Immunotherapy in Parkinson’s disease: Current status and future directions

Chatterjee, Diptaman; Kordower, Jeffrey H.

doi:10.1016/j.nbd.2019.104587

Cited by 52 publications

(45 citation statements)

References 143 publications

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“…It is important to note that for αSyn pathology to transmit from neuron-to-neuron, the lysosomal exocytosis mechanism is more in line with the following observations, which underline that the extracellular pool of pathogenic αSyn is likely not membrane-enveloped as in exosomes, extracellular vesicles, or nanotubes, but is non-enveloped: a) the stark pathology and rapid propagation caused by inoculated pre-formed fibrils (Luk et al, 2012;Luk et al, 2009;Paumier et al, 2015;Rey et al, 2018;Rey et al, 2013;Volpicelli-Daley et al, 2011b), b) the efficacy of humoral and cellular immunotherapy against αSyn (reviewed in (Chatterjee and Kordower, 2019)), c) the efficacy of passive immunization using antibodies against αSyn epitopes (reviewed in (Chatterjee and Kordower, 2019)), and d) much of the extracellular αSyn has been found as nonenveloped (Borghi et al, 2000;El-Agnaf et al, 2003;Sung et al, 2005), while a minority of αSyn is contained in extracellular vesicles or exosomes (Ejlerskov et al, 2013;Emmanouilidou et al, 2010;Jang et al, 2010). Key gaps still remain in how the pathogenic αSyn species are targeted and trafficked to lysosomes, as well as in the fate of extra cellular αSyn aggregates following their release from neurons:…”

Section: Discussionsupporting

confidence: 65%

Lysosomal Exocytosis Releases Pathogenic α-Synuclein Species from Neurons

Fels

et al. 2021

Preprint

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Considerable evidence supports the release of pathogenic aggregates of the neuronal protein α-Synuclein (αSyn) into the extracellular space. While this release is proposed to instigate the neuron-to-neuron transmission and spread of αSyn pathology in synucleinopathies including Parkinson's disease, the molecular-cellular mechanism(s) remain unclear. Here we show that pathogenic species of αSyn accumulate within neuronal lysosomes in mouse brains and primary neurons. We then find that neurons release these pathogenic αSyn species via SNARE-dependent lysosomal exocytosis; proposing a central mechanism for exocytosis of aggregated and degradation-resistant proteins from neurons.

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Section: Discussionsupporting

confidence: 65%

Lysosomal Exocytosis Releases Pathogenic α-Synuclein Species from Neurons

Fels

et al. 2021

Preprint

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“…A second vaccination with PD03A resulted in a clear dose-dependent immune response against the α-syn-targeted epitope over time, with antibody reactivation upon booster immunization (NCT02267434); however, a parallel phase 1 study did not find any immune responses (NCT02270489) [ 132 , 133 ]. Multiple immunotherapeutic agents for PD are currently in clinical trials ( Table 2 ) [ 134 ].…”

Section: Role Of Igs In Pdmentioning

confidence: 99%

The Functional Roles and Applications of Immunoglobulins in Neurodegenerative Disease

Sim

Park

2020

IJMS

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Natural autoantibodies, immunoglobulins (Igs) that target self-proteins, are common in the plasma of healthy individuals; some of the autoantibodies play pathogenic roles in systemic or tissue-specific autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus. Recently, the field of autoantibody-associated diseases has expanded to encompass neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), with related studies examining the functions of Igs in the central nervous system (CNS). Recent evidence suggests that Igs have various effects in the CNS; these effects are associated with the prevention of neurodegeneration, as well as induction. Here, we summarize the functional roles of Igs with respect to neurodegenerative disease (AD and PD), focusing on the target antigens and effector cell types. In addition, we review the current knowledge about the roles of these antibodies as diagnostic markers and immunotherapies.

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“…It also appears that αSyn and tau are propagated between cells in the brain and this would involve αSyn and tau in the ISF in intercellular spaces in the brain 22,16,23,24 . Immunotherapies have been introduced for the removal of αSyn, tau, and Aβ from the brains of patients with dementia 25 . Most research, however, has concentrated on immunotherapy for AD, entailing the removal of Aβ.…”

Section: Introductionmentioning

confidence: 99%

Peri‐arterial pathways for clearance of α‐Synuclein and tau from the brain: Implications for the pathogenesis of dementias and for immunotherapy

Nimmo

Johnston

Dodart³

et al. 2020

Alzheimer's & Dementia: Diagnosis, Assessment &

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Introduction Accumulation of amyloid beta (Aβ), α‐synuclein (αSyn), and tau in dementias indicates their age‐related failure of elimination from the brain. Aβ is eliminated along basement membranes in walls of cerebral arterioles and leptomeningeal arteries (intramural peri‐arterial drainage [IPAD]); IPAD is impaired with age. We test the hypothesis that αSyn and tau are also eliminated from the normal brain along IPAD pathways. Methods Soluble αSyn or tau was injected into mouse hippocampus. Animals were perfused 5 minutes to 7 days post‐injection. Blood vessels were identified by ROX‐SE for light‐sheet and immunolabeling for confocal microscopy. IPAD was quantified by measuring the proportion of arterioles with αSyn/tau. Results αSyn and tau are eliminated from the brain by IPAD but with different dynamics. Discussion Age‐related failure of IPAD may play a role in the pathogenesis of synucleinopathies and tauopathies. αSyn persists within IPAD at 24 hours, which may affect immunotherapy for αSyn.

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Immunotherapy in Parkinson’s disease: Current status and future directions

Cited by 52 publications

References 143 publications

Lysosomal Exocytosis Releases Pathogenic α-Synuclein Species from Neurons

Lysosomal Exocytosis Releases Pathogenic α-Synuclein Species from Neurons

The Functional Roles and Applications of Immunoglobulins in Neurodegenerative Disease

Peri‐arterial pathways for clearance of α‐Synuclein and tau from the brain: Implications for the pathogenesis of dementias and for immunotherapy

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