Summary Progressive supranuclear palsy (PSP), previously believed to be a common cause of atypical parkinsonism, is now recognised as a range of motor and behavioural syndromes that are associated ...with a characteristic 4-repeat tau neuropathology. New research criteria that recognise early presentations of PSP and operationalise diagnosis of the full spectrum of clinical phenotypes have been reported. The Movement Disorders Society PSP diagnostic criteria include syndromes with few or mild symptoms that are suggestive of underlying PSP pathology and could provide an opportunity for earlier therapeutic interventions in the future. These criteria also include definitions for variant PSP syndromes with different patterns of movement, language, or behavioural features than have been conclusively associated with PSP pathology. Data from new diagnostic biomarkers can be combined with the clinical features of disease to increase the specificity of the new criteria for underlying PSP pathology. Because PSP is associated with tau protein abnormalities, there is growing interest in clinical trials of new tau-directed therapies. These therapies are hypothesised to have disease-modifying effects by reducing the concentration of toxic forms of tau in the brain or by compensating for loss of tau function. Since tau pathology is also central to Alzheimer's disease and chronic traumatic encephalopathy, a successful tau therapeutic for PSP might inform treatment of other neurodegenerative diseases.
With the hope that disease-modifying treatments could target the molecular basis of Parkinson's disease, even before the onset of symptoms, we propose a biologically based classification. Our ...classification acknowledges the complexity and heterogeneity of the disease by use of a three-component system (SynNeurGe): presence or absence of pathological α-synuclein (S) in tissues or CSF; evidence of underlying neurodegeneration (N) defined by neuroimaging procedures; and documentation of pathogenic gene variants (G) that cause or strongly predispose to Parkinson's disease. These three components are linked to a clinical component (C), defined either by a single high-specificity clinical feature or by multiple lower-specificity clinical features. The use of a biological classification will enable advances in both basic and clinical research, and move the field closer to the precision medicine required to develop disease-modifying therapies. We emphasise the initial application of these criteria exclusively for research. We acknowledge its ethical implications, its limitations, and the need for prospective validation in future studies.
The activation of the unfolded protein response, particularly via the PERK pathway, has been suggested as a promising therapeutic approach in tauopathies, a group of neurodegenerative disorders ...characterized by the abnormal phosphorylation and aggregation of tau protein. So far, a shortage of available direct PERK activators has been limiting the progresses in this field. Our study aimed at the development of a cell-free screening assay enabling the detection of novel direct PERK activators. By applying the catalytic domain of recombinant human PERK, we initially determined ideal conditions of the kinase assay reaction, including parameters such as optimal kinase concentration, temperature, and reaction time. Instead of using PERK's natural substrate proteins, eIF2α and NRF2, we applied SMAD3 as phosphorylation-accepting protein and successfully detected cell-free PERK activation and inhibition by selected modulators (e.g., calcineurin-B, GSK2606414). The developed assay revealed to be sufficiently stable and robust to assess an activating EC50-value. Additionally, our results suggested that PERK activation may take place independent of the active site which can be blocked by a kinase inhibitor. Finally, we confirmed the applicability of the assay by measuring PERK activation by MK-28, a recently described PERK activator. Overall, our data show that a cell-free luciferase-based assay with the recombinant human PERK kinase domain and SMAD3 as substrate protein is capable of detecting PERK activation, which enables to screen large compound libraries for direct PERK activators, in a high-throughput-based approach. These activators will be useful for deepening our understanding of the PERK signaling pathway, and may also lead to the identification of new therapeutic drug candidates for neurodegenerative tauopathies.
Four-repeat tauopathies Rösler, Thomas W; Tayaranian Marvian, Amir; Brendel, Matthias ...
Progress in neurobiology,
09/2019, Volume:
180
Journal Article
Peer reviewed
Tau is a microtubule-associated protein with versatile functions in the dynamic assembly of the neuronal cytoskeleton. Four-repeat (4R-) tauopathies are a group of neurodegenerative diseases defined ...by cytoplasmic inclusions predominantly composed of tau protein isoforms with four microtubule-binding domains. Progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease or glial globular tauopathy belong to the group of 4R-tauopathies. The present review provides an introduction in the current concept of 4R-tauopathies, including an overview of the neuropathological and clinical spectrum of these diseases. It describes the genetic and environmental etiological factors, as well as the contemporary knowledge about the pathophysiological mechanisms, including post-translational modifications, aggregation and fragmentation of tau, as well as the role of protein degradation mechanisms. Furthermore, current theories about disease propagation are discussed, involving different extracellular tau species and their cellular release and uptake mechanisms. Finally, molecular diagnostic tools for 4R-tauopathies, including tau-PET and fluid biomarkers, and investigational therapeutic strategies are presented. In summary, we report on 4R-tauopathies as overarching disease concept based on a shared pathophysiological concept, and highlight the challenges and opportunities on the way towards a causal therapy.
Parkinson's disease is a chronic neurodegenerative movement disorder affecting people mainly beyond their 50s. Geriatric patients with Parkinson's disease experience a specific profile of ...comorbidities. Multimorbidity and resulting polypharmacotherapy are frequent at this age. Comorbid diseases, widely spread, involve arterial hypertension, ischemic heart disease, heart failure, atrial fibrillation, polyneuropathy, diabetes mellitus, cerebrovascular disease, sarcopenia, and frailty. Following years of drug development, levodopa is still the most effective drug for the treatment of motor symptoms. However, a wide range of other drugs are available with specific effects, contraindications, and complications. The treatment of geriatric patients with Parkinson's disease is challenging and requires the cooperation of multidisciplinary teams. A careful assessment of a patient's Parkinson's disease symptoms, comorbidities, medication, vital signs, and resources is crucial for an effective and safe therapy. Laboratory tests can assist in the identification of contraindications for specific treatments. Identifying potentially inadequate drugs from prescription lists can lead to a better targeted treatment for geriatric patients with Parkinson's disease. Future research should help develop a more evidence-based therapy of geriatric patients with Parkinson's disease. For this purpose, randomized controlled trials of geriatric patients are urgently needed. An international register concerning issues of safer drug application and monitoring could help to implement a better treatment.
β-adrenoreceptors and the risk of Parkinson's disease Hopfner, Franziska; Höglinger, Günter U; Kuhlenbäumer, Gregor ...
Lancet neurology,
March 2020, 2020-Mar, 2020-03-00, 20200301, Volume:
19, Issue:
3
Journal Article
Peer reviewed
β-adrenoceptors are widely expressed in different human organs, mediate important body functions and are targeted by medications for various diseases (such as coronary heart disease and heart attack) ...and many β-adrenoceptor acting drugs are listed on the WHO Model List of Essential Medicines. According to current treatment guidelines, more than a billion patients with neurological disorders have an indication for the use of β-adrenoceptor antagonists (mainly migraine and essential tremor).
An observational study reported a link between the chronic use of the β-adrenoceptor antagonist propranolol and an increased risk of Parkinson's disease, while the chronic use of the β-adrenoceptor agonists was associated with a decreased risk. Further support of this association was provided by a dose-dependent decrease in the risk of Parkinson's disease with chronic β-adrenoceptor agonist (eg, salbutamol) use, and by functional data indicating a possible underlying molecular mechanism. Five additional epidemiological studies have examined the modulation of the risk of Parkinson's disease as a result of the use of β-adrenoceptor-acting drugs in different populations. Overall, similar estimates but different interpretations of the associations were provided. Several findings suggest that the increase in risk of Parkinson's disease associated with β-adrenoceptor antagonists use can be explained by reverse causation because prodromal Parkinson's disease is often associated with non-specific action tremor, which is usually treated with propranolol. The lower risk of Parkinson's disease seen in patients receiving β-adrenoceptor agonists is likely to be indirectly mediated by smoking because smoking has a strong inverse association with Parkinson's disease (people that smoke have a reduced risk of developing Parkinson's disease). Smoking also causes chronic obstructive pulmonary disease, which is treated with β-adrenoceptor-agonist medications. Even if causal, the effect of β-adrenoceptor antagonists on the risk of Parkinson's disease would be small compared with other Parkinson's disease risk factors and would be similar to the risk evoked by pesticide exposure. The estimated risk of Parkinson's disease because of β-adrenoceptor antagonists use corresponds to one case in 10 000 patients after 5 years of propranolol use, and would be considered a very rare adverse effect. Thus, not using β-adrenoceptor antagonists would severely harm patients with recommended indications, such as heart disease or migraine. Similarly, 50 000 people would have to be treated for 5 years with salbutamol to prevent Parkinson's disease in one patient, suggesting that primary preventive therapy studies on disease modification are not warranted.
Epidemiological evidence for a causal relationship between use of β2-adrenoceptor antagonists and the increased risk of Parkinson's disease is weak, with other explanations for the association being more probable. Future observational studies are warranted to clarify this association. However, given the very low risk associated with propranolol, most clinicians are unlikely to change their treatment approach.
Neurodegenerative diseases are a heterogeneous group of maladies, characterized by progressive loss of neurons. These diseases involve an intricate pattern of cross-talk between different types of ...cells to maintain specific signaling pathways. A component of such intercellular cross-talk is the exchange of various types of extracellular vesicles (EVs). Exosomes are a subset of EVs, which are increasingly being known for the role they play in the pathogenesis and progression of neurodegenerative diseases, e.g., synucleinopathies and tauopathies. The ability of the central nervous system exosomes to cross the blood-brain barrier into blood has generated enthusiasm in their study as potential biomarkers. However, the lack of standardized, efficient, and ultra-sensitive methods for the isolation and detection of brain-derived exosomes has hampered the development of effective biomarkers. Exosomes mirror heterogeneous biological changes that occur during the progression of these incurable illnesses, potentially offering a more comprehensive outlook of neurodegenerative disease diagnosis, progression and treatment. In this review, we aim to discuss the challenges and opportunities of peripheral biofluid-based brain-exosomes in the diagnosis and biomarker discovery of Alzheimer's and Parkinson's diseases. In the later part, we discuss the traditional and emerging methods used for the isolation of exosomes and compare their advantages and disadvantages in clinical settings.
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