(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.
September 10, 2025 at 7:19 PM
(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.
September 10, 2025 at 7:14 PM
(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.
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.
September 10, 2025 at 7:14 PM
(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.
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.
September 10, 2025 at 7:14 PM
(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.
September 10, 2025 at 7:13 PM
(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.
September 10, 2025 at 7:13 PM
(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!).
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!).
September 10, 2025 at 7:12 PM
(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!).
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.
September 10, 2025 at 7:11 PM
(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.