scholarly journals Toward a Disease-Modifying Therapy of Alpha-Synucleinopathies: New Molecules and New Approaches Came into the Limelight

Molecules ◽  
2021 ◽  
Vol 26 (23) ◽  
pp. 7351
Author(s):  
Matthew Upcott ◽  
Kirill D. Chaprov ◽  
Vladimir L. Buchman
Keyword(s):  
Clinical Trials ◽  
Lewy Bodies ◽  
Alpha Synuclein ◽  
Therapeutic Window ◽  
Disease Modifying Therapy ◽  
Stage Of Development ◽  
Phase Ii Clinical Trials ◽  
Modifying Effect ◽  
Disease Modifying ◽  
Alpha Synuclein Aggregation

The accumulation of the various products of alpha-synuclein aggregation has been associated with the etiology and pathogenesis of several neurodegenerative conditions, including both familial and sporadic forms of Parkinson’s disease (PD) and dementia with Lewy bodies (DLB). It is now well established that the aggregation and spread of alpha-synuclein aggregation pathology activate numerous pathogenic mechanisms that contribute to neurodegeneration and, ultimately, to disease progression. Therefore, the development of a safe and effective disease-modifying therapy that limits or prevents the accumulation of the toxic intermediate products of alpha-synuclein aggregation and the spread of alpha-synuclein aggregation pathology could provide significant positive clinical outcomes in PD/DLB cohorts. It has been suggested that this goal can be achieved by reducing the intracellular and/or extracellular levels of monomeric and already aggregated alpha-synuclein. The principal aim of this review is to critically evaluate the potential of therapeutic strategies that target the post-transcriptional steps of alpha-synuclein production and immunotherapy-based approaches to alpha-synuclein degradation in PD/DLB patients. Strategies aimed at the downregulation of alpha-synuclein production are at an early preclinical stage of drug development and, although they have shown promise in animal models of alpha-synuclein aggregation, many limitations need to be resolved before in-human clinical trials can be seriously considered. In contrast, many strategies aimed at the degradation of alpha-synuclein using immunotherapeutic approaches are at a more advanced stage of development, with some in-human Phase II clinical trials currently in progress. Translational barriers for both strategies include the limitations of alpha-synuclein aggregation models, poor understanding of the therapeutic window for the alpha-synuclein knockdown, and variability in alpha-synuclein pathology across patient cohorts. Overcoming such barriers should be the main focus of further studies. However, it is already clear that these strategies do have the potential to achieve a disease-modifying effect in PD and DLB.

Are lysosomes potential therapeutic targets for Parkinson’s disease?

2021 ◽  
Vol 20 ◽  
Author(s):  
A. Petese ◽  
V. Cesaroni ◽  
S. Cerri ◽  
F. Blandini
Keyword(s):  
Neurodegenerative Disorder ◽  
Association Studies ◽  
Lewy Bodies ◽  
Alpha Synuclein ◽  
Genome Wide Association Studies ◽  
Lysosomal Dysfunction ◽  
Genome Wide ◽  
Nigrostriatal Neurons ◽  
Disease Modifying Treatment ◽  
Alpha Synuclein Aggregation

Background: Parkinson´s disease (PD) is the second most common neurodegenerative disorder, affecting 2-3% of the population over 65 years old. In addition to progressive degeneration of nigrostriatal neurons, the histopathological feature of PD is the accumulation of misfolded α-synuclein protein in abnormal cytoplasmatic inclusions, known as Lewy bodies (LBs). Recently, genome-wide association studies (GWAS) have indicated a clear association of variants within several lysosomal genes with risk for PD. Newly evolving data have been shedding light on the relationship between lysosomal dysfunction and alpha-synuclein aggregation. Defects in lysosomal enzymes could lead to the insufficient clearance of neurotoxic protein materials, possibly leading to selective degeneration of dopaminergic neurons. Specific modulation of lysosomal pathways and their components could be considered a novel opportunity for therapeutic intervention for PD. Aim: The purpose of this review is to illustrate lysosomal biology and describe the role of lysosomal dysfunction in PD pathogenesis. Finally, the most promising novel therapeutic approaches designed to modulate lysosomal activity, as a potential disease-modifying treatment for PD will be highlighted.

scholarly journals Endogenous alpha-synuclein monomers, oligomers and resulting pathology: let’s talk about the lipids in the room

2019 ◽  
Vol 5 (1) ◽  
Author(s):  
Bryan A. Killinger ◽  
Ronald Melki ◽  
Patrik Brundin ◽  
Jeffrey H. Kordower
Keyword(s):  
Lewy Bodies ◽  
Alpha Synuclein ◽  
Biological Origin ◽  
Lewy Pathology ◽  
Molecular Weights ◽  
Intrinsically Disordered ◽  
Bona Fide ◽  
Membrane Bound ◽  
Soluble Species ◽  
Alpha Synuclein Aggregation

Abstract Alpha-synuclein is an intrinsically disordered, highly dynamic protein that pathogenically aggregates into inclusion structures called Lewy bodies, in several neurogenerative diseases termed synucleinopathies. Despite its importance for understanding disease, the oligomerization status of alpha-synuclein in healthy cells remains unclear. Alpha-synuclein may exist predominantly as either a monomer or a variety of oligomers of different molecular weights. There is solid evidence to support both theories. Detection of apparent endogenous oligomers are intimately dependent on vesicle and lipid interactions. Here we consider the possibility that apparent endogenous alpha-synuclein oligomers are in fact conformations of membrane-bound alpha-synuclein and not a bona fide stable soluble species. This perspective posits that the formation of any alpha-synuclein oligomers within the cell is likely toxic and interconversion between monomer and oligomer is tightly controlled. This differs from the hypothesis that there is a continuum of endogenous non-toxic oligomers and they convert, through unclear mechanisms, to toxic oligomers. The distinction is important, because it clarifies the biological origin of synucleinopathy. We suggest that a monomer-only, lipid-centric view of endogenous alpha-synuclein aggregation can explain how alpha-synuclein pathology is triggered, and that the interactions between alpha-synuclein and lipids can represent a target for therapeutic intervention. This discussion is well-timed due to recent studies that show lipids are a significant component of Lewy pathology.

Cutaneous cryptococcosis in a patient taking fingolimod for multiple sclerosis: Here come the opportunistic infections?

2017 ◽  
Vol 23 (2) ◽  
pp. 297-299 ◽  
Author(s):  
Adam F Carpenter ◽  
Shikha J Goodwin ◽  
Peter F Bornstein ◽  
Andrew J Larson ◽  
Christine K Markus
Keyword(s):  
Multiple Sclerosis ◽  
Clinical Trials ◽  
Case Report ◽  
Skin Lesion ◽  
Opportunistic Infections ◽  
Oral Disease ◽  
Disease Modifying Therapy ◽  
Post Marketing ◽  
Disease Modifying ◽  
Cutaneous Cryptococcosis

Background: Fingolimod is an oral disease-modifying therapy for relapsing forms of multiple sclerosis, which acts by sequestering lymphocytes within lymph nodes. Objective: To describe a case of extrapulmonary cryptococcosis in a patient taking fingolimod. Methods: Case report. Results: A 47-year-old man developed a non-healing skin lesion approximately 16 months after starting treatment with fingolimod. Biopsy revealed cryptococcosis. Fingolimod was discontinued and the lesion resolved with antifungal therapy. Conclusion: Despite few reported opportunistic infections in the pivotal clinical trials and first few years post-marketing, there has been a recent increase in reported AIDS-defining illnesses in patients taking fingolimod. Neurologists should be alert for opportunistic infections in their patients using this medication.

scholarly journals Blood Plasma of Patients with Parkinson’s Disease Increases Alpha-Synuclein Aggregation and Neurotoxicity

2016 ◽  
Vol 2016 ◽  
pp. 1-14 ◽  
Author(s):  
Peng Wang ◽  
Xin Li ◽  
Xuran Li ◽  
Weiwei Yang ◽  
Shun Yu
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Alternative Pathway ◽  
Lewy Bodies ◽  
Normal Subjects ◽  
Alpha Synuclein ◽  
Phosphatase 2A ◽  
Alpha Synuclein Aggregation ◽  
The Brain ◽  
Neighboring Neuron

A pathological hallmark of Parkinson’s disease (PD) is formation of Lewy bodies in neurons of the brain. This has been attributed to the spread of α-synuclein (α-syn) aggregates, which involves release of α-syn from a neuron and its reuptake by a neighboring neuron. We found that treatment with plasma from PD patients induced more α-syn phosphorylation and oligomerization than plasma from normal subjects (NS). Compared with NS plasma, PD plasma added to primary neuron cultures caused more cell death in the presence of extracellular α-syn. This was supported by the observations that phosphorylated α-syn oligomers entered neurons, rapidly increased accumulated thioflavin S-positive inclusions, and induced a series of metabolic changes that included activation of polo-like kinase 2, inhibition of glucocerebrosidase and protein phosphatase 2A, and reduction of ceramide levels, all of which have been shown to promote α-syn phosphorylation and aggregation. We also analyzed neurotoxicity of α-syn oligomers relative to plasma from different patients. Neurotoxicity was not related to age or gender of the patients. However, neurotoxicity was positively correlated with H&Y staging score. The modification in the plasma may promote spreading of α-syn aggregates via an alternative pathway and accelerate progression of PD.

scholarly journals Possible Role of Amyloidogenic Evolvability in Dementia with Lewy Bodies: Insights from Transgenic Mice Expressing P123H β-Synuclein

2020 ◽  
Vol 21 (8) ◽  
pp. 2849
Author(s):  
Masayo Fujita ◽  
Gilbert Ho ◽  
Yoshiki Takamatsu ◽  
Ryoko Wada ◽  
Kazutaka Ikeda ◽  
...  
Keyword(s):  
Dementia With Lewy Bodies ◽  
Lewy Bodies ◽  
Gene Mutations ◽  
Major Constituent ◽  
Motor Deficits ◽  
Missense Mutations ◽  
Axonal Swelling ◽  
Disease Modifying Therapy ◽  
Progressive Neurodegeneration ◽  
Disease Modifying

Dementia with Lewy bodies (DLB) is the second most prevalent neurodegenerative dementia after Alzheimer’s disease, and is pathologically characterized by formation of intracellular inclusions called Lewy bodies, the major constituent of which is aggregated α-synuclein (αS). Currently, neither a mechanistic etiology nor an effective disease-modifying therapy for DLB has been established. Although two missense mutations of β-synuclein (βS), V70M and P123H, were identified in sporadic and familial DLB, respectively, the precise mechanisms through which βS mutations promote DLB pathogenesis remain elusive. To further clarify such mechanisms, we investigated transgenic (Tg) mice expressing P123H βS, which develop progressive neurodegeneration in the form of axonal swelling and non-motor behaviors, such as memory dysfunction and depression, which are more prominent than motor deficits. Furthermore, cross-breeding of P123H βS Tg mice with αS Tg mice worsened the neurodegenerative phenotype presumably through the pathological cross-seeding of P123H βS with αS. Collectively, we predict that βS misfolding due to gene mutations might be pathogenic. In this paper, we will discuss the possible involvement of amyloidogenic evolvability in the pathogenesis of DLB based on our previous papers regarding the P123H βS Tg mice. Given that stimulation of αS evolvability by P123H βS may underlie neuropathology in our mouse model, more radical disease-modifying therapy might be derived from the evolvability mechanism. Additionally, provided that altered βS were involved in the pathogenesis of sporadic DLB, the P123H βS Tg mice could be used for investigating the mechanism and therapy of DLB.

scholarly journals HAVING A GO AT SPINAL MUSCULAR ATROPHY WITH SPINRAZA

2017 ◽  
Vol 10 (6) ◽  
pp. 16
Author(s):  
Balaji O ◽  
Amita D ◽  
Sereen Rt ◽  
Navin Ap
Keyword(s):  
Cystic Fibrosis ◽  
Clinical Trials ◽  
Spinal Muscular Atrophy ◽  
Drug Administration ◽  
Muscular Atrophy ◽  
Food And Drug Administration ◽  
Neurological Condition ◽  
Disease Modifying Therapy ◽  
Different Types ◽  
Disease Modifying

Spinal muscular atrophy (SMA), a neurological condition which is genetically mediated is the second most common infantile disease causing morbidity and mortality next to cystic fibrosis. It is of five different types with each type having different severity outcomes. For almost three decades, only supportive measures were advocated in the treatment of SMA. Recently, Biogen’s Spinraza came out as the first disease modifying therapy to treat infantile as well as adult SMA. This review throws light on the pharmacological aspects of the drug; its approval by Food and Drug Administration and various completed clinical trials as well ongoing clinical trials.

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