Basic science breaks through: New therapeutic advances in Parkinson's disease

Brundin, Patrik; Atkin, Graham; Lamberts, Jennifer T.

doi:10.1002/mds.26332

Cited by 17 publications

(19 citation statements)

References 56 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…There are multiple reports showing that various therapies can attenuate αSyn pathology in transgenic mouse models (reviewed in [42]). However, only one previous report, using a peripherally administered monoclonal anti-αSyn antibody showed that prefibrillar αSyn aggregate induced α-synucleinopathy can be blocked in vivo [43].…”

Section: Discussionmentioning

confidence: 99%

Inflammatory pre-conditioning restricts the seeded induction of α-synuclein pathology in wild type mice

Koller¹,

Brooks²,

Golde³

et al. 2017

Mol Neurodegeneration

View full text Add to dashboard Cite

BackgroundCell-to-cell transmission of α-synuclein (αSyn) is hypothesized to play an important role in disease progression in synucleinopathies. This process involves cellular uptake of extracellular amyloidogenic αSyn seeds followed by seeding of endogenous αSyn. Though it is well known that αSyn is an immunogenic protein that can interact with immune receptors, the role of innate immunity in regulating induction of αSyn pathology in vivo is unknown. Herein, we explored whether altering innate immune activation affects induction of αSyn pathology in wild type mice.MethodsWe have previously demonstrated that recombinant adeno-associated virus (AAV) mediated expression of the inflammatory cytokine, Interleukin (IL)-6, in neonatal wild type mice brains leads to widespread immune activation in the brain without overt neurodegeneration. To investigate how IL-6 expression affects induction of αSyn pathology, we injected mouse wild type αSyn fibrils in the hippocampus of AAV-IL-6 expressing mice. Control mice received AAV containing an Empty vector (EV) construct. Two separate cohorts of AAV-IL-6 and AAV-EV mice were analyzed in this study: 4 months or 2 months following intrahippocampal αSyn seeding.ResultsHere, we show that IL-6 expression resulted in widespread gliosis and concurrently reduced αSyn inclusion pathology induced by a single intra-hippocampal injection of exogenous amyloidogenic αSyn. The reduction in αSyn inclusion pathology in IL-6 expressing mice was time-dependent. Suppression of αSyn pathology was accompanied by reductions in both argyrophilic and p62 immunoreactive inclusions.ConclusionsOur data supports a beneficial role of inflammatory priming of the CNS in wild type mice challenged with exogenous αSyn. A likely mechanism is efficient astroglial scavenging of exogenous αSyn, at least early in the disease process, and in the absence of human αSyn transgene overexpression. Given evidence that a pro-inflammatory environment may restrict seeding of αSyn pathology, this can be used to design anti-αSyn immunobiotherapies by harnessing innate immune function.Electronic supplementary materialThe online version of this article (doi:10.1186/s13024-016-0142-z) contains supplementary material, which is available to authorized users.

show abstract

Section: Discussionmentioning

confidence: 99%

Inflammatory pre-conditioning restricts the seeded induction of α-synuclein pathology in wild type mice

Koller¹,

Brooks²,

Golde³

et al. 2017

Mol Neurodegeneration

View full text Add to dashboard Cite

show abstract

“…It should be recognized that none of the currently available models of PD are perfect. However, it is fair to conclude that when these models, including most classic models, are used carefully, their contributions to our understanding of the neurobiology of PD and their role in promoting new therapies are phenomenal and clearly outweigh the shortcomings.…”

Section: The Present: Facts and Features Dr Parkinson Couldn't Envisagementioning

confidence: 99%

“…An alternative hypothesis is that the pathology in PD can be explained by intrinsic phenotypes of vulnerable neurons. The following 3 uncommon traits are shared by the small collection of neurons at risk in PD: long, highly branched axons with many alpha‐synuclein enriched vesicular release sites; autonomous pacemaking activity that triggers a pronounced elevation in cytosolic Ca 2+ concentration; and high basal mitochondrial oxidant stress . Each of these traits plays to the PD triumvirate.…”

Section: The Future: Unresolved Challenges and Developmentsmentioning

confidence: 99%

Past, present, and future of Parkinson's disease: A special essay on the 200th Anniversary of the Shaking Palsy

et al. 2017

View full text Add to dashboard Cite

This article reviews and summarizes 200 years of Parkinson’s disease. It comprises a relevant history of Dr. James Parkinson’s himself and what he described accurately and what he missed from today’s perspective. Parkinson’s disease today is understood as a multietiological condition with uncertain etiopathogenesis. Many advances have occurred regarding pathophysiology and symptomatic treatments, but critically important issues are still pending resolution. Among the latter, the need to modify disease progression is undoubtedly a priority. In sum, this multiple-author article, prepared to commemorate the bicentenary of the shaking palsy, provides a historical state-of-the-art account of what has been achieved, the current situation, and how to progress toward resolving Parkinson’s disease.

show abstract

“…It is thus of utmost importance to find therapies to counteract the neurodegeneration and restore the neuronal circuits in the brain of PD patients. Previous research on pathophysiological processes in PD has also helped to identify novel and promising targets for neuroprotection (Brundin et al, 2015; Kalia et al, 2015; Lindholm et al, 2016). Unfortunately many novel molecules and trophic factors showing promising data in preclinical experiments and animal models of PD have failed to recapitulate these in more rigorous clinical trials (Kalia et al, 2015; Lindholm et al, 2016).…”

mentioning

confidence: 99%

c-Abl Inhibitors Enable Insights into the Pathophysiology and Neuroprotection in Parkinson’s Disease

Lindholm

Pham

Cascone

et al. 2016

Front. Aging Neurosci.

View full text Add to dashboard Cite

Parkinson’s disease (PD) is a progressive neurodegenerative disorder causing movement disabilities and several non-motor symptoms in afflicted patients. Recent studies in animal models of PD and analyses of brain specimen from PD patients revealed an increase in the level and activity of the non-receptor tyrosine kinase Abelson (c-Abl) in dopaminergic neurons with phosphorylation of protein substrates, such as α-synuclein and the E3 ubiquitin ligase, Parkin. Most significantly inhibition of c-Abl kinase activity by small molecular compounds used in the clinic to treat human leukemia have shown promising neuroprotective effects in cell and animal models of PD. This has raised hope that similar beneficial outcome may also be observed in the treatment of PD patients by using c-Abl inhibitors. Here we highlight the background for the current optimism, reviewing c-Abl and its relationship to pathophysiological pathways prevailing in PD, as well as discussing issues related to the pharmacology and safety of current c-Abl inhibitors. Clearly more rigorously controlled and well-designed trials are needed before the c-Abl inhibitors can be used in the neuroclinic to possibly benefit an increasing number of PD patients.

show abstract

Basic science breaks through: New therapeutic advances in Parkinson's disease

Cited by 17 publications

References 56 publications

Inflammatory pre-conditioning restricts the seeded induction of α-synuclein pathology in wild type mice

Inflammatory pre-conditioning restricts the seeded induction of α-synuclein pathology in wild type mice

Past, present, and future of Parkinson's disease: A special essay on the 200th Anniversary of the Shaking Palsy

c-Abl Inhibitors Enable Insights into the Pathophysiology and Neuroprotection in Parkinson’s Disease

Contact Info

Product

Resources

About