$161 million over three years

 

# # # # The Aligning Science Across Parkinson’s (or ASAP) initiative is a major new source of funding for Parkinson’s research. And I mean MAJOR! It is a global basic research initiative focused on fostering collaboration and resources to better understand the underlying causes of Parkinson’s. A return to basics in order to get a better grip on the biology of the disease. Recently, the initiative announced their first round of grant awardees – handing out US$161 million for 3 year projects. This is one of the largest single rounds of research funding for Parkinson’s research ever! In today’s post, we will look at what ASAP is, what the awarded projects will be investigating, and what this means for Parkinson’s research. # # # #

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NIH Parkinson’s research funding. Source: NIH

In 2016, the US National Institutes of Health (NIH – the world’s largest funder of medical research) allocated $161 million to Parkinson’s research.

It was a small fraction of the $30+ billion spent by the NIH on medical research that year, but it was still a much needed amount of money invested into research on this neurodegenerative condition.

This week, a major new Parkinson’s research program – called Aligning Science Across Parkinson’s (or ASAP – click here to read a previous SoPD post on this initiative) – announced the rewarding of $161 million in research funding to 21 projects involving 96 research leaders from 60 institutions across 11 countries (and 31 of the research leaders are female). Importantly, all of them are seeking to “accelerate targeted basic research and move us toward more meaningful advancements for Parkinson’s” (Click here to read the annoucement).

Think about that for a second:

ASAP has basically just allocated the same amount of funding to Parkinson’s research as the entire US Government did in 2016.

Wow!

Wow indeed!

It is certainly the largest single round of funding specifically for Parkinson’s that I have ever heard of.

More importantly, it is the kind of research funding that will hopefully allow for serious shifting of the needle. It provides researchers the freedom to be bold and audacious. To take a few risks and try really new things.

What kind of research is being funded?

In the announcement, ASAP lists the awardees and their projects. The funding round involved two separates areas of grants:

• Biology of Parkinson’s-associated genetics
• Neuro-immune interaction

We know that genetic risk factors (tiny variations in specific areas of our DNA) are associated with an increased risk of developing Parkinson’s (Click here to read a recent SoPD post on this topic). By investigating the biological pathways associated with these risk factors, researchers have been able to build not only broad new theories of the underlying biology of Parkinson’s, but also a wide range of potential therapeutic targets (many of which are now being explored in clinical trials).

The projects awarded funding in this area included:

1. Mapping the LRRK2 signaling pathway and its interplay with other Parkinson’s disease components – this study team – led by Prof Dario Alessi – seeks to provide novel insights into how genetic mutations in the LRRK2 gene can cause Parkinson’s. Specifically they want to decipher what controls the activity of LRRK2 (Click here to read a previous SoPD post on the work of Prof Alessi, pictured below, and colleagues, and click here for a review of all things LRRK2 by Prof Alessi).

2. Impaired integration of organelle function in Parkinson’s disease – organelles are tiny membrane bound structures that perform specific functions within a cell (think of lysosomes, mitochrondria, etc). This project team – led by Prof Pietro De Camilli – will be using a range of tools to test the hypothesis that the functions of multiple Parkinson’s-associated genes converge on common biological pathways involving organelles within vulnerable cell types (Click here to read one of Prof De Camilli’s recent reports in this area).

3. Dissecting the mechanisms underlying disease progression – this project team – led by Prof John Hardy (pictured below in the thick of it) – will be testing whether modulating Parkinson’s-associated enzymes (think GBA) influences the course of pathology spread in a pre-clinical model of progression. They hope to determine a better understanding of the genetics of rate of progression (Click here to read a recent review of this field by Prof Hardy).“Identifying ‘risk genes’ is providing incredible insight into the biological mechanisms involved in tipping the balance from health to disease” – Prof John Hardy (Source)

4. Mechanisms overwhelming protein and organelle quality control in Parkinson’s disease – led by Prof J. Wade Harper, this research team will be looking at dysfunctional proteostasis (or the failure of cellular quality control mechanisms for protein production), and testing ways to maintain/augment the quality control capacity in the hope of providing new therapeutic strategies for Parkinson’s (Click here to read a recent report from Prof Harper’s lab exploring this idea in the context of PARKIN).

5. Mechanisms of mitochondrial damage control by PINK1 and Parkin – the goal of this project – led by Prof James Hurley – is to to figure out how Parkinson’s-associated protein PINK1 & Parkin work together to prevent disease (Click here to read previous SoPD posts about Parkin & PINK1).

6. In vivo approach to elucidate the pathobiology of Parkinson’s-associated genes using Human diseased neurons – led by Prof Deniz Kirik, this team will use patient-derived cells from genetic forms of Parkinson’s. But rather than studying these cells in a petri dish, they will be studying them in the environment of the living brain. Given this ‘unique paradigm’, the researchers hope to reveal cellular components of underlying the pathology of Parkinson’s.

7. Senescence in Parkinson’s disease and related disorders – this project will examine whether cellular senescence is a pathogenic component of Parkinson’s and test if drugs targeting senescent cells can be used as a disease-modifying therapy for the condition. This team is led by Prof Michael Lee. We have previously discussed cellular senescence on the SoPD – click here to read an example.

8. Cellular mechanism of LRRK2 in health and disease – this team, led by Prof Samara Reck-Peterson, will be exploring the biological function of the Parkinson’s-associated protein LRRK2. Members of this team have recently published multiple impressive research reports, firstly on the structure of LRRK2 (Click here to read more about this), and also on the influence of LRRK2 on microtubules (the highways of cells) and how LRRK2 (imaged below) might be blocking transportation of proteins around cells (Click here to read more about this).
   

9. Dissecting genetic interactions of Parkinson’s disease-associated risk loci – this project is being led by Prof Donald Rio and it will be focused on sophisticated genomic functional analysis in 3-dimensional brain organoids to determine how diverse genetic factors interact and contribute to the risk of developing Parkinson’s.

10. Parkinson5D: Deconstructing proximal disease mechanisms across cells, space, and progression – Prof Clemens Scherzer (pictured below) is leading this team and they will be exploring how Parkinson’s-associated genetic variants function through not only cell-specific mechanisms, but also brain region- and disease stage-dependent mechanisms (sounds epic!). Prof Scherzer led previous research highlighting  beta-agonists as a potential therapy for PD (Click here to read a previous SoPD post on this topic).
    

11. IMPACT-PD – Implications of polyamine and glucosylceramide transport in Parkinson’s disease -led by Dr Peter Vangheluwe, this team will be dissecting the neuroprotective effect of lysosomal polyamine and glucosylceramide transporters. Earlier this year, members of this team published an impressive report demonstrating that loss of ATP13A2 disrupts lysosomal polyamine export (Click here to read more about this). This project will hopefully be digging deeper into this biology.

12. Defining the cellular and molecular determinants of variable genetic penetrance in Parkinson’s disease – Prof Lorenz Studer (pictured below) is the researcher behind the stem cell transplantation technology that Bluerock Therapeutics and Bayer are taking to the clinic (Click here to read an SoPD post about this). In this new study, he and his team of collaborators will be investigating the genetic, age-related, and cell-type-specific factors that make some individuals vulnerable to developing Parkinson’s. Prof Studer’s research group recently published similar work on austim (Click here to read more about this).
    

13. Understanding inherited and acquired genetic variation in Parkinson’s disease through single-cell multi-omics analyses: A unique data resource – this team (led by Prof Thierry Voet) will be analyzing 4,500,000 single cells from the brain and gut from individuals who lived with (and without) Parkinson’s. Stop and read that sentence again: 4.5 MILLION single cells!!!  This analysis will let the researchers discover the genetic variants, and importantly, the types of brain and/or gut cells in which activity is disturbed.

14. Mapping the PD Brain: Oligomer-driven functional genomics – led by Prof Nick Wood, this team will focused on identifying where the Parkinson’s originates in the body using alpha-synuclein oligomers, how these oligomers effect function, and the impact of genetic risk factors in these processes. Below is a video of Prof Wood discussing the genetics of Parkinson’s:

 

In addition to these projects looking at the biology of Parkinson’s-associated genetics, there are also a string of projects being funded by ASAP that will be investigating the ‘Neuro-immune interaction’ in Parkinson’s – these will be exploring how the brain and immune system may be influencing each other.

Inflammation refers to a process by which the immune system communicates when things go wrong in the body or there is injury. Chronic neuroinflammation has long been implicated in Parkinson’s (Click here to read a previous SoPD post about this).

The inflammatory process. Source: Trainingcor

The Neuro-immune interaction project awarded ASAP funding include:

1. From cancer associations to altered immunity in the pathogenesis of Parkinson’s disease – led by Dr Xiqun Chen, this team brings together experts across different fields with the goal of exploring why alterations in the LRRK2 and Parkin genes can cause both Parkinson’s and certain types of cancers. They will be testing a hypothesis that immune system dysregulation is the reason.

2. Role of PD-related proteins as drivers of disease through modulation of innate and adaptive immunity – Prof Michel Desjardins and collaborators will be investigating how mutations in proteins associated with Parkinson’s (such as PINK1, Parkin, LRRK2, VPS35 and GBA) affect the function of immune cells both in cell culture as well as in mouse models of Parkinson’s (Click here to read a previous SoPD post exploring some of Prof Desjardin’s research).

3. Tracing the origin and progression of Parkinson’s disease through the neuro-immune interactome – this team, led by Prof David Hafler, will be examining the idea that in a subset of cases, Parkinson’s is being initiated by an autoimmune event involving alpha-synuclein in the gut. From there it is interactions between the immune system and cells in the peripheral and central nervous systems that establish the disease in the brain.

4. Activation of transposable elements as a trigger of neuroinflammation in Parkinson’s disease – Transposable elements, also known as “jumping genes” are DNA sequences that move from one location on the genome to another. They make up make up almost half of our genome, and this team, led by Prof Johan Jakobsson, will be seeking to determine whether transposable elements are active in tissues from people with Parkinson’s, and if they can induce inflammation in the brain (Click here to read a review of Transposable Elements in neurodevelopment and neurodegeneration, written by Prof Jakobsson). And below is a video introducing transposable elements (aka transposons):

1. Co-pathologies drive neuroinflammation and progression in PD – this team, led by Prof Jeffrey Kordower, will be generating novel nonhuman primate models of Parkinson’s using alpha synuclein preformed fibrils, AAV-tau, and beta amyloid. The study will involve both aging and genetic engineering.

2. The genome-microbiome axis in the cause of Parkinson disease: Mechanistic insights and therapeutic implications from experimental models and a genetically stratified patient population – Prof Anthony Schapira (pictured below – who is the lead investigator behind the ambroxol clinical trial program for Parkinson’s – Click here to read a previous SoPD post about that) is leading this team which will be looking at people with GBA genetic variants to see if their risk for Parkinson’s is influenced by the bacteria in their gut. They will also be trying to determine if the bacteria increases alpha-synuclein transport from gut to brain.

3. Adaptive immunity in the etiology and progression of Parkinson’s disease – led by Prof David Sulzer, this team will be investigating activated T cells – a type of immune cell – and whether (in Parkinson’s) they mistake normal nerve cells in the body as foreign invaders. This would be an example of autoimmunity and this error may be critical in the initiation of PD (Click here to read a previous SoPD post on some of Prof Sulzer’s research in this area).

By the way, Prof Sulzer is an amazing guy – not only is he at the top of his game academically – leading a world-class research group at one of the best universities in the world, but he is also an accomplished composer and musician across a variety of genres. Performing under the stage name Dave Soldier, he is has produced a vast amount of music (Click here to learn more about this). Of particular interest has been his work with the Thai orphan elelphant orchestra:

 

What do we think of the ASAP projects?

I don’t like giving opinions because 10 times out of 9 I am usually wrong. Plus, it is difficult to say much as not a lot of information has been provided about the proposed work beyond the general topic of each project team. Many of the abstracts are rather vague. I’m sure over the next three years a lot more clarity will develop, but at present it is hard to judge.

While it is important to get a better understanding of Parkinson’s-associated proteins/genes that are currently being targetted in clinical trials (such as LRRK2 and GBA), I am really pleased by some  of the ASAP funding being focused on lesser known Parkinson’s genes/proteins. More of this is really needed. Since 1997 there have been over 9,800 research reports published on “Parkinson’s” and “alpha synuclein”, but less than 300 reports mentioning the Parkinson’s-associated gene “ATP13A2”. It is good to see some of this funding going towards covering novel targets, and hopefully in a few years time we will be able to look back to this moment as agents modulating ATP13A2-related pathways enter clinical testing.

I am also hugely impressed by the scale of these projects. For example, just a few years ago analysing the RNA from a single cell was quite a technological trick (Click here for a review of the history of that field). But now research groups are conducting studies involving the sequencing of RNA from 4.5 million single cells! Some of the researchers have really grasped this opportunity by the horns and taken advantage to propose some audacious projects – this is also what we really need! Expect an exponential growth in openly available data.

Openly available data?

Yes, in addition to the overall goal of ASAP (“to fund a basic research program that amplifies and coordinates the efforts of researchers around the world, both inside and outside of the existing Parkinson’s community“), the initiative also has some major objectives which could be rather transformational for the way we conduct research. These objectives include:

• Supporting meaningful collaboration
• Generating research resources
• Democratizing data

And it is this last one that is important (as we shall be discussing in an up coming SoPD post).

Democratizing data?

Yes, ASAP is putting a lot of effort into making “data and other research objects discoverable, publicly available, and fully integrated into the PD data ecosystem” (Source).

Interesting, so what does it all mean?

We are not finished just yet.

There’s more?

Yes.

On September 22 2020, ASAP will be opening up another request for research applications.

Huh?

They will be looking for new projects that focus primarily on “Circuitry and Brain-body Interactions”. And this will be inclusive of genetics and neuro-immune contributors to Parkinson’s.

Another $161 million?

That is not clear. All we know at present is that another round of funding applications will be invited.

So what does it all mean?

ASAP represents an incredible new source of research funding for the Parkinson’s community. They are taking a back-to-basics approach to tackling Parkinson’s – stepping back from the current theories and hypotheses, and asking what do we really know about this condition(s).

The size and scale of the program is extremely encouraging. This is a real injection of capital, that is enboldening scientists to think outside the box and take some ambitious risks. It is one of those moments where you wish you had a time machine and could jump forward 3-4 years to see outcomes.

Fingers crossed some real insights will come from this investment.

 

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The banner for today’s post was sourced from ASAP.