The Michael J. Fox Foundation’s Strategies for Accelerating Translation of LRRK2 into Therapies for Parkinson Disease

Padmanabhan, Shalini; Fiske, Brian; Baptista, Marco A. S.

doi:10.3390/cells9081878

Cited by 7 publications

(6 citation statements)

References 48 publications

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“…It is important to note that all of our work has been done in cells expressing endogenous amounts of LRRK2 therefore eliminating confounding factors associated with overexpression paradigms. Our collective data enhances our understanding of the role of LRRK2 in immune cell function and is clearly important in the context of LRRK2-based therapies including small molecule kinase inhibitors and antisense technology which are at various stages of clinical trials ( Ahmadi Rastegar and Dzamko, 2020 ; Padmanabhan et al, 2020 ).…”

Section: Discussionmentioning

confidence: 81%

Abrogation of LRRK2 dependent Rab10 phosphorylation with TLR4 activation and alterations in evoked cytokine release in immune cells

Nazish

Arber

Piers

et al. 2021

Neurochemistry International

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LRRK2 protein is expressed prominently in immune cells, cell types whose contribution to LRRK2-associated genetic Parkinson’s disease (PD) is increasingly being recognised. We investigated the effect of inflammatory stimuli using RAW264.7 murine macrophage cells as model systems. A detailed time course of TLR2 and TLR4 stimulation was investigated through measuring LRRK2 phosphorylation at its specific phospho-sites, and Rab8 and Rab10 phosphorylation together with cytokine release following treatment with LPS and zymosan. LRRK2 phosphorylation at Ser935, Ser955 and Ser973 was increased significantly over untreated conditions at 4–24h in both WT-LRRK2 and T1348N-LRRK2 cell lines to similar extents although levels of Ser910 phosphorylation were maintained at higher levels throughout. Importantly we demonstrate that LPS stimulation significantly decreased phospho-Rab10 but not phospho-Rab8 levels over 4–24h in both WT-LRRK2 and T1348N-LRRK2 cell lines. The dephosphorylation of Rab10 was not attributed to its specific phosphatase, PPM1H as the levels remained unaltered with LPS treatment. MAPK phosphorylation occurred prior to LRRK2 phosphorylation which was validated by blocking TLR4 and TLR2 receptors with TAK242 or Sparstolonin B respectively. A significant decrease in basal level of TNFα release was noted in both T1348N-LRRK2 and KO-LRRK2 cell lines at 48h compared to WT-LRRK2 cell line, however LPS and zymosan treatment did not cause any significant alteration in the TNFα and IL-6 release between the three cell lines. In contrast, LPS and zymosan caused significantly lower IL-10 release in T1348N-LRRK2 and KO-LRRK2 cell lines. A significant decrease in phospho-Rab10 levels was also confirmed in human IPS-derived macrophages with TLR4 activation. Our data demonstrates for the first time that LRRK2-dependent Rab10 phosphorylation is modulated by LPS stimulation, and that cytokine release may be influenced by the status of LRRK2. These data provide further insights into the function of LRRK2 in immune response, and has relevance for understanding cellular dysfunctions when developing LRRK2-based inhibitors for clinical treatment.

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Section: Discussionmentioning

confidence: 81%

Abrogation of LRRK2 dependent Rab10 phosphorylation with TLR4 activation and alterations in evoked cytokine release in immune cells

Nazish

Arber

Piers

et al. 2021

Neurochemistry International

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“…LRRK2 also plays important role in regulation of protein translation, neurites morphogenesis, dynamics of the cytoskeletal and intracellular trafficking, synapse formation. These findings of kinase-dependent neurodegeneration support drug makers to generate LRRK2 kinase inhibitor as a therapeutic strategy for PD [7]. Pathologically more than 80% of autopsy examined cases show the presence of LRRK2 with Lewy bodies.…”

Section: Lrrrk2 and Snca Gene Mutations (Autosomal Dominance)mentioning

confidence: 65%

Genetic Basis and Novel Treatment Strategies in Parkinson's Disease – A Review

Gangadhar¹

2021

Int J Pharm Pharmacol

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Parkinson's disease (PD) is the 2nd most common progressive neurodegenerative disorder after Alzheimer's disease. Approximately 60000 are diagnosed with Parkinson's disease each year and more than 10 million people are living with PD. PD is a neurodegenerative disorder in addition to the causes of PD are so many, it's not caused by a single pathophysiologic disturbance. So many drugs are available to treat PD but all are only for symptomatic relief no one drug is a disease-modifying agent. Although so many targets are available for targeting the Synuclein alpha, mitochondrial oxidative stress, autophagy, targeting glial cell inflammation, targeting metal ion homeostasis. But till now no one drug is successful in targeting these targets. In this review, we have summarized the genetic basis and novel targets available for the disease-modifying strategy for PD.

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“…Better understanding of the disease for the public moves a step towards tailored person-centredness, enabling others to see people with PD as a person living an everyday life. The Michael J Fox Foundation leads PD research in the US, seeking a cure and raising awareness to reduce stigma through fundraising and advocacy [78]. However, there is a lack of similar interventions and campaigns in the UK PD community.…”

Section: Discussionmentioning

confidence: 99%

Exploring public perceptions and awareness of Parkinson’s disease: A scoping review

Crooks,

Carter,

Wilson

et al. 2023

PLoS ONE

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Background Parkinson’s disease (PD) is a common neurological disease affecting around 1% of people above sixty years old. It is characterised by both motor and non-motor symptoms including tremor, slow movement, unsteady gait, constipation and urinary incontinence. As the disease progresses, individuals living with the disease are likely to lose their independence and autonomy, subsequently affecting their quality of life. People with PD should be supported to live well within their communities but there has been limited research regarding what the public know about PD. This review aims to develop an understanding of how the public view people living with PD, which has the potential to aid the development of an educational resource for the future to improve public awareness and understanding of PD. The purpose of this scoping review is to review and synthesise the literature on the public perception and attitudes towards people living with PD and identify and describe key findings. Aim This scoping review aims to explore public perceptions and awareness of Parkinson’s Disease among diverse populations, encompassing beliefs, knowledge, attitudes, and the broader societal context influencing these perceptions. Methods A scoping review of the literature was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-analysis extension for ScR (PRISMA-ScR). Four electronic databases were searched systematically (CINAHL Plus, Medline, PsycINFO and International Bibliography of the Social Sciences). The Joanna Briggs Institute Critical Appraisal Tools (JBI) were used to assess the quality of primary studies, however, all relevant studies were considered regardless of their methodological quality. The ‘Population-Concept-Context’ framework was used in the screening process to identify eligible papers. Results A total of 23 studies were included in the review representing global research in quantitative (n = 12) and mixed methods approaches (n = 11). All 23 studies adopted some aspect of cross-sectional design. Three themes emerged from the studies, the first being public knowledge of symptoms, causes and treatment of PD and this highlighted a lack of understanding about the disease. Secondly, the review identified public attitudes towards PD, highlighting the social consequences of the disease, including the association between PD and depression, isolation and loss of independence. Finally, the third theme highlighted that there was a paucity of educational resources available to help increase public understanding of PD. Conclusion Findings from this scoping review have indicated that public awareness of PD is a growing area of interest. To our knowledge, this is the first scoping review on this topic and review findings have indicated that public knowledge and attitudes towards PD vary internationally. The implications of this are that people with PD are more likely to be a marginalised group within their communities. Future research should focus on understanding the perception of the public from the perspective of people with PD, the development of interventions and awareness campaigns to promote public knowledge and attitude and further high-quality research to gauge public perceptions of PD.

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The Michael J. Fox Foundation’s Strategies for Accelerating Translation of LRRK2 into Therapies for Parkinson Disease

Cited by 7 publications

References 48 publications

Abrogation of LRRK2 dependent Rab10 phosphorylation with TLR4 activation and alterations in evoked cytokine release in immune cells

Abrogation of LRRK2 dependent Rab10 phosphorylation with TLR4 activation and alterations in evoked cytokine release in immune cells

Genetic Basis and Novel Treatment Strategies in Parkinson's Disease – A Review

Exploring public perceptions and awareness of Parkinson’s disease: A scoping review

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