Low soluble amyloid-β 42 is associated with smaller brain volume in Parkinson's disease

Espay, Alberto J.; Lafontant, David-Erick; Poston, Kathleen L.; Caspell‐Garcia, Chelsea; Marsili, Luca; Cho, Hyunkeun Ryan; McDaniel, Colin; Kim, Nessa; Coffey, Christopher S.; Mahajan, Abhimanyu; Ezzat, Kariem; Sturchio, Andrea

doi:10.1016/j.parkreldis.2021.10.010

Cited by 9 publications

(3 citation statements)

References 28 publications

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“…It is apparent that there is a quantitative loss of active, functional, soluble, unstable α-Syn protein because of its transition into insoluble, inactive, highly stable cross-β inclusions, and consequently, a loss of physiological functions of α-Syn, which are critical for neuronal survival. Such depleted α-Syn levels have been associated with smaller brain volume and neurotoxicity in PD, where higher levels of α-Syn are required for the preservation of the brain volume [97]. On the other hand, overexpression of α-Syn levels (toxic dose effect) has been associated with more malignant phenotypes [98] because of its propensity to aggregate through nucleation and the consequent reduction of the normal protein levels.…”

Section: Evidence Of Phenotypic Switching and Structure-toxicity Rela...mentioning

confidence: 99%

Nonintuitive Immunogenicity and Plasticity of Alpha-Synuclein Conformers: A Paradigm for Smart Delivery of Neuro-Immunotherapeutics

Abioye,

Akintade,

Mitchell

et al. 2024

Pharmaceutics

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: Despite the extensive research successes and continuous developments in modern medicine in terms of diagnosis, prevention, and treatment, the lack of clinically useful disease-modifying drugs or immunotherapeutic agents that can successfully treat or prevent neurodegenerative diseases is an ongoing challenge. To date, only one of the 244 drugs in clinical trials for the treatment of neurodegenerative diseases has been approved in the past decade, indicating a failure rate of 99.6%. In corollary, the approved monoclonal antibody did not demonstrate significant cognitive benefits. Thus, the prevalence of neurodegenerative diseases is increasing rapidly. Therefore, there is an urgent need for creative approaches to identifying and testing biomarkers for better diagnosis, prevention, and disease-modifying strategies for the treatment of neurodegenerative diseases. Overexpression of the endogenous α-synuclein has been identified as the driving force for the formation of the pathogenic α-synuclein (α-Syn) conformers, resulting in neuroinflammation, hypersensitivity, endogenous homeostatic responses, oxidative dysfunction, and degeneration of dopaminergic neurons in Parkinson’s disease (PD). However, the conformational plasticity of α-Syn proffers that a certain level of α-Syn is essential for the survival of neurons. Thus, it exerts both neuroprotective and neurotoxic (regulatory) functions on neighboring neuronal cells. Furthermore, the aberrant metastable α-Syn conformers may be subtle and difficult to detect but may trigger cellular and molecular events including immune responses. It is well documented in literature that the misfolded α-Syn and its conformers that are released into the extracellular space from damaged or dead neurons trigger the innate and adaptive immune responses in PD. Thus, in this review, we discuss the nonintuitive plasticity and immunogenicity of the α-Syn conformers in the brain immune cells and their physiological and pathological consequences on the neuroimmune responses including neuroinflammation, homeostatic remodeling, and cell-specific interactions that promote neuroprotection in PD. We also critically reviewed the novel strategies for immunotherapeutic delivery interventions in PD pathogenesis including immunotherapeutic targets and potential nanoparticle-based smart drug delivery systems. It is envisioned that a greater understanding of the nonintuitive immunogenicity of aberrant α-Syn conformers in the brain’s microenvironment would provide a platform for identifying valid therapeutic targets and developing smart brain delivery systems for clinically effective disease-modifying immunotherapeutics that can aid in the prevention and treatment of PD in the future.

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Section: Evidence Of Phenotypic Switching and Structure-toxicity Rela...mentioning

confidence: 99%

Nonintuitive Immunogenicity and Plasticity of Alpha-Synuclein Conformers: A Paradigm for Smart Delivery of Neuro-Immunotherapeutics

Abioye,

Akintade,

Mitchell

et al. 2024

Pharmaceutics

View full text Add to dashboard Cite

show abstract

“…7 High SNCA expression (REP1 genotypes) is "paradoxically" associated with better motor and cognitive outcomes, 8 and high, not low, α-synuclein levels are associated with preservation of brain volume in PD. 9 Physically, proteins do not replicate; they precipitate. This irreversible process of nucleation follows the second law of thermodynamics and Gibbs free energy equation.…”

Section: A New Paradigm: Proteinopeniamentioning

confidence: 99%

“…Even in those with genetically overexpressed α-synuclein, such as SNCA duplication, the levels of soluble α-synuclein are low, not high . High SNCA expression (REP1 genotypes) is “paradoxically” associated with better motor and cognitive outcomes, and high, not low, α-synuclein levels are associated with preservation of brain volume in PD …”

Section: A New Paradigm: Proteinopeniamentioning

confidence: 99%