Exophers (how cells/neurons get rid of waste in ESCRT-independent pathway) [intermediate filament (IF) D class proteins IFD-1 and IFD-2]

[Alex K Chen]

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The documentation of multiple IFs and aggregate collection factors (IFD-1/IF, IFD-2/IF, hNFL, FTT-2/14-3-3, HSP-1/HSP1) localized to the same soma compartment with shared functional capacity to modulate exopher extrusion levels support an intersection between aggresome biology and extrusion

 

https://www.biorxiv.org/content/10.1101/2022.08.03.501714v2.full#F16

 

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Our data also suggest that intermediate filament assembly at polyQ aggregates may follow a complex biogenesis in which “coverage” of aggregates with IFDs (i.e., co-localization) appears complete initially (at the young adult time in which neuronal exopher production is at its early peak), but with time, the polyQ collection domain supersedes the IFD capacity to fully surround the large aggregate. We noticed that under single copy expression of tagged IFD and HttQ74 reporters, extensive co-localization of IFD and aggregates is common; but when HttQ128 is highly expressed from multi-copy transgenes, IFDs do not fully envelop HttQ128 (Supplementary Figure 16) and the proportion of HttQ128 to IFD increases. Noteworthy is that dynamic patterns of polyQ concentration have also been reported in vivo in C. elegans [76] and in HEK cells [77], however functional significance and relationship to IFs have not been parsed out.

In mammals, some IFs “uncoat” from aggresomes prior to lysosome-mediated degradation for internal content degradation in a mechanism that involves subunits released from over-stressed proteasomes [78, 79]. It is interesting to speculate that partial coverage, or “uncoating”, induced under high proteostress or later in life might compromise an exophergenesis trigger. The impact of partially associated configuration of IFs and HttPolyQ on neuronal health awaits detailed study.

 

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At the cell biological level, intermediate filament proteins IFD-1 and IFD-2 concentrate into stress-responsive juxtanuclear puncta that are strikingly analogous in position and composition to what has been reported for mammalian aggresomes; additional cargo adapter/aggresome component 14-3-3/FTT-2 is also needed for efficient exophergenesis. The conserved nature of the associated biology is suggested by our finding that expression of human neuronal intermediate filament protein hNFL in C. elegans neurons can localize to the IF-aggresome and functionally substitute for C. elegans ifd-2 in exopher production.

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Most of these mammalian aggresome features are in common with the IFD-associated puncta in proteo-stressed C. elegans touch neurons, including collection of aggregated polyQ protein, enrichment in folding chaperones, ubiquitin, and dynein motor adapters, and a requirement for intact microtubules and dynein activity to collect such materials into one or two juxtanuclear sites. FTT-2/14-3-3, and possibly the associated chaperone partner HSP-1/Hsc70, aggresome formation components, impact exopher levels.

 

Edited October 26, 2023 by InquilineKea

[Alex K Chen]

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ambiguity if they require autophagy

mammalian cardiomyocyte paper shows a requirement for autophagy in exopher release.

original c elegans 2017 paper: if you knock down autophagy, more exophers occur

another conflicting paper: autophagy does upregulate exophers

you have to be clear on *what* tissue.

in this paper going to be published, it says a new form of autophagy (not macro) that is required for exophers

depends on what stage of autophagy (canonical vs LC3/phagocytosis)

model in c elegans: look at a certain kind of neuron (it is embedded in glial like hypodermis).

if you think if your hand pushing into a balloon, completely enveloped in another cell, embedded in a glial like cell

"does the exopher from neuron also enter theother cell. you can see the lysosomal system of surrounding glial cell rapidly attack the exopher material. if it is not successful at degradating, it passes trash to pseudocseulome, cavity-like cell [scavenger cell]

when trash once originated in the neuron gets thrown out into glia and then pseudocselome (once neuronally derived material and holds it in storage). multiple trash pass-offs. with each trash pass-off, there is a chance the aggregate poses a threat to receiving cell (eg seeding). trash passing through one tissue to another mimics pathogenesis

CR/fasting increases exophers
we dont have a marker to detect exophers

Nfl - neurofilament light chain (if u express intermediates in the neurons, it forms as aggregates extruded by exophers)

level of nfl in the blood can dictate progression of certain diseases like ALS. exopher can describe how a neuronally traversed protein can go through multiple tissues.

look at a population of ADHD and look at levels of Nfl in the blood (you can buy test kits)

KO endogenous decrepid microglia, repopulate with good stem cells in the brain and become functional microglia

 

 

 

[Alex K Chen]