-onset sporadic cases. The importance of genetic testing is expected to increase in the near future in the PD field. Here, the author provides a brief update on the genetics of the monogenic forms of PD.
- PMID:
- 16175160
- [PubMed - indexed for MEDLINE]
[The genetics of Parkinson disease].
Source
Institutt for nevromedisin, Det medisinske fakultet, Norges teknisk-naturvitenskapelige universitet.
Abstract
BACKGROUND:
Parkinson's disease, PD, is the second most common neurodegenerative disorder. A genetic component in Parkinson's disease was long thought to be unlikely, but recent genetic studies have identified several genes associated with the disease.
MATERIAL AND METHODS:
A review of the literature and personal experiences from genetic studies in central Norway are presented.
RESULTS:
Nine loci on the human genome have been linked to Parkinson's disease. Mutations in the alfa-synuclein, parkin, DJ-1, and arguably UCH-L1 genes are identified for familial PD. Recently a locus on chromosome 1 was linked to common late-onset PD in the Icelandic population. Iceland's population is primarily of Norse descent. This locus may be of significant importance to Norwegian PD patients.
INTERPRETATION:
The genes and loci identified have improved our understanding of the pathogenesis in PD significantly. This knowledge may help to create new treatment strategies for PD.
[Type I neurodegeneration with brain iron accumulation, (NBIA-I, formerly Hallervorden-Spatz disease). Part II -- neuropathologic manifestation, novel genetic aspects and pathogenesis].
Source
Zakładu Neuropatologii, Instytutu Psychiatrii i Neurologii w Warszawie. bertrand@ipin.edu.pl
Abstract
In NBIA-1 major histopathological changes in the central nervous system are observed mostly in the subcortical pallido-nigral system. They consist in the presence of brown pigment deposits (containing iron), axonal spheroids, as well as Lewy neurities and cytoplasmic inclusions in the oligodendroglia (both the latter contain pathological alfa-synuclein). However, the histopathological pattern is most the diversified as regards the intensity and range of typical structural changes. The gene of the disease has been very recently identified and mapped on the short arm of the chromosome 20p13.-p12.3. The discovery of the NBIA-1 gene is a great advance in the search for a causal cure for this devastating disease. Its etiopathogenesis has not been fully explained yet. However, the gene identification allows to hypothesize that vitamin B5 metabolism may be disturbed at least in some NBIA-1 patients. Disturbance of vitamin B5 metabolism may cause an oxidative stress leading to degenerative and atrophic changes, most pronounced in the subcortical pallido-nigral system and in the retina.
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