metallothionein and Brain-Diseases

Metallothioneins are a family of proteins which are able to bind metals intracellularly, so their main function is to regulate the cellular metabolism of essential metals. There are 4 major isoforms of MTs (I-IV), three of which have been localized in the central nervous system. MT-I and MT-II have been localized in the spinal cord and brain, mainly in astrocytes, whereas MT-III has been found mainly in neurons. MT-I and MT-II have been considered polyvalent proteins whose main function is to maintain cellular homeostasis of essential metals such as zinc and copper, but other functions have also been considered: detoxification of heavy metals, regulation of gene expression, processes of inflammation, and protection against free radicals generated by oxidative stress. On the other hand, the MT-III has been related in events of pathogenesis of neurodegenerative diseases such as Parkinson and Alzheimer. Likewise, the participation of MTs in other neurological disorders has also been reported. This review shows recent evidence about the role of MT in the central nervous system and its possible role in neurodegenerative diseases as well as in brain disorders.

Topics: Animals; Brain Diseases; Metallothionein; Rats

The divalent cation zinc is an integral requirement for optimal cellular processes, whereby it contributes to the function of over 300 enzymes, regulates intracellular signal transduction, and contributes to efficient synaptic transmission in the central nervous system. Given the critical role of zinc in a breadth of cellular processes, its cellular distribution and local tissue level concentrations remain tightly regulated via a series of proteins, primarily including zinc transporter and zinc import proteins. A loss of function of these regulatory pathways, or dietary alterations that result in a change in zinc homeostasis in the brain, can all lead to a myriad of pathological conditions with both acute and chronic effects on function. This review aims to highlight the role of zinc signaling in the central nervous system, where it may precipitate or potentiate diverse issues such as age-related cognitive decline, depression, Alzheimer's disease or negative outcomes following brain injury.

Topics: Animals; Biological Transport; Brain; Brain Diseases; Carrier Proteins; Homeostasis; Humans; Iron; Metallothionein; Signal Transduction; Zinc

Prion and other amyloid-forming diseases represent a group of neurodegenerative disorders that affect both animals and humans. The role of metal ions, especially copper and zinc is studied intensively in connection with these diseases. Their involvement in protein misfolding and aggregation and their role in creation of reactive oxygen species have been shown. Recent data also show that metal ions not only bind the proteins with high affinity, but also modify their biochemical properties, making them important players in prion-related diseases. In particular, the level of zinc ions is tightly regulated by several mechanisms, including transporter proteins and the low molecular mass thiol-rich metallothioneins. From four metallothionein isoforms, metallothionein-3, a unique brain-specific metalloprotein, plays a crucial role only in this regulation. This review critically evaluates the involvement of metallothioneins in prion- and amyloid-related diseases in connection with the relationship between metallothionein isoforms and metal ion regulation of their homeostasis.

Topics: Amyloidosis; Animals; Brain Diseases; Humans; Metallothionein; Prion Diseases

Since the seminal discoveries of Bert Vallee regarding zinc and metallothioneins (MTs) more than 50 years ago, thousands of studies have been published concerning this fascinating story. One of the most active areas of research is the involvement of these proteins in the inflammatory response in general, and in neuroinflammation in particular. We describe the general aspects of the inflammatory response, highlighting the essential role of the major cytokine interleukin-6, and review briefly the expression and function of MTs in the central nervous system in the context of neuroinflammation. Particular attention is paid to the Tg2576 Alzheimer disease mouse model and the preliminary results obtained in mice into which human Zn(7)MT-2A was injected, which suggest a reversal of the behavioral deficits while enhancing amyloid plaque load and gliosis.

Topics: Alzheimer Disease; Animals; Behavior, Animal; Brain Diseases; Humans; Inflammation; Interleukin-6; Metallothionein

Topics: 6-Aminonicotinamide; Animals; Brain; Brain Diseases; Brain Injuries; Central Nervous System; Central Nervous System Diseases; DNA Fragmentation; Humans; Immunohistochemistry; In Situ Nick-End Labeling; Inflammation Mediators; Lymphocyte Activation; Macrophages; Metallothionein; Necrosis; Neovascularization, Pathologic; Neurofibrillary Tangles; Oxidative Stress; Tumor Necrosis Factor-alpha

I have briefly detailed in this review the role of astrocytes in MeHg neurotoxicity, emphasizing the mechanisms and significance of astrocytic swelling in neuropathological conditions. I have also described the functions of brain MTs and have reported recent observations on their propensity to attenuate cytotoxicity. While it is unclear why three different MT genes are expressed in the brain, this redundancy should allow for greater accumulation of MTs under stressful conditions compared to its accumulation if only a single gene was present. Another explanation may be that genes encoding functionally identical MTs might be regulated independently, thus permitting cell-specific MT expression. Finally, each of the three MT isoforms may have distinct functions. As discussed herein, astrocytic MTs afford protection from the acute cytotoxic effects of MeHg, reversing the effect of this organometal on RVD and inhibition of taurine release. Whether other vital cellular functions are protected by MTs will have to await future studies, as will the mechanisms associated with MT-induced cellular protection. That the resistance to heavy metal toxicity is closely related to the cellular ability to synthesize MTs, raises interesting questions regarding the potential involvement of heavy metals in neurodegenerating (amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease) under conditions of compromised MT synthesis. Future studies on the expression and regulation of MT genes are likely to culminate in novel strategies for manipulating intracellular MT levels, providing insight to their role in both health and disease.

Topics: Animals; Astrocytes; Brain Diseases; Humans; Metallothionein; Methylmercury Compounds; Models, Neurological; Neuroprotective Agents; Neurotoxins

The effects of two major isoforms of metallothioneins (MTs), MT-I and -II, on dopaminergic neurotoxicity of 6-hydroxydopamine (6-OHDA) were examined using intracerebroventricularly 6-OHDA-injected MT-I, II knock-out (KO) mice. The loss of dopamine neurons in the substantia nigra pars compacta induced by the 6-OHDA injection was significantly aggravated in the MT-I, II KO mice, compared with that in the 6-OHDA-injected wild-type mice. The present results, taken together with the antioxidant properties of MT-I and -II suggest that MT-I and -II exert neuroprotective effects against the dopaminergic neurotoxicity of 6-OHDA at the nigral cell body by scavenging free radicals.

Topics: Animals; Brain; Brain Diseases; Denervation; Dopamine Plasma Membrane Transport Proteins; Injections, Intraventricular; Membrane Glycoproteins; Membrane Transport Proteins; Metallothionein; Mice; Mice, Knockout; Nerve Tissue Proteins; Neurotoxins; Oxidopamine; Reactive Oxygen Species; Sympatholytics; Tyrosine 3-Monooxygenase

To study the neurophysiological functions of metallothioneins (MTs), localization of MT-I and -II was examined immunohistochemically in a variety of brain lesions in dogs, including infarct, laminar cortical necrosis, hemorrhage, invasive growth of tumour, inflammatory lesions in granulomatous meningoencephalitis and distemper encephalitis. MT-I and -II were demonstrated in both nucleus and cytoplasm of hypertrophic astrocytes in most brain lesions examined regardless of the type, size, localization and duration of the lesions. In addition, MT expression was stronger in a population of hypertrophic astrocytes localizing inside of the surviving brain tissue rather than those localizing at the boundary between the surviving brain tissue and necrotic area, where severe inflammatory changes were developing. These results suggest that MT-I and -II may play roles not only in protection of neurons from metals and free radicals ubiquitous in the inflammatory lesions but also in repair of injured neural tissues.

Topics: Adenocarcinoma; Animals; Astrocytes; Brain Diseases; Brain Neoplasms; Cerebral Hemorrhage; Cerebral Infarction; Distemper; Dog Diseases; Dogs; Encephalitis, Viral; Female; Glial Fibrillary Acidic Protein; Hypertrophy; Inflammation; Male; Meningoencephalitis; Metallothionein; Necrosis; Neoplasm Invasiveness; Pituitary Neoplasms

We report a boy of East Indian origin, aged 2 years and 10 months, who died suddenly and unexpectedly. Autopsy findings showed marked cerebral swelling with herniation and histological evidence of marked cerebral edema with perivascular protein leakage, indicating blood-brain barrier disruption. Energy dispersive X-ray microprobe analysis of the brain demonstrated the presence of cadmium and a marked increase in sulfur, predominantly intracellular, both within neuroglial, and to a lesser degree endothelial, cells. Localization was predominantly in the nucleus. Analysis of the kidney showed cadmium deposition in renal tubules and in the basal lamina of podocytes within the glomerulus. Although the environmental source of cadmium remains unknown, we speculate that acute cadmium toxicity led to brain intracellular accumulation with resultant cellular dysfunction, blood-brain barrier disruption, and lethal cerebral edema.

Topics: Blood-Brain Barrier; Brain Diseases; Brain Edema; Cadmium; Child, Preschool; Humans; Kidney; Male; Metallothionein