Syncoilin, an intermediate filament-like protein linked to the dystrophin associated protein complex in skeletal muscle

Syncoilin is a member of the intermediate filament protein family, highly expressed in skeletal and cardiac muscle. Syncoilin binds α-dystrobrevin, a component of the dystrophin associated protein complex (DAPC) located at the muscle cell membrane, and desmin, a muscle-specific intermediate filament protein, thus providing a link between the DAPC and the muscle intermediate filament network. This link may be important for muscle integrity and force transduction during contraction, a theory that is supported by the reduced force-generating capacity of muscles from syncoilin-null mice. Additionally, syncoilin is found at increased levels in the regenerating muscle fibres of patients with muscular dystrophies and mouse models of muscle disease. Therefore, syncoilin may be important for muscle regeneration in response to injury. The aims of this article are to review current knowledge about syncoilin and to discuss its possible functions in skeletal muscle. Received 21 May 2008; received after revision 10 July 2008; accepted 18 July 2008     

Pelizaeus-Merzbacher disease: Genetic and cellular pathogenesis

Pelizaeus-Merzbacher disease (PMD) and the allelic spastic paraplegia type 2 (SPG2) arise from mutations in the X-linked gene encoding myelin proteolipid protein (PLP). Analysis of mutations affecting PLP, the major protein in central nervous system myelin, has revealed previously unsuspected roles for myelinating glia in maintaining the integrity of the nervous system. The disease spectrum for PMD and SPG2 is extraordinarily broad and can be best understood by accounting not only for the wide range of mutations that can occur but also for the effects of PLP1 mutations on both cell autonomous and non-cell autonomous processes in myelinating cells. Appreciating the wide range of genetic and cellular effects of PLP1 mutations is important for patient and family counseling, understanding disease pathogenesis, and, ultimately, for developing future disease-specific therapies. Received 24 April 2006; received after revision 3 July 2006; accepted 9 October 2006     

Monogenetic determinants of Alzheimer's disease: APP mutations

Mutations within exons 16 and 17 of the β-amyloid precursor protein (APP) gene were the first known cause of familial Alzheimer's disease. These mutations are rare and have been reported in a handful of families exhibiting autosomal dominant inheritance of Alzheimer's disease with age of onset around 50 years. In vitro and in vivo studies have demonstrated that each of these mutations alters proteolytic processing of APP, resulting in an increase in the production of Aβ42, a highly fibrillogenic peptide, that spontaneously aggregates and deposits in the brain. Transgenic mice carrying a mutant human APP gene also show age-dependent β-amyloid (Aβ) deposition in the brain. The rate of deposition in these mice can be modified by apolipoprotein E expression.     

Keratins: a structural scaffold with emerging functions

Intermediate filament proteins form an essential part of the cytoskeleton and provide topological order to cells and tissues. These features result from their intrinsic property of self-organization and their response to extrinsic cues. Keratins represent the largest subgroup among all intermediate filament proteins and are differentially expressed as pairs of type I and type II intermediate filament proteins in epithelia. Their primary function is to impart mechanical strength to cells. This function is illustrated by patients with keratin mutations and by gene-deficient mice. Additional functions include their participation in the response to stress, cell signalling and apoptosis, and thus the keratin cytoskeleton appears far more dynamic than previously anticipated. This may result from hyperphosphorylation and possibly from interaction with associated proteins. How signalling networks affect keratin organization, turnover and function and vice versa will be a major challenge for future investigations.     

Is the ubiquitin-proteasome system impaired in Huntington’s disease?

Ubiquitylated inclusion bodies (IBs) found in Huntington’s disease (HD) postulate an impaired ubiquitin-proteasome system. However, this hypothesis remains controversial. In vitro-generated polyglutamine aggregates failed to inhibit purified proteasomes, while filamentous huntingtin aggregates isolated from mice resulted in inhibition. However, similarly isolated IBs did not, thus suggesting that IB formation is protective by sequestering smaller inhibitory aggregates. Accordingly, proteasome-activity assays in IB-containing mouse brain homogenates did not show decreased activity. On the contrary, some of the endoproteolytic proteasome activities increased, probably due to altered subunit composition. However, activity was found decreased in postmortem human HD tissue. Finally, evidence supporting the hypothesis was found in HD cell models expressing fluorescent ubiquitin-proteasome system reporters but not in retina of SCA-7 mice with similar reporters. In summary, it seems that mutant huntingtin, probably in intermediate aggregate forms, has the potential to inhibit proteasome activity, but the global status of the system in HD brain tissue is not yet fully elucidated.     

Effect of olfactory ensheathing cells on reactive astrocytes <Emphasis Type="Italic">in vitro</Emphasis>

Olfactory ensheathing cells have been used in several studies to promote repair in the injured spinal cord. However, cellular interaction between olfactory ensheathing cells and glial cells induced to be reactive in the aftermath of injury site has not been investigated. Using an in vitro model of astrogliosis, we show that reactive astrocytes expressed significantly less glial fibrillary acidic protein (GFAP) when cultured both in direct contact with olfactory ensheathing cells and when the two cell types were separated by a porous membrane. Immunofluorescence staining also suggested that reactive astrocytes showed decreased chondroitin sulfate proteoglycans in the presence of olfactory ensheathing cells, although the reduction was not statistically significant. No down-regulation of GFAP was observed when reactive astrocytes were similarly cultured with Schwann cells. Cell viability assay and bromodeoxyuridine uptake showed that proliferation of reactive astrocytes was significantly increased in the presence of olfactory ensheathing cells and Schwann cells. Received 27 February 2007; received after revision 30 March 2007; accepted 3 April 2007     

Chimeras of human lysozyme and α-lactalbumin: an interesting tool for studying partially folded states during protein folding

Protein folding is an extremely active field of research where biology, chemistry, computer science and physics meet. Although the study of protein-folding intermediates in general and equilibrium intermediates in particular has grown considerably in recent years, many questions regarding the conformational state and the structural features of the various partially folded intermediate states remain unanswered. Performing kinetic measurements on proteins that have had their structures modified by site-directed mutagenesis, the so-called protein-engineering method, is an obvious way to gain fine structural information. In the present review, this method has been applied to a variety of proteins belonging to the lysozyme/α-lactalbumin family. Besides recombinants obtained by point mutations of individual critical residues, chimeric proteins in which whole structural elements (10 – 25 residues) from α-lactalbumin were inserted into a human lysozyme matrix are examined. The conformational properties of the equilibrium intermediate states are discussed together with the structural characterization of the partially unfolded states encountered in the kinetic folding pathway. Received 28 May 1998; received after revision 6 July 1998; accepted 6 July 1998     

Where, when and how much: regulation of myelin proteolipid protein gene expression

The myelin proteolipid protein (PLP) gene (Plp) encodes the most abundant protein found in myelin from the central nervous system (CNS). Expression of the gene is regulated in a spatiotemporal manner with maximal levels of expression occurring in oligodendrocytes during the active myelination period of CNS development, although other cell types in the CNS as well as in the periphery can express the gene to a much lower degree. In oligodendrocytes, Plp gene expression is tightly regulated. Underexpression or overexpression of the gene has been shown to have adverse effects in humans and other vertebrates. In light of this strict control, this review provides an overview of the current knowledge of Plp gene regulation.Received 4 August 2003; received after revision 17 September 2003; accepted 24 September 2003     

Mitochondrial DNA replication and disease: insights from DNA polymerase γ mutations

DNA polymerase γ (pol γ), encoded by POLG, is responsible for replicating human mitochondrial DNA. About 150 mutations in the human POLG have been identified in patients with mitochondrial diseases such as Alpers syndrome, progressive external ophthalmoplegia, and ataxia-neuropathy syndromes. Because many of the mutations are described in single citations with no genotypic family history, it is important to ascertain which mutations cause or contribute to mitochondrial disease. The vast majority of data about POLG mutations has been generated from biochemical characterizations of recombinant pol γ. However, recently, the study of mitochondrial dysfunction in Saccharomyces cerevisiae and mouse models provides important in vivo evidence for the role of POLG mutations in disease. Also, the published 3D-structure of the human pol γ assists in explaining some of the biochemical and genetic properties of the mutants. This review summarizes the current evidence that identifies and explains disease-causing POLG mutations.     

Pycnogenol enhances immune and haemopoietic functions in senescence-accelerated mice

Pycnogenol (procyanidin extracted from Pinus maritima) has been shown to be a potent free radical scavenger and an antioxidant phytochemical. The effects of pycnogenol on immune and haemopoietic dysfunction in senescence-accelerated mice (SAM), as a murine model of accelerated ageing, were determined. SAMP8, a strain of senile-prone mice, exhibit learning and memory deficits, immunodeficiency and dysfunction of the haemopoietic system. Oral feeding with pycnogenol for 2 months significantly improved their T- and B-cell function. Pycnogenol also augmented the proliferative capacity of haemopoietic progenitors of bone marrow in SAMP8. These data suggest that pycnogenol may be useful for either retardation or restoration of parameters associated with ageing. Received 3 July 1998; accepted 28 July 1998     

Metallothionein expression in the central nervous system of multiple sclerosis patients

Multiple sclerosis (MS) is a major chronic demyelinating and inflammatory disease of the central nervous system (CNS) in which oxidative stress likely plays a pathogenic role in the development of myelin and neuronal damage. Metallothioneins (MTs) are antioxidant proteins induced in the CNS by tissue injury, stress and some neurodegenerative diseases, which have been postulated to play a neuroprotective role. In fact, MT-I+II-deficient mice are more susceptible to developing experimental autoimmune encephalomyelitis (EAE), and treatment of Lewis rats with Zn-MT-II reduces EAE severity. We show here that, as in EAE, MT-I+II proteins were expressed in brain lesions of MS patients. Cells expressing MT-I+II were mainly astrocytes and activated monocytes/macrophages. Interestingly, the levels of MT-I+II were slightly increased in the inactive MS lesions in comparison with the active lesions, suggesting that MTs may be important in disease remission.     

Huntington’s disease: from huntingtin function and dysfunction to therapeutic strategies

Huntington’s disease (HD) is a neurodegenerative disorder that usually starts in middle age and is characterized by involuntary movements (chorea), personality changes and dementia, leading to death within 10–20 years. The defective gene in HD contains a trinucleotide CAG repeat expansion within its coding region that expresses a polyglutamine repeat in the protein huntingtin. Together with the characteristic formation of aggregates in HD, aberrant protein interactions and several post-translational modifications affect huntingtin during disease progression and lead to the dysfunction and death of selective neurons in the brains of patients. The exact molecular mechanisms by which mutant huntingtin induces cell death are not completely understood but may involve the gain of new toxic functions and the loss of the beneficial properties of huntingtin. This review focuses on the cellular functions in which huntingtin is involved and how a better understanding of pathogenic pathways can lead to new therapeutic approaches. Received 24 May 2006; received after revision 5 July 2006; accepted 23 August 2006     

Oxygen intervention in the regulation of gene expression: the photosynthetic bacterial paradigm

The means by which oxygen intervenes in gene expression has been examined in considerable detail in the metabolically versatile bacterium Rhodobacter sphaeroides. Three regulatory systems are now known in this organism, which are used singly and in combination to modulate genes in response to changing oxygen availability. The outcome of these regulatory events is that the molecular machinery is present for the cell to obtain energy by means that are best suited to prevailing conditions, while at the same time maintaining cellular redox balance. Here, we explore the dangers associated with molecular oxygen relative to the various metabolisms used by R. sphaeroides, and then present the most recent findings regarding the features and operation of each of the three regulatory systems which collectively mediate oxygen control in this organism.Received 26 June 2003; received after revision 30 July 2003; accepted 8 August 2003     

Novel estrogen receptor coregulators and signaling molecules in human diseases

The steroid hormone estrogen and signaling from its receptors are increasingly recognized as critical mediators of a variety of organ-specific biological processes. Recent advances in the identification and functional characterization of novel estrogen receptor interacting proteins clearly show the complexity of hormonal signaling regulation, but may also contribute to our understanding of the roles of estrogen signaling in normal physiology and the pathobiology of human disease.Received 12 June 2003; received after revision 21 July 2003; accepted 29 July 2003     

NLRP3 inflammasome activation in macrophage cell lines by prion protein fibrils as the source of IL-1β and neuronal toxicity

Prion diseases are fatal transmissible neurodegenerative diseases, characterized by aggregation of the pathological form of prion protein, spongiform degeneration, and neuronal loss, and activation of astrocytes and microglia. Microglia can clear prion plaques, but on the other hand cause neuronal death via release of neurotoxic species. Elevated expression of the proinflammatory cytokine IL-1β has been observed in brains affected by several prion diseases, and IL-1R-deficiency significantly prolonged the onset of the neurodegeneration in mice. We show that microglial cells stimulated by prion protein (PrP) fibrils induced neuronal toxicity. Microglia and macrophages release IL-1β upon stimulation by PrP fibrils, which depends on the NLRP3 inflammasome. Activation of NLRP3 inflammasome by PrP fibrils requires depletion of intracellular K⁺, and requires phagocytosis of PrP fibrils and consecutive lysosome destabilization. Among the well-defined molecular forms of PrP, the strongest NLRP3 activation was observed by fibrils, followed by aggregates, while neither native monomeric nor oligomeric PrP were able to activate the NLRP3 inflammasome. Our results together with previous studies on IL-1R-deficient mice suggest the IL-1 signaling pathway as the perspective target for the therapy of prion disease.     

Astrocytes in multiple sclerosis: A product of their environment

It has long been thought that astrocytes, like other glial cells, simply provide a support mechanism for neuronal function in the healthy and inflamed central nervous system (CNS). However, recent evidence suggests that astrocytes play an active and dual role in CNS inflammatory diseases such as multiple sclerosis (MS). Astrocytes not only have the ability to enhance immune responses and inhibit myelin repair, but they can also be protective and limit CNS inflammation while supporting oligodendrocyte and axonal regeneration. The particular impact of these cells on the pathogenesis and repair of an inflammatory demyelinating process is dependent upon a number of factors, including the stage of the disease, the type and microenvironment of the lesion, and the interactions with other cell types and factors that influence their activation. In this review, we summarize recent data supporting the idea that astrocytes play a complex role in the regulation of CNS autoimmunity.     

Urochordates carry multiple genes for goose-type lysozyme and no genes for chicken- or invertebrate-type lysozymes

Genome clones and expressed sequence tags (ESTs) from the ascidian Ciona intestinalis and from the larvacean Oikopleura dioica were analysed for the presence of lysozyme-encoding genes. Two genes were found to potentially code for goose-type lysozymes in Oikopleura, while three or possibly more g-type proteins form the lysozyme complement of C. intestinalis, and at least one of these genes from each species is expressed based on EST data. No genes for chicken- or invertebrate-type lysozymes were found in either urochordate species. Consistent with this finding, extracts of Oikopleura animals possessed hydrolysing activity on bacterial cell walls, and this activity was not inhibited in the presence of a known inhibitor of chicken-type lysozyme. A wide range of isoelectric points for the predicted lysozymes from Ciona (pI 4.4, 6.4 and 9.9) and from Oikopleura (pI 5.0 and 8.0) suggests tissue-specific adaptations as well as specific functional roles of the lysozymes. Comparisons of gene structures, encoded sequences, cysteine residue content and their positions in the proteins indicate that the g-type lysozymes of Ciona intestinalis are more closely related to those of vertebrates than are the g-type lysozymes of Oikopleura. Multiple genes from each species may result from separate and lineage-specific duplications followed by functional specialisation.Received 29 June 2003; received after revision 24 July 2003; accepted 29 July 2003     

Alzheimer’s disease and CADASIL are heritable,adult-onset dementias that both involve damaged small blood vessels

This essay explores an alternative pathway to Alzheimer’s dementia that focuses on damage to small blood vessels rather than late-stage toxic amyloid deposits as the primary pathogenic mechanism that leads to irreversible dementia. While the end-stage pathology of AD is well known, the pathogenic processes that lead to disease are often assumed to be due to toxic amyloid peptides that act on neurons, leading to neuronal dysfunction and eventually neuronal cell death. Speculations as to what initiates the pathogenic cascade have included toxic abeta peptide aggregates, oxidative damage, and inflammation, but none explain why neurons die. Recent high-resolution NMR studies of living patients show that lesions in white matter regions of the brain precede the appearance of amyloid deposits and are correlated with damaged small blood vessels. To appreciate the pathogenic potential of damaged small blood vessels in the brain, it is useful to consider the clinical course and the pathogenesis of CADASIL, a heritable arteriopathy that leads to damaged small blood vessels and irreversible dementia. CADASIL is strikingly similar to early onset AD in that it is caused by germ line mutations in NOTCH 3 that generate toxic protein aggregates similar to those attributed to mutant forms of the amyloid precursor protein and presenilin genes. Since NOTCH 3 mutants clearly damage small blood vessels of white matter regions of the brain that lead to dementia, we speculate that both forms of dementia may have a similar pathogenesis, which is to cause ischemic damage by blocking blood flow or by impeding the removal of toxic protein aggregates by retrograde vascular clearance mechanisms.     

RNA and protein-dependent mechanisms in tauopathies: consequences for therapeutic strategies

Tauopathies are a group of neurodegenerative diseases characterised by intracellular deposits of the microtubule-associated protein tau. The most typical example of a tauopathy is Alzheimer’s disease. The importance of tau in neuronal dysfunction and degeneration has been demonstrated by the discovery of dominant mutations in the MAPT gene, encoding tau, in some rare dementias. Recent developments have shed light on the significance of tau phosphorylation and aggregation in pathogenesis. Furthermore, emerging evidence reveals the central role played by tau pre-mRNA processing in tauopathies. The present review focuses on the current understanding of tau-dependent pathogenic mechanisms and how realistic therapies for tauopathies can be developed. Received 3 December 2006; received after revision 23 February 2007; accepted 20 March 2007     

Retention of atherogenic lipoproteins in atherogenesis

Atherosclerosis is a multifactorial disease whose pathogenesis is still unclear. Mounting evidence, however, supports the concept that subendothelial retention of apoB100-containing lipoproteins is the initiating event in atherogenesis. Subsequently, a series of biological responses to this retained material leads to specific molecular and cellular processes that promote lesion formation.Received 3 July 2003; received after revision 13 August 2003; accepted 15 August 2003