| 1. |
- Aniszewska, Agata, et al.
(författare)
-
Modeling Parkinson's disease-related symptoms in alpha-synuclein overexpressing mice
- 2022
-
Ingår i: Brain and Behavior. - : John Wiley & Sons. - 2162-3279 .- 2162-3279. ; 12:7
-
Forskningsöversikt (refereegranskat)abstract
- Background: Intracellular deposition of alpha-synuclein (alpha-syn) as Lewy bodies and Lewy neurites is a central event in the pathogenesis of Parkinson's disease (PD) and other alpha-synucleinopathies. Transgenic mouse models overexpressing human alpha-syn, are useful research tools in preclinical studies of pathogenetic mechanisms. Such mice develop alpha-syn inclusions as well as neurodegeneration with a topographical distribution that varies depending on the choice of promoter and which form of alpha-syn that is overexpressed. Moreover, they display motor symptoms and cognitive disturbances that to some extent resemble the human conditions.Purpose: One of the main motives for assessing behavior in these mouse models is to evaluate the potential of new treatment strategies, including their impact on motor and cognitive symptoms. However, due to a high within-group variability with respect to such features, the behavioral studies need to be applied with caution. In this review, we discuss how to make appropriate choices in the experimental design and which tests that are most suitable for the evaluation of PD-related symptoms in such studies.Methods: We have evaluated published results on two selected transgenic mouse models overexpressing wild type (L61) and mutated (A30P) alpha-syn in the context of their validity and utility for different types of behavioral studies.Conclusions: By applying appropriate behavioral tests, alpha-syn transgenic mouse models provide an appropriate experimental platform for studies of symptoms related to PD and other alpha-synucleinopathies.
|
|
| 2. |
- Ingelsson, Martin
(författare)
-
Alpha-Synuclein Oligomers-Neurotoxic Moleculesin Parkinson's Disease and Other Lewy Body Disorders
- 2016
-
Ingår i: Frontiers in Neuroscience. - : Frontiers Media SA. - 1662-4548 .- 1662-453X. ; 10
-
Forskningsöversikt (refereegranskat)abstract
- Adverse intra- and extracellular effects of toxic a-synuclein are believed to be central to the pathogenesis in Parkinson's disease and other disorders with Lewy body pathology in the nervous system. One of the physiological roles of a-synuclein relates to the regulation of neurotransmitter release at the presynapse, although it is still unclear whether this mechanism depends on the action of monomers or smaller oligomers. As for the pathogenicity, accumulating evidence suggest that prefibrillar species, rather than the deposits per se, are responsible for the toxicity in affected cells. In particular, larger oligomers or protofibrils of a-synuclein have been shown to impair protein degradation as well as the function of several organelles, such as the mitochondria and the endoplasmic reticulum. Accumulating evidence further suggest that oligomers/protofibrils may have a toxic effect on the synapse, which may lead to disrupted electrophysiological properties. In addition, recent data indicate that oligomeric a-synuclein species can spread between cells, either as free-floating proteins or via extracellular vesicles, and thereby act as seeds to propagate disease between interconnected brain regions. Taken together, several lines of evidence suggest that a-synuclein have neurotoxic properties and therefore should be an appropriate molecular target for therapeutic intervention in Parkinson's disease and other disorders with Lewy pathology. In this context, immunotherapy with monoclonal antibodies against a-synuclein oligomers/protofibrils should be a particularly attractive treatment option.
|
|
| 3. |
- Lau, Heather H. C., et al.
(författare)
-
The existence of A beta strains and their potential for driving phenotypic heterogeneity in Alzheimer's disease
- 2021
-
Ingår i: Acta Neuropathologica. - : Springer. - 0001-6322 .- 1432-0533. ; 142:1, s. 17-39
-
Forskningsöversikt (refereegranskat)abstract
- Reminiscent of the human prion diseases, there is considerable clinical and pathological variability in Alzheimer's disease, the most common human neurodegenerative condition. As in prion disorders, protein misfolding and aggregation is a hallmark feature of Alzheimer's disease, where the initiating event is thought to be the self-assembly of A beta peptide into aggregates that deposit in the central nervous system. Emerging evidence suggests that A beta, similar to the prion protein, can polymerize into a conformationally diverse spectrum of aggregate strains both in vitro and within the brain. Moreover, certain types of A beta aggregates exhibit key hallmarks of prion strains including divergent biochemical attributes and the ability to induce distinct pathological phenotypes when intracerebrally injected into mouse models. In this review, we discuss the evidence demonstrating that A beta can assemble into distinct strains of aggregates and how such strains may be primary drivers of the phenotypic heterogeneity in Alzheimer's disease.
|
|
| 4. |
- Lindström, Veronica, et al.
(författare)
-
Immunotherapy targeting alpha-synuclein, with relevance for future treatment of Parkinson's disease and other Lewy body disorders
- 2014
-
Ingår i: Immunotherapy. - 1750-743X .- 1750-7448. ; 6:2, s. 141-153
-
Forskningsöversikt (refereegranskat)abstract
- Immunotherapy targeting a-synuclein has evolved as a potential therapeutic strategy for neurodegenerative diseases, such as Parkinson's disease, and initial studies on cellular and animal models have shown promising results. alpha-synuclein vaccination of transgenic mice reduced the number of brain inclusions, whereas passive immunization studies demonstrated that antibodies against the C-terminus of alpha-synuclein can pass the blood-brain barrier and affect the pathology. In addition, preliminary evidence suggests that transgenic mice treated with an antibody directed against alpha-synuclein oligomers/protofibrils resulted in reduced levels of such species in the CNS. The underlying mechanisms of immunotherapy are not yet fully understood, but may include antibody-mediated clearance of pre-existing aggregates, prevention of protein propagation between cells and microglia-dependent protein clearance. Thus, immunotherapy targeting alpha-synuclein holds promise, but needs to be further developed as a future disease-modifying treatment in Parkinson's disease and other alpha-synucleinopathies.
|
|
| 5. |
- Lööv, Camilla, et al.
(författare)
-
alpha-Synuclein in Extracellular Vesicles : Functional Implications and Diagnostic Opportunities
- 2016
-
Ingår i: Cellular and molecular neurobiology. - : Springer Science and Business Media LLC. - 0272-4340 .- 1573-6830. ; 36:3, s. 437-448
-
Forskningsöversikt (refereegranskat)abstract
- Fibrillar inclusions of intraneuronal alpha-synuclein can be detected in certain brain areas from patients with Parkinson's disease (PD) and other disorders with Lewy body pathology. These insoluble protein aggregates do not themselves appear to have a prominent neurotoxic effect, whereas various alpha-synuclein oligomers appear harmful. Although it is incompletely known how the pre-fibrillar species may be pathogenic, they have been detected both within and on the outside of exosomes and other extracellular vesicles (EVs), suggesting that such structures may mediate toxic alpha-synuclein propagation between neurons. Vesicular transfer of alpha-synuclein may thereby contribute to the hierarchical spreading of pathology seen in the PD brain. Although the regulation of alpha-synuclein release via EVs is not understood, data suggest that it may involve other PD-related molecules, such as LRRK2 and ATP13A2. Moreover, new evidence indicates that CNS-derived EVs in plasma have the potential to serve as biomarkers for diagnostic purposes. In a recent study, levels of alpha-synuclein were found to be increased in L1CAM-positive vesicles isolated from plasma of PD patients compared to healthy controls, and follow-up studies will reveal whether alpha-synuclein in EVs could be developed as a future disease biomarker. Preferentially, toxic prefibrillar alpha-synuclein oligomers should then be targeted as a biomarker-as evidence suggests that they reflect the disease process more closely than total alpha-synuclein content. In such studies, it will be essential to adopt stringent EV isolation protocols in order to avoid contamination from the abundant pool of free plasma alpha-synuclein in different aggregational states.
|
|
| 6. |
- Vaikath, Nishant N., et al.
(författare)
-
Antibodies against alpha-synuclein : tools and therapies
- 2019
-
Ingår i: Journal of Neurochemistry. - : WILEY. - 0022-3042 .- 1471-4159. ; 150:5, s. 612-625
-
Forskningsöversikt (refereegranskat)abstract
- Synucleinopathies including Parkinson's disease, dementia with Lewy bodies and multiple system atrophy are characterized by the abnormal accumulation and propagation of alpha-synuclein (alpha-syn) pathology in the central and peripheral nervous system as Lewy bodies or glial cytoplasmic inclusions. Several antibodies against alpha-syn have been developed since it was first detected as the major component of Lewy bodies and glial cytoplasmic inclusions. Over the years, researchers have generated specific antibodies that alleviate the accumulation of intracellular aggregated alpha-syn and associated pathology in cellular and preclinical models of synucleinopathies. So far, antibodies have been the first choice as tools for research and diagnosis and currently, a wide variety of antibody fragments have been developed as an alternative to full-length antibodies for increasing its therapeutic usefulness. Recently, conformation specific antibody-based approaches have been found to be promising as therapeutic strategies, both to block alpha-syn aggregation and ameliorate the resultant cytotoxicity, and as diagnostic tools. In this review, we summarize different alpha-syn specific antibodies and provide their usefulness in tackling synucleinopathies.
|
|
