Caspase-cleaved tau accumulation in neurodegenerative diseases associated with tau and α-synuclein pathology

Alzheimers disease (AD), Picks disease (PiD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and dementia with Lewy bodies (DLB) are diseases associated with the accumulation of tau or -synuclein. In AD, -amyloid (A)-associated caspase activation and cleavage of tau at Asp⁴²¹ (Tau) may be an early step in neurofibrillary tangle (NFT) formation. To examine whether Tau accumulates in other diseases not characterized by extracellular A accumulation, we examined PiD, PSP, and CBD cases in comparison to those without extensive tau accumulation including frontotemporal lobar degeneration without Pick bodies (FTLD) and control cases. Additionally, we studied Tau accumulation in DLB cases associated with intracellular -synuclein. Tau was observed in all disease cases except non-PiD FTLD and controls. These results demonstrate that the accumulation of Tau may represent a common pathway associated with abnormal accumulation of intracellular tau or -synuclein and may be relatively less dependent on the extracellular accumulation of A in non-AD dementias.     

Translation stalling and ribosome collision leading to proteostasis failure: implications for neurodegenerative diseases

<正>Proteostasis denotes a cellular state in which protein synthesis,folding,and degradation are maintained at a homeostatic state such that an intact yet dynamic proteome is preserved.Cellular capacity to preserve proteostasis declines with age,which is assumed to contribute to the pathogenesis of age-related diseases.Proteostasis failure manifested as the formation of aberrant     

Involvement of α-synuclein in Parkinson's disease and other neurodegenerative disorders

Summary. A major step in the elucidation of the pathogenesis of neurodegenerative disorders was the identification of a mutation in the α-synuclein gene in autosomal dominant Parkinson's disease (PD). α-Synuclein is the main component of Lewy bodies (LB), the neuropathological hallmark of PD. Moreover, a fragment of α-synuclein (NAC) is the second major component of amyloid plaques in Alzheimer's disease (AD). Recent studies of other neurodegenerative disorders such as dementia with LB (DLB), multiple system atrophy (MSA) and amyotrophic lateral sclerosis (ALS) also revealed intracellular accumulations of α-synuclein in affected brain regions. This may indicate that these disorders partially share common pathogenic mechanisms. Recent data provide first insights into the physiological function of α-synuclein and support the concept of an essential role of α-synuclein in neurodegeneration. Increasing knowledge on the pathogenic molecular mechanisms of neurodegeneration and of the pathophysiological function of α-synuclein in particular may influence future development of therapeutic strategies in neurodegenerative disorders. Received April 9, 1999; accepted June 16, 1999     

Inducing α-synuclein compaction: a new strategy for inhibiting α-synuclein aggregation?

<正>Proteins might misfold during translation and folding or even once they are in their native states, due to stochastic fluctuations, destabilizing mutations or cellular stress. Aberrant protein species are usually detected and either refolded or cleared by the protein quality control machinery(Ciechanover and Kwon, 2015). When misfolded protein conformers     

Peptide aptamer-mediated modulation of prion protein α-cleavage as treatment strategy for prion and other neurodegenerative diseases

正Despite intensive research,most neurodegenerative diseases cannot be cured and for some of them no treatment is available to increase survival or quality of life.Among the latter are prion diseases,fatal and transmissible neurodegenerative diseases of humans and other animals.Exam-     

ATP-binding cassette transporters as possible targets for the intervention of neurodegenerative diseases

<正>ATP-binding cassette (ABC) tra nsporters are ubiquitous membrane-bound proteins that are responsible for the translocation of a broad spectrum of substrates across cellular membranes,including lipids,amino acids,nucleosides,sugars,and xenobiotics.Interestingly,ABC transporters are highly expressed in the brain.     

The emerging role of probiotics in neurodegenerative diseases: new hope for Parkinson's disease?

Neurodegenerative disease etiology is still unclear, but different contributing factors, such as lifestyle and genetic factors are involved. Altered components of the gut could play a key role in the gut-brain axis, which is a bidirectional system between the central nervous system and the enteric nervous system. Variations in the composition of the gut microbiota and its function between healthy people and patients have been reported for a variety of human disorders comprising metabolic, autoimmune, cancer, and, notably, neurodegenerative disorders. Diet can alter the microbiota composition, affecting the gutbrain axis function. Different nutraceutical interventions have been devoted to normalizing gut microbiome dysbiosis and to improving biological outcomes in neurological conditions, including the use of probiotics. Preclinical and clinical investigations discussed in this review strengthen the correlation between intestinal microbiota and brain and the concept that modifying the microbiome composition may improve brain neurochemistry, modulating different pathways. This review will discuss the potential use of probiotics for Parkinson's disease prevention or treatment or as adjuvant therapy, confirming that gut microbiota modulation influences different pro-survival pathways. Future investigations in Parkinson's disease should consider the role of the gut-brain axis and additional comprehension of the underlying mechanisms is extremely necessary.     

HDAC6 α-tubulin deacetylase: a potential therapeutic target in neurodegenerative diseases

Multiple sclerosis (MS) is a relatively common debilitating neurologic disease that affects people in early adulthood. While the characteristic pathology of MS has been well described, the etiology of the disease is not well understood, despite decades of research and the identification of strong genetic and environmental candidates for susceptibility. A question central to all diseases, but posed specifically for MS at the XVI European Charcot Foundation Lecture, was 'Can MS be prevented?' To address this question, we have evaluated the available data regarding nutritional and environmental factors that may be related to MS susceptibility and suggest the extent to which a potential intervention may reduce disease burden. It is our opinion that intervention, particularly supplementation with vitamin D, could have a dramatic impact on disease prevalence. Understanding that any intervention or behavioral modification will surely act in the context of genetic susceptibility and unidentified stochastic events, it is likely that not all MS is 'preventable'. Epidemiologic observation has provided key insights into environmental and nutritional factors that may alter one's susceptibility to MS, however, there are still many questions in unraveling the etiology of this complex disease.     

Editor's Choice——Application of genetic engineering for the treatment of neurodegenerative diseases

Gene therapy has been shown to be an effective m ethod for protecting neural functions in the substantia nigra,as well as for treating Parkinson’s disease.The regulatiion     

Endothelial lipopigment as an indicator of α-tocopherol deficiency in two equine neurodegenerative diseases

Two spontaneous neurodegenerative diseases of the horse, equine motor neuron disease (EMND) and equine degenerative myeloencephalopathy (EDM), have been associated with -tocopherol deficiency, and both were characterized by prominent accumulations of endothelial lipopigment in the small vessels of the spinal cord. These endothelial pigment deposits appear to be reversible. In EMND horses pasture-supplemented for 9 months or more after the progression of weakness and wasting had arrested, there was very little endothelial lipopigment. The origin and the potential effects of these endothelial lipopigment accumulations are discussed.     

Therapeutic potential of α7 nicotinic receptor agonists to regulate neuroinflammation in neurodegenerative diseases

Neurodegenerative diseases, such as Alzheimer's, Parkinson's and Huntington's diseases, are all character-ized by a component of innate immunity called neuroinflammation. Neuronal loss and neuroinflammation are two phenomena closely linked. Hence, the neuroinflammation is a relevant target for the management of the neurodegenerative diseases given that, to date, there is no treatment to stop neuronal loss. Several studies have investigated the potential effects of activators of alpha 7 nicotinic acetylcholine receptors in animal models of neurodegenerative diseases. These receptors are widely distributed in the central nervous system. After activation, they seem to mediate the cholinergic anti-inflammatory pathway in the brain. This anti-inflammatory pathway, first described in periphery, regulates activation of microglial cells considered as the resident macrophage population of the central nervous system. In this article, we shortly review the agonists of the alpha 7 nicotinic acetylcholine receptors that have been evaluatedin vivo and we focused on the selective positive allosteric modulators of these receptors. These compounds represent a key element to enhance receptor activity only in the presence of the endogenous agonist.     

The role of alpha-synuclein in neurodegenerative diseases: a potential target for new treatment strategies?

Alpha-synuclein (AS) is the main constituent of Lewy bodies. There is an ongoing discussion if overexpression is already dangerous, or if toxicity is subjected to oligomers, protofibrils or mature aggregates. The facts that the central hydrophobic part of AS is also a constituent of amyloid plaques in Alzheimer's disease (AD) and that a majority of patients have Lewy bodies and Lewy neurites in specific brain areas raised our interest in the contribution of AS to AD pathogenesis. The N-terminal amino acid sequence 1-15 of beta-synuclein (BS) seems to be a natural antiaggregation factor for AS. We synthesized a library with different sequence variations. Several of these peptides displayed neuroprotective activity in tissue culture models of neurodegeneration induced by oxidative stress or beta-amyloid 1-42. In spite of the fact that these peptides have a short half-life, a significant in vivo reduction in brain plaque load and improvement of behavior was demonstrated in amyloid precursor protein transgenic mice after intranasal treatment for 2 months. KEGV, the shortest sequence, was also active after intraperitoneal application. The in vitro effects cannot be explained by the antiaggregatory potential, but most likely by interaction of BS derivates with antiapoptotic PI3/Akt or antioxidative pathways. The possibility that BS-derived peptidomimetics act as neuroprotectants and prevent protein misfolding suggests therapeutic usefulness.     

Dopamine-depletion and increased α-synuclein load induce degeneration of cortical cholinergic fibers in mice

Cognitive dysfunction can be common among Parkinson's disease (PD) patients, and multiplication of the gene α-synuclein (αsyn) increases the risk of dementia. Here, we studied the role of dopamine-depletion and increased αsyn load and aggregation on cholinergic structures in vivo. Wild-type (WT) and mice with A30P αsyn overexpression were treated subacutely with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and the number of cholinergic cells in their nucleus basalis magnocellularis-substantia innominata (NBM-SI), their cortical fiber density and their expression of different genes 1day or 90 days after the last MPTP-injection were measured. Long-term dopamine depletion decreased the expression of choline acetyl transferase (ChAT) in the NBM-SI of WT mice, but no neuron loss was observed. In contrast, cortical cholinergic fiber density was decreased three months after MPTP-injection. Increased brain-derived neurotrophic factor expression could maintain cholinergic functions under these conditions. Expression of A30P αsyn in six-months-old transgenic mice resulted in decreased tyrosine receptor kinase B expression, and lower cortical cholinergic fiber density. Dopamine-depletion by MPTP induced cholinergic cell loss in the NBM-SI and increased cortical fiber loss. Our findings may explain why cholinergic cells are more vulnerable in PD, leading to an increased probability of dementia.     

Evaluation of α-synuclein as a novel cerebrospinal fluid biomarker in different forms of prion diseases

Introduction

Accurate diagnosis of prion diseases and discrimination from alternative dementias gain importance in the clinical routine, but partial overlap in cerebrospinal fluid (CSF) biomarkers impedes absolute discrimination in the differential diagnostic context.

Progressive neurodegenerative and behavioural changes induced by AAV-mediated overexpression of α-synuclein in midbrain dopamine neurons

Parkinson's disease (PD) is characterised by the progressive loss of nigral dopamine neurons and the presence of synucleinopathy. Overexpression of α-synuclein in vivo using viral vectors has opened interesting possibilities to model PD-like pathology in rodents. However, the attempts made so far have failed to show a consistent behavioural phenotype and pronounced dopamine neurodegeneration. Using a more efficient adeno-associated viral (AAV) vector construct, which includes a WPRE enhancer element and uses the neuron-specific synapsin-1 promoter to drive the expression of human wild-type α-synuclein, we have now been able to achieve increased levels of α-synuclein in the transduced midbrain dopamine neurons sufficient to induce profound deficits in motor function, accompanied by reduced expression of proteins involved in dopamine neurotransmission and a time-dependent loss of nigral dopamine neurons, that develop progressively over 2-4 months after vector injection. As in human PD, nigral cell loss was preceded by degenerative changes in striatal axons and terminals, and the appearance of α-synuclein positive inclusions in dystrophic axons and dendrites, supporting the idea that α-synuclein-induced pathology hits the axons and terminals first and later progresses to involve also the cell bodies. The time-course of changes seen in the AAV-α-synuclein treated animals defines distinct stages of disease progression that matches the pre-symptomatic, early symptomatic, and advanced stages seen in PD patients. This model provides new interesting possibilities for studies of stage-specific pathologic mechanisms and identification of targets for disease-modifying therapeutic interventions linked to early or late stages of the disease.     

c-Abl kinase at the crossroads of healthy synaptic remodeling and synaptic dysfunction in neurodegenerative diseases

Our ability to learn and remember depends on the active formation,remodeling,and elimination of synapses.Thus,the development and growth of synapses as well as their weakening and elimination are essential for neuronal rewiring.The structural reorganization of synaptic complexes,changes in actin cytos keleton and organelle dynamics,as well as modulation of gene expression,determine synaptic plasticity.It has been proposed that dys regulation of these key synaptic homeostatic processes underlies ...     

Role of advanced glycation on aggregation and DNA binding properties of α-synuclein

Parkinson's disease (PD) is a neurodegenerative disease with multiple etiologies. Advanced glycation end products (AGEs) accumulate in the aging brain and could be one of the reasons for age-related diseases like PD. Oxidative stress also leads to the formation of AGEs and may be involved in neurodegeneration by altering the properties of proteins. α-Synuclein is involved in pathogenesis of PD and there are limited studies on the role of AGE-α-synuclein in neurodegeneration. We studied the aggregation and DNA binding ability of AGE-α-synuclein in vitro. α-Synuclein is glycated using methylglyoxal and formation of AGE-α-synuclein is characterized using fluorescence studies, intrinsic tyrosine fluorescence, and fructosamine estimation. The results indicated that AGE-α-synuclein aggregates into smaller globular-like aggregates compared to fibrils formed with native α-synuclein. Further, it is found that AGE-α-synuclein induced conformational changes in scDNA from B-form to B-C-A mixed conformation. Additionally, AGE-α-synuclein altered DNA integrity as evidenced by the melting temperature, ethidium bromide, and DNAse I sensitivity studies. AGE-α-synuclein converted biphasic Tm to higher monophasic Tm. The Tm of AGE-α-synuclein-scDNA complex is more than that of native α-synuclein-scDNA complex, indicating that AGE-α-synuclein stabilized the uncoiled scDNA. AGE-α-synuclein could stabilize the uncoiled scDNA, as shown by the decrease in the number of ethidium bromide binding molecules per base pair of DNA. DNAse I sensitive studies indicated that both AGE-α-synuclein-scDNA and α-synuclein-scDNA are resistant to DNAse I digestion. The relevance of these findings to neuronal cell death is discussed.