Hands up all those who have heard of a protein called LC3B?

[jeffreyn]

Well, we may be hearing a lot about it in the future, if a group of Canadian researchers (or someone else) can find a way to (re-)activate LC3B and "turn the [alpha-synuclein] degradation pathway back on"!

"They discovered that in Parkinson's neurons, misfolded synuclein binds to another protein called LC3B. Normally, LC3B targets misfolded proteins to be degraded. In Parkinson's disease, the study showed, LC3 gets trapped in the protein aggregates and is inactivated.

Without degradation, the cells eject the aggregates, which then spread to nearby neurons, propagating the disease throughout the brain.

'Normally misfolded proteins are degraded. We found a pathway by which synuclein is being secreted and released from neurons instead of being degraded,' said Ryan. 'We hope to turn the degradation pathway back on and stop the spread of disease.'

The team showed that activating LC3B restores degradation, enabling cells to clear the misfolded proteins and prevent disease spread."

eurekalert.org/pub_releases...

[jimcaster]

This is intriguing. Any idea what their next step is?

[jeffreyn in reply to jimcaster]

The final sentence of the research paper says: "... we propose that sequestration of LC3B monomers into α-syn microaggregates may represent a target for early intervention that might halt α-syn seeding via exosomes by restoring lysosomal degradation."

Perhaps the team will focus on this "target", while waiting for another research group to reproduce their results.

cell.com/cell-reports/fullt...

[jimcaster in reply to jeffreyn]

Thanks. I admit that I don't understand a single substantive thing in this paper and I understand that the pace of progress is slow. I just hope one of these seemingly encouraging projects bear fruit in time to be of value to PwP. It's odd to be encouraged and frustrated at the same time...

[jeffreyn in reply to jimcaster]

When you read the discussion section of the research paper, you can see that it is full of "ifs and buts". The writer of the press release threw all those "ifs and buts" away.

[faridaro]

Here is an article mentioning LC3B levels related to treatment of mice with 3 different doses (10, 30, and 60 µM) of Ambroxol for 5 days:

nature.com/articles/s41598-...

"To analyse autophagy flux, we detected LC3B-II protein levels in neurons upon ambroxol treatment. We found that ambroxol significantly increased LC3B-II to similar levels at both doses (at 10 µM: 199%, p = 0.02; at 30 µM: 203%, p = 0.003, Fig. 2A)"

Here is something to be aware of:

" The 60 µM dose caused cell death (63% decrease in the number of live cells, p = 0.003, Fig SI 1A), while 10 or 30 μM had no significant effect on cell death. Consequently, we excluded the highest dose from further studies. The morphology of the neurons was further analysed by measuring the neurite length upon ambroxol treatment at doses 10 and 30 µM. There was no evidence of significant alterations in neurite length at these two dosages (Fig SI 1B), thus we continued our study treating neurons with 10 and 30 µM of ambroxol for 5 days."

[jeffmayer in reply to faridaro]

Call me thick but I don't understand a single word why do these people talk in riddles

[faridaro in reply to jeffmayer]

Understand your frustration, because this is the language of biochemistry which I am not familiar with neither and was able only to get a gist of this study hoping that some forum members with advanced degrees in this field will be able to comment and may be explain it in layperson's terminology. What I get is that 'autophagy flux' mentioned in the article is the process of cleaning out of damaged cells in order to regenerate healthier cells and measuring the rate of this activity.

The original article posted by Jeffreyn talks about degradation (clearing) of misfolded proteins (alpha synuclein) by activating LC3B protein which was increased in mice treated with 3 different doses of Ambroxol.

So according to the above, it seems that Ambroxol might be able to help activate metabolic pathway of clearing alpha synuclein and couple of months ago there was a lengthy discussion on this forum regarding its treatment: healthunlocked.com/cure-par...

[jeffmayer]

Maybe there's hope after all