New company to focus on biomolecular condensates

[lgelb]

Here is the PR. It will be a while before anything comes of this preclinical work, but it's good to see a group of blue-chip players anteing up for ALS research. And this is a different approach.

 

[KevinM]

Fascinating. Thanks Laurie.

 

[Fusia]

Yes, very fascinating approach, and lots of big players/money. It is interesting that ALS is one of the two diseases they are focusing on first with this approach since it sounds like it could be applied to many diseases…

 

[Clearwater AL]

To add to Laurie’s “Here’s the PR”.

This what I was somewhat referring to as I have been
following Alzheimers research closely.

Normal proteostasis ensures that proteins are produced and folded appropriately before they are trafficked to precise locations. It also acts to ensure that abnormal or excess proteins are degraded to prevent the accumulation of unwanted products.4,5

Protein misfolding may occur due to genetic or environmental factors and often leads to loss of function. Misfolded proteins may accumulate, form intermediate oligomers or fibrils, and, eventually, mature aggregates, all of which can be toxic to the cells .3,7.

Biomolecular Condensates in relationship to Neurodegenerative Diseases...

Inclusion body myositis
Amyotrophic lateral sclerosis
Parkinson’s disease
Huntington's disease
*Alzheimer's disease

Let’s hope.

Below for those who may want to follow in regards to cell numbers

Glial, Axon, Dendrite and others.

 

[Ed340hp]

With mRNA in the vaccine news, and the slowly evolving understanding of how biomolecular condensates formation and disposal may be directed by mRNA to help cells control division and error check the new cell for acceptance or rejection (cell death), along with post division cell debris breakdown and transport, the combined research may yield an understanding of what causes neuron cell mortality and ALS scaring and debris accumulation (as a type of cellular auto-immune disease).

Biomolecular condensates amplify mRNA decapping by coupling protein interactions with conformational changes in Dcp1/Dcp2​

Cellular mRNA is highly regulated from its initial transcription to eventual degradation and much of this regulation arises from coordinated interactions with proteins (Moore, 2005). The assembly and organization of messenger ribonucleoprotein (mRNP) complexes has functional consequences on the transcript, dictating whether it is spliced, exported from the nucleus, actively translated, or degraded. It has become increasingly appreciated that many mRNPs accumulate in biomolecular condensates under normal and stressed conditions. Splicing and pre-mRNA processing factors are localized to nuclear Cajal bodies and paraspeckles, for example, while proteins involved in translational repression and degradation are enriched in cytoplasmic stress granules (SGs) and P-bodies (PBs), respectively (Courchaine et al., 2016; Decker and Parker, 2012; Müller-McNicoll and Neugebauer, 2013).

Biomolecular condensates have emerged as a mechanism to control numerous cellular reactions in distinct ways: partitioning proteins to regulate productive interactions, increasing the local concentration to accelerate enzymatic activity, buffering of activity to prevent aberrant transcription, and thermodynamically coupling interactions to enforce directionality in ribosome assembly (Banani et al., 2016; Gallego et al., 2020; Hnisz et al., 2017; Riback et al., 2020; Sheu-Gruttadauria and MacRae, 2018). The emergent properties afforded by formation of an extensive interaction network in condensates also have the potential to enhance enzymatic activity beyond local concentration effects (Banani et al., 2017). Such enzymatic enhancements could arise from the coupling of enzyme allostery to interactions that span the diameter of condensates. How the collective properties across length scales are coupled to enzyme catalysis is poorly understood.

More at the link.

The assembly of P-bodies, similar to other biomolecular condensates, relies on a network of multivalent interactions between resident proteins often mediated by intrinsically disordered regions (IDRs) (Boeynaems et al., 2018; Hyman et al., 2014). Many factors associated with 5’-3’ decay contain structured domains flanked by IDRs important for recruitment to P-bodies, interactions with RNA, and other decay protein cofactors (Jonas and Izaurralde, 2013). This includes the conserved decapping complex, comprised of the catalytic subunit Dcp2 and its obligate activator Dcp1, which is responsible for hydrolysis of the 7-methylguanosine (m7G) cap from mRNA (Arribas-Layton et al., 2013; Beelman et al., 1996; Dunckley and Parker, 1999; Wang et al., 2002). Decapping is generally considered the irreversible step in 5’-3’ RNA decay, committing the transcript to rapid degradation, and represents a critical checkpoint in regulating mRNA turnover (Mugridge et al., 2018; Nagarajan et al., 2013). In addition to being a major component of cellular P-bodies, Dcp2 function has been implicated in spinal muscular atrophy, innate immunity, and the interferon response (Abernathy and Glaunsinger, 2015; Li et al., 2012; Shukla and Parker, 2014). Mammalian Dcp1 is cleaved by poliovirus, leading to its degradation and disruption of P-bodies (Dougherty et al., 2011).

Our findings suggest droplet composition can tune conformational dynamics of enzymes to affect activity, which may be an emergent property of biomolecular condensates that is used for controlling RNA degradation and other biochemical reactions in cells.

ALS cell mortality research may benefit from the funding spent on mRNA derived vaccine research, and the cooperative roles mRNA and biomolecular condensates play in healthy cell division and/or aberrant transcription.

 

[Ed340hp]

A link to a quick overview of the ALS approach proposed by Faze:

ALS

 

[Lancasterlanie]

Thank you for sharing. Fascinating science, I'd try it. Nice to see some hope on the horizon. If not for me for someone in the future.

 

[Statius@]

A late comment re:curcummin. I was taking the version Bedlack recommended for his study for some time. Later after some cardiac issues I was put on apixobam (Eliquis) a blood thinner. A pharmacist at the VA when he found I was taking both strongly recommended I stop tthe curcummin since it would have similar effects to the Eliquis, essentially doubling the blood thinning effect. I haven't researched this further but did stop the curcummin.

Ed

 

[Ed340hp]

A competitor to Faze, Dewpoint, is also employing similar research into ALS.

Watch the video window in the link and use the three dots in the corner to open a menu, to enlarge the video window.

Approach | Dewpoint

 

[gpduffy]

This sounds amazing - will there be human clinic trials soon?

 

[Nikki J]

Not any time soon unfortunately

 

[Ed340hp]

More mRNA Research (for MS).
Researchers report using novel mRNA “vaccine” to treat mice with MS-like disease – further research

Researchers report using novel mRNA “vaccine” to treat mice with MS-like disease – further research needed to translate to people​

January 13, 2021


Investigators at the Johannes Gutenberg University in Mainz, Germany, and colleagues have reported success in reducing inflammation and disease activity in mouse models of MS by injecting messenger RNA that had been manipulated to deliver to the immune system the codes of molecular targets thought to be involved in the development of MS.

• The goal is to induce immune tolerance to the targets (“antigens”) – in this case components of the protective myelin coating that is damaged by immune attacks in MS – without compromising normal protective immune responses.
• The researchers delivered a modified messenger RNA, containing the code for part of a myelin component, to the mice after the MS-like disease EAE (experimental autoimmune encephalomyelitis) had begun. They reported less severe disease than would normally occur.
• Analysis of immune system activity indicated reduced inflammation and an uptick of regulatory cells capable of tamping down immune attacks specific to myelin. Importantly, they also found that the immune response to a non-myelin target was unchanged.
• Various forms of mRNA are being explored as therapies for diseases in humans. These researchers hope that delivering coded instructions for myelin antigens using their modified mRNA will increase chances of success and lead to a future new therapy for people with MS that may spare the beneficial activities of the immune system while stopping MS-specific immune activity.

Comment: There is considerable interest in this study because it uses similar technology to the Pfizer-BioNT COVID-19 vaccine, but applied to a different purpose. This early result in mice will require considerable testing before this approach can lead to clinical trials in people.

“A noninflammatory mRNA vaccine for treatment of experimental autoimmune encephalomyelitis,” by Drs. Christina Krienke, Ugur Sahin, and colleagues, was published in Science on January 8, 2021 (Vol. 371, Issue 6525, pp. 145-153).