Abnormal Protein Deposition Research Articles

Heterozygosity at Polymorphic Codon 219 in Variant Creutzfeldt-Jakob Disease

Genetic variants of the prion protein gene (PRNP) strongly determine susceptibility to prion diseases. All tested patients with definite variant Creutzfeldt-Jakob disease (vCJD) are homozygous for methionine at a common polymorphism at codon 129. A further genetic polymorphism at codon 219, a common variant in several Asian populations, is considered protective against sporadic CJD. To report a finding of heterozygosity at codon 219 in 2 patients with vCJD. Case reports. MRC (Medical Research Council) Prion Unit and Department of Neurodegenerative Disease, University College London Institute of Neurology, and National Prion Clinic, National Hospital for Neurology and Neurosurgery. Patients Two patients with clinical and investigation findings consistent with the diagnoses of probable vCJD. Clinical and genetic findings. A 34-year-old man had a 15-month history of behavioral change progressing to ataxia, dysarthria, involuntary choreiform movements, and severe cognitive impairment. Cerebrospinal fluid analysis was positive for 14-3-3 protein, electroencephalography showed generalized slowing, and magnetic resonance imaging revealed thalamic high signal bilaterally, typical of vCJD. A 31-year-old woman had a 16-month history of cognitive decline, ataxia, involuntary choreiform movements, and myoclonic jerks. Magnetic resonance imaging showed bilateral pulvinar high signal. The diagnosis was confirmed by a tonsillar biopsy demonstrating abnormal prion protein deposition in a typical pattern for vCJD. PRNP sequencing showed a methionine homozygous codon 129 genotype and an E219K polymorphism in both patients. The E219K polymorphism is neutral or may even confer susceptibility to vCJD. The observations are interpretable in the context of the conformational selection model of prion replication. A barrier to prion disease transmission depends on the degree to which permitted pathologic conformations of the prion protein overlap between the inoculum and the host.

FUS mutations in sporadic juvenile ALS

Deposition of abnormal proteins constitutes a major hallmark of the neurodegenerative diseases. The appearance of abnormal protein deposits in neurons consistently precedes cell death in the same population, as best documented in the hierarchical progression of Parkinson disease1 and Alzheimer disease.2 In most instances, mutations in the corresponding gene have been identified only in a subset of those affected, usually in patients with a distinct family history. That the cytoplasm of motor neurons harbors abnormal protein deposits in amyotrophic lateral sclerosis (ALS) has been known for some time; those deposits bind ubiquitin nonspecifically, but it was only in 2006 that TDP-43 was pinpointed as an associated protein in over 90% of cases.3 TDP-43 is normally located in neuronal and glial nuclei but in ALS it appears in cytoplasmic inclusions. Importantly, mutations in the encoding gene, TARDBP , were discovered recently in familial ALS (FALS).4 Ubiquitinated inclusions of TDP-43 also were observed in neuronal and glial cytoplasm in the majority of patients with frontotemporal lobar degeneration (FTLD-U), the most common form of frontotemporal dementia. The presence of TDP-43 …

Amylose systémique découverte par une atteinte trachéobronchique

Amyloidosis is a spectrum of disease characterized by the abnormal deposition of fibril amyloid-related proteins in the extracellular space. The most common types of amyloidosis are AL and AA amyloidosis. Amyloidosis is also classified according to the extent of the deposition as systemic or localized. Respiratory amyloidosis is classified as laryngeal, tracheobronchial or parenchymal amyloidosis. Tracheobronchial amyloidosis is classically known as a rare manifestation of the localized disease. A few cases only of systemic amyloidosis presenting as a tracheobronchial disease have been reported. We here report a 26-year-old man who presented with hemoptysis related to a systemic tracheal primary amyloidosis.

Alpha‐Synuclein Stimulation of Astrocytes: Potential Role for Neuroinflammation and Neuroprotection

Selective loss of neurons, abnormal protein deposition and neuroinflammation are the common pathological features of neurodegenerative diseases, and these features are closely related to one another. In Parkinson's disease, abnormal aggregation and deposition of α-synuclein is known as a critical event in pathogenesis of the disease, as well as in other related neurodegenerative disorders, such as dementia with Lewy bodies and multiple system atrophy. Increasing evidence suggests that α-synuclein aggregates can activate glial cells to induce neuroinflammation. However, how an inflammatory microenvironment is established and maintained by this protein remains unknown. Findings from our recent study suggest that neuronal α-synuclein can be directly transferred to astrocytes through sequential exocytosis and endocytosis and induce inflammatory responses from astrocytes. Here we discuss potential roles of astrocytes in a cascade of events leading to α-synuclein-induced neuroinflammation.

Is 123I-MIBG cardiac scintigraphy a surrogate marker for Parkinson’s disease?

Why do we use cardiac scintigraphy in the diagnosis of an intracranial disorder? In Parkinson’s disease, the Braak hypothesis suggests that Lewy bodies accumulate starting from the medulla and spreading upward to the cerebral cortex. During this evolution, the accumulation of Lewy bodies in the midbrain damages the dopaminergic cells and leads to dysfunction of the dopaminergic projections from the midbrain to the striatum (mesostriatum), limbic system (mesolimbic), and the cerebral cortex (mesocortical). Finally, deposition of Lewy bodies on the cerebral cortex produces dementia with Lewy bodies [1]. As well as this dopaminergic dysfunction, Parkinson’s disease is associated with widespread damage to the nervous system. This is not specific to Parkinson’s disease, but is also seen in other neurodegenerative disorders, such as Alzheimer’s disease and amyotrophic lateral sclerosis (ALS). These neurodegenerative disorders have similar metabolic tendencies (except ALS), and abnormal protein deposition (Lewy bodies in Parkinson’s disease, and amyloid protein and neurofibrillary tangles in Alzheimer’s disease) are the main pathological processes. These abnormally accumulated proteins damage not only neurons but also astrocytes. With regard to Parkinson’s disease, noradrenergic neurons (mainly located in the locus caeruleus) and serotonergic neurons (in raphe nuclei) are damaged and produce symptoms of the syndromes associated with deficiency of these neurotransmitters. For example, noradrenalin has a strong influence on the sympathetic functions, resulting in Wallenberg’s syndrome (lateral medullary infarction) which may include Horner’s syndrome due to dysfunction of the sympathetic downward innervation to the pupil as well as the face. In this context, cardiac sympathetic innervation is disturbed in relatively advanced stages of Parkinson’s disease, and accordingly noradrenergic dysfunction will not appear in the early stages of Parkinson’s disease. This trend is discussed in the article in this issue by Ishibashi et al. [2] and in another report [3], in which careful consideration was given to the heart/mediastinum ratio. Similar disorders, such as multiple system atrophy, also reveal sympathetic nerve degeneration [4]. These disorders with parkinsonism may be a contamination and hindrance to the correct diagnosis of Parkinson’s disease. In the 1990s, pandysautonomia, a variant of GuillainBarre syndrome affecting mainly the autonomic nervous system, was found to be associated with various kinds of autonomic dysfunction, and it was found that cardiac scintigraphy showed a marked decrease in MIBG accumulation [5]. This syndrome includes mainly autonomic failure, relatively sudden onset, dysuria, orthostatic hypotension, hypohidrosis, and impotence. MIBG is suitable for diagnosing these kinds of systemic autonomic dysfunction. Originally, MIBG was used in the diagnosis of damaged tissue of the heart. Muscles with sympathetic innervation are also damaged in cardiac muscle disorders and reduced uptake of MIBG from the sympathetic nerve terminals is regarded as indicating cardiac tissue damage [6]. Therefore, in the diagnosis of autonomic nervous system dysfunction using MIBG we have to assume that the patient has intact heart muscles, i.e. no infarcted or ischaemic areas in the heart or myocardial problems, such as cardiomyopathy. Furthermore, from a technical point of view, it is not easy to This Editorial Commentary refers to the article http://dx.doi.org/ 10.1007/s00259-009-1202-1.

The lysosome and neurodegenerative diseases

It has long been believed that the lysosome is an important digestive organelle. There is increasing evidence that the lysosome is also involved in pathogenesis of a variety of neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. Abnormal protein degradation and deposition induced by lysosomal dysfunction may be the primary contributor to age-related neurodegeneration. In this review, the possible relationship between lysosome and various neurodegenerative diseases is described.

Cardiac Amyloidosis: The Importance of a Multidisciplinary Approach

Cardiac amyloidosis is associated with the interstitial deposition of abnormal protein in the myocardium, which can lead to a form of restrictive cardiomyopathy with a poor prognosis. This protein can have a number of different origins, which give rise to various subtypes of amyloidosis that have different prognoses and that require different therapeutic approaches. Drugs commonly used in heart failure have little effect in amyloidosis and the use of heart transplantation is controversial because amyloidosis is a multi-organ disease and because there is a possibility of disease recurrence in the graft. The use of new techniques to identify the specific amyloidosis subtype, the emergence of novel ways of preventing or decreasing amyloid production, the ability to monitor responses to therapy and, above all, the introduction of multidisciplinary teams that can implement a combination of therapies, including multiple organ transplantation, have contributed to a substantial improvement in the prognosis of this disease.

Pathologic correlates of diffusion MRI changes in Creutzfeldt-Jakob disease

The cause of hyperintense magnetic resonance changes and reduced apparent diffusion coefficient (ADC) in specific brain regions of patients with Creutzfeldt-Jakob disease (CJD) is unknown. Our aim was to determine the neuropathologic correlates of antemortem water ADC and normalized T2-weighted changes in patients with CJD. Ten patients with CJD and 10 sex- and age-matched healthy controls were studied by DWI and T2-weighted echoplanar MRI. At postmortem, patients with CJD were evaluated for semiquantitative assessment of gliosis and neuronal loss, spongiform changes, and abnormal PrP protein deposition in four cortical regions (occipital, parietal, and temporal cortex, and cingulate gyrus), thalamus, and striatum for a total of 60 regions of interest (ROI). Gliosis and neuronal loss correlated very highly with each other in the 60 ROIs. Where status spongiosus was absent, spongiform change correlated very highly with gliosis and neuronal loss in the cortex, but not in deep gray matter. Spongiform change was also significantly correlated with PrPSc load in both cortical and deep gray ROIs. In deep gray matter, ADC decreased with increasing spongiform change (R2 = 0.78; p < 0.001) and PrPSc load (R2 = 0.51; p = 0.003). In the cortex, ADC decreased with increases in all three, highly correlated, pathologic scores. Antemortem reductions in ADC values, typically found in patients with Creutzfeldt-Jakob disease (CJD), are correlated with spongiform changes seen at autopsy. This could be clearly established in the striatum and thalamus of our patients with CJD where the extent of spongiform change was not significantly correlated with gliosis or neuronal loss.

Structural Polymorphism of 441-Residue Tau at Single Residue Resolution

Alzheimer disease is characterized by abnormal protein deposits in the brain, such as extracellular amyloid plaques and intracellular neurofibrillary tangles. The tangles are made of a protein called tau comprising 441 residues in its longest isoform. Tau belongs to the class of natively unfolded proteins, binds to and stabilizes microtubules, and partially folds into an ordered β-structure during aggregation to Alzheimer paired helical filaments (PHFs). Here we show that it is possible to overcome the size limitations that have traditionally hampered detailed nuclear magnetic resonance (NMR) spectroscopy studies of such large nonglobular proteins. This is achieved using optimal NMR pulse sequences and matching of chemical shifts from smaller segments in a divide and conquer strategy. The methodology reveals that 441-residue tau is highly dynamic in solution with a distinct domain character and an intricate network of transient long-range contacts important for pathogenic aggregation. Moreover, the single-residue view provided by the NMR analysis reveals unique insights into the interaction of tau with microtubules. Our results establish that NMR spectroscopy can provide detailed insight into the structural polymorphism of very large nonglobular proteins.

Primary amyloidosis involving mediastinal lymph nodes diagnosed by EBUS-TBNA

Amyloidosis is an uncommon disease caused by the deposition of abnormal proteins within the soft tissues. Mediastinal lymph node involvement of the disease is rare. When mediastinal lymph nodes are affected, tissue sampling is required for obtaining a firm diagnosis. Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is a minimally invasive method of sampling tissues from mediastinal and hilar lymph nodes. We report a case of primary amyloidosis involving mediastinal lymph nodes successfully diagnosed by EBUS-TBNA.

Heidenhain variant of Creutzfeldt-Jakob disease: An autopsy study from India.

Prion diseases are rare, progressive and fatal neurodegenerative diseases characterized by long incubation period and short clinical course. We present a rare case of Heidenhain variant of Creutzfeldt-Jakob disease, occurring in a 55-year-old lady presenting with dementia, cortical blindness, and myoclonic jerks. She succumbed to the disease within 8 weeks of onset of symptoms. MRI revealed hyperintense signals on T2WI and fluid attenuated inversion recovery (FLAIR) images in basal ganglia and fronto-temporal and parietal cortex, sparing thalamus, striate cortex and globus pallidum. Abundant abnormal prion protein deposits (PrPsc) were detected in caudate, putamen, thalamus, cingulate and striate cortex, in comparison to frontal and parietal cortex while no deposits were found in globus pallidum. MRI changes did not correlate with degree of spongy change, gliosis or prion protein deposition. The cause for abnormal signal changes in MRI and FLAIR images remains unclear.

Longitudinal imaging: change and causality

Longitudinal studies that use MRI scans performed over multiple time-points have been increasingly employed in the study of different neurological disorders, including degenerative dementia, multiple sclerosis, and epilepsy. Although it is well established that increased rates of brain atrophy occur in degenerative dementia and multiple sclerosis, recent data have further described these changes and demonstrated that they correlate with both cognitive and functional decline. Advanced voxel-level techniques have also provided detailed descriptions of regional patterns of change, and a few studies have started to investigate changes over multiple MRI enabling the trajectories of brain loss over time to be determined. Researchers have also started to more thoroughly investigate the underlying causes of brain atrophy. Correlations have been observed between rate of brain atrophy and the presence of abnormal protein deposits in the brain in dementia, and the lesion burden in multiple sclerosis. However, longitudinal studies on epilepsy have been inconsistent, with very little recent data. Recent data further support the suggestion that longitudinal MRI provides a good biomarker of disease progression in dementia and multiple sclerosis, though more work needs to be performed to define the role of longitudinal imaging in epilepsy.

Is Tau Aggregation Toxic or Protective?

Abnormal protein deposits are a common feature of many human diseases including Alzheimer's disease. In Alzheimer's disease, the appearance of tangles, composed of the microtubule associated protein tau, correlates with both cell death and symptom severity. However, are tau filaments simply markers of disease progression, or are they directly responsible for cell death? Due to conflicting findings from cell and animal models, it remains controversial whether tau polymers or smaller pre-fibrillar aggregates or tau monomers are the toxic species. Indeed, if monomeric or oligomeric species are mediators of disease, formation of larger tau filaments may prove beneficial to affected cells. This review will examine the findings regarding the toxicity of various tau species.

Trehalose impairs aggregation of PrPSc molecules and protects prion-infected cells against oxidative damage

Neurodegenerative disorders such as Alzheimer’s, Huntington’s, and prion diseases are characterized by abnormal protein deposits in the brain of affected patients. In prion diseases, a key event in the pathogenesis is the conversion of the normal prion protein (PrPc) into abnormal protease resistant PrPSc deposits, a phenomenon associated with a higher sensitivity to oxidative stress in vitro. In cellular models of Alzheimer and Huntington diseases, the disaccharide trehalose has been shown to be effective in inhibiting huntingtin and Aβ peptide aggregates and reducing their associated toxicity. We show in this study that trehalose treatment of prion-infected cells decreases the size of de novo produced PrPSc aggregates and modify their subcellular localization. Despite the fact that trehalose does not modify the protease resistance properties of PrPSc molecules, it significantly protects prion-infected cells from induced oxidative damage, suggesting that this compound is of therapeutic interest.

Chlamydophila Pneumoniae and the Etiology of Late-Onset Alzheimer's Disease

Sporadic, late-onset Alzheimer's disease (LOAD) is a non-familial, progressive neurodegenerative disease that is now the most common and severe form of dementia in the elderly. That dementia is a direct result of neuronal damage and loss associated with accumulations of abnormal protein deposits in the brain. Great strides have been made in the past 20 years with regard to understanding the pathological entities that arise in the AD brain, both for familial AD ( approximately 5% of all cases) and LOAD ( approximately 95% of all cases). The neuropathology observed includes: neuritic senile plaques (NSPs), neurofibrillary tangles (NFTs), neuropil threads (NPs), and often deposits of cerebrovascular amyloid. Genetic, biochemical, and immunological analyses have provided a relatively detailed knowledge of these entities, but our understanding of the "trigger" events leading to the many cascades resulting in this pathology and neurodegeneration is still quite limited. For this reason, the etiology of AD, in particular LOAD, has remained elusive. However, a number of recent and ongoing studies have implicated infection in the etiology and pathogenesis of LOAD. This review focuses specifically on infection with Chlamydophila (Chlamydia) pneumoniae in LOAD and how this infection may function as a "trigger or initiator" in the pathogenesis of this disease.

Letale familiäre Insomnie - Eine seltene Differenzialdiagnose in der Demenzabklärung

Fatal familial insomnia (FFI)--first reported in 1986--is a hereditary prion disease with autosomal-dominant inheritance, caused by a missense-mutation at codon 178 of the prion-protein gene (PRNP) on chromosome 20. A methionine-valine polymorphism at codon 129 of PRNP expresses different phenotypes. The clinical features of FFI are characterized by a disrupted sleep-wake cycle with resulting fluctuations of vigilance, autonomic hyperactivation, myoclonus, motor abnormalities and by cognitive disturbances. The age of onset is between middle to late adulthood (51 +/- 7.1 years), disease duration varies between 8 and 72 months (18.4 +/- 17.3 months) and is ultimately fatal. We report the case of a 57-year-old man with a diagnosed FFI by molecular-genetic investigation who suffered from increasing memory- and sleep-disturbance as well as physical restlessness and impotence for 9 months. Clinical features were motor symptoms, generalized myoclonus and hyperactivity with reduced attention and concentration. The neuropsychological findings were a severe disturbance of attention and memory as well as incipient deficits in executive functions. The cranial MRI and repeated EEG were normal; in detailed laboratory tests including CSF no abnormalities were detected. The clinical course was characterized by rapid decline of the motor and cognitive skills; the patient died 15 months after onset. Histological analysis showed the typical changes of FFI (spongiform changes at hippocampus and regio entorhinalis, severe gliosis in the thalamus and mild deposits of abnormal prion protein).

Gastrointestinal Manifestations of Amyloidosis

Amyloidosis is characterized by extracellular deposition of abnormal protein. There are six types: primary, secondary, hemodialysis-related, hereditary, senile, and localized. Primary (AL) amyloidosis is associated with monoclonal light chains in serum and/or urine with 15% of patients having multiple myeloma. Secondary (AA) amyloidosis is associated with inflammatory, infectious, and neoplastic diseases. The presentation is protean, including macroglossia, a dilated and atonic esophagus, gastric polyps or enlarged folds, and luminal narrowing or ulceration of the colon. Amyloid deposition in the gastrointestinal (GI) tract is greatest in the small intestine. The symptoms include diarrhea, steatorrhea, or constipation. Pseudo-obstruction carries a particularly grave prognosis, often not responding to pro-motility agents. Hepatic involvement is common, but the clinical manifestations are usually mild with hepatomegaly and an elevated alkaline phosphatase level. Biopsies to diagnose amyloidosis can be taken from the fat, kidney, intestine, or bone marrow. The safety of liver biopsies is controversial. With Congo Red stain, amyloid appears red in normal light and apple-green in polarized light. Treatment for AL amyloidosis is chemotherapy and stem cell transplantation; treatment for AA amyloidosis is control of the underlying disease. Amyloidosis should be considered in patients with proteinuria, cardiomyopathy, hepatomegaly (with mildly abnormal liver tests), peripheral and autonomic neuropathy, weight loss, and GI symptoms.

Mood, cognition and in vivo protein imaging: the emerging nexus in clinical neuroscience

Disorders of mood and cognition overlap in the elderly and there is an emerging consensus that both groups of disorders share neurobiological substrates. Salient peer reviewed articles focusing on late-life depression, structural neuroimaging and recent developments in positron emission tomography based in vivo protein imaging. Epidemiological and clinical evidence indicates that mood and cognition in the elderly are clinically inter-related and common neurobiological mechanisms may underlie both groups of disorders. Degenerative, vascular and related mechanisms like genetically programmed abnormal protein deposition may provide the underlying neurobiological links between these disorders. Modern neuroimaging approaches such as positron emission tomography (PET) based in vivo protein binding may help further elucidate common pathophysiological mechanisms and assist in the early identification of patients at risk for developing dementia over time. These developments have important mechanistic and public health significance in the elderly.

Functional multivesicular bodies are required for autophagic clearance of protein aggregates associated with neurodegenerative disease

The endosomal sorting complexes required for transport (ESCRTs) are required to sort integral membrane proteins into intralumenal vesicles of the multivesicular body (MVB). Mutations in the ESCRT-III subunit CHMP2B were recently associated with frontotemporal dementia and amyotrophic lateral sclerosis (ALS), neurodegenerative diseases characterized by abnormal ubiquitin-positive protein deposits in affected neurons. We show here that autophagic degradation is inhibited in cells depleted of ESCRT subunits and in cells expressing CHMP2B mutants, leading to accumulation of protein aggregates containing ubiquitinated proteins, p62 and Alfy. Moreover, we find that functional MVBs are required for clearance of TDP-43 (identified as the major ubiquitinated protein in ALS and frontotemporal lobar degeneration with ubiquitin deposits), and of expanded polyglutamine aggregates associated with Huntington's disease. Together, our data indicate that efficient autophagic degradation requires functional MVBs and provide a possible explanation to the observed neurodegenerative phenotype seen in patients with CHMP2B mutations.

Oxidative Stress in Desminopathies and Myotilinopathies: A Link between Oxidative Damage and Abnormal Protein Aggregation

Myotilinopathies and desminopathies are subgroups of myofibrillar myopathies (MFM) caused by mutations in myotilin and desmin genes, respectively. They are characterized by the presence of protein aggregates in muscle cells. As oxidation of proteins facilitates their aggregation and makes them more resistant to proteolysis, the present study was geared to analyze oxidative stress in MFM. For this purpose, markers of glycoxidation, lipoxidation and nitration were examined with gel electrophoresis and Western blotting, single immunohistochemistry, and double- and triple-labeling immunofluorescence and confocal microscopy in muscle biopsies from patients suffering from myotilinopathy and desminopathy. Increased levels of glycation-end products (AGEs), N-carboxymethyl-lysine (CML) and N-carboxyethyl-lysine (CEL), malondialdehyde-lysine (MDAL), 4-hydroxynonenal (HNE) and nitrotyrosine (N-tyr) were found in MFM. Furthermore, aberrant expression of AGE, CML, CEL, MDAL and HNE, as well as of neuronal, inducible and endothelial nitric oxide synthases (nNOS, iNOS, eNOS), and superoxide dismutase 2 (SOD2), was found in muscle fibers containing protein aggregates in myotilinopathies and desminopathies. AGE, ubiquitin and p62 co-localized in several muscle fibers in MFM. As oxidized proteins are vulnerable to misfolding and are resistant to degradation by the UPS, the present observations support a link between oxidative stress, protein aggregation and abnormal protein deposition in MFMs.