How does rapid, transparent sharing accelerate #Parkinsons research? 🧪

Kicking off our #OpenScienceWeek highlights, Cole Sitron, PhD (@pelletfraction.bsky.social) of CRN Team Harper, explains how Open Science lays the foundation for faster, more equitable discovery ⬇️

#ScienceForAll

Thanks Leo!

Thanks Elias!

(9/9) We hope you enjoy the paper! It was made possible via collaboration with the labs of @harperlabhms.bsky.social and @irinadudanova.bsky.social, and funding from @asapresearch.parkinsonsroadmap.org, @synergy-munich.bsky.social , and @embo.org.

(8/9) We are also very excited about the concept of ‘collateral degradation’ as a potential new mechanism of aggregate toxicity. In this model, aggregate-targeting E3 ligases inadvertently ubiquitinate other proteins that are bound to the aggregates, leading to their degradation and depletion.

(7/9) Why is this important?
Endolysosomal stress is a hallmark of PD and other neurodegenerative diseases. Our work shows how feedback between α-syn aggregation and ESCRT dysfunction could act as an amplifier of this stress.

(6/9) In other words, α-syn aggregates + ESCRT dysfunction fuel each other in a vicious cycle.

(5/9) That damage matters: inclusions make endolysosomes leaky. More exogenous fibrils can escape through holes in endolysosomal membranes → seed more α-syn aggregation → trap even more ESCRT-III.

(4/9) This gradually depletes the ESCRT-III pool. And without ESCRT, cells lose their main defense against endolysosomal damage.

(3/9) Trapping ESCRT-III proteins has 2 consequences:
1) They can’t reach damaged endolysosomes to repair them.
2) They get “inadvertently” ubiquitinated on the α-syn aggregates, and degraded in a process we call “collateral degradation” (more on that later!).

(2/9) We found that CHMP2B, an ESCRT-III protein, binds only aggregated (not soluble) α-syn. Once bound, CHMP2B and other ESCRT-III proteins get trapped in inclusions. This mirrors findings of CHMP2B-positive Lewy Bodies in PD patients.

Why are α-synuclein aggregates in Parkinson’s disease (PD) toxic at the cell biological level?

Our new study shows that α-syn fibrils hijack the ESCRT membrane repair system, triggering a feedback loop that worsens aggregation.

You can find it at: authors.elsevier.com/sd/article/S...

A new preprint from CRN Team Harper found that the depletion of ESCRT-III weakens membranes, allowing alpha-synuclein aggregates to spread and cause damage.

Authors: @harperlabhms.bsky.social
@harvardcellbio.bsky.social @pelletfraction.bsky.social

🔗 Check out the full #preprint: shorturl.at/69Ha6