In Search of Target Mechanisms to Enhance Aggrephagy
Aggrephagy is a comparatively poorly understood cell maintenance mechanism that targets aggregated proteins, distinct from the ubiquitin-proteasome system that disposes of misfolded or otherwise problematic proteins. Alterations to protein structure break the proper function of the protein, and damaged machinery causes problems to a cell. Protein aggregation is a feature of neurodegenerative conditions, and scientists are in search of ways to encourage cells to more rapidly and efficiently remove these aggregates before they accumulate to pathological levels.
The ubiquitin-proteasome system (UPS) and autophagy are the two primary cellular pathways of misfolded or damaged protein degradation that maintain cellular proteostasis. When the proteasome is dysfunctional, cells compensate for impaired protein clearance by activating aggrephagy, a type of selective autophagy, to eliminate ubiquitinated protein aggregates; however, the molecular mechanisms by which impaired proteasome function activates aggrephagy remain poorly understood.
Here, we demonstrate that activation of aggrephagy is transcriptionally induced by the transcription factor NRF1 in response to proteasome dysfunction. Although NRF1 has been previously shown to induce the expression of proteasome genes after proteasome inhibition (i.e., the proteasome bounce-back response), our genome-wide transcriptome analyses identified autophagy-related p62 and GABARAPL1 as genes directly targeted by NRF1. Intriguingly, NRF1 was also found to be indispensable for the formation of p62-positive puncta and their colocalization with ULK1 and TBK1, which play roles in p62 activation via phosphorylation. Consistently, NRF1 knockdown substantially reduced the phosphorylation rate of p62.
Finally, NRF1 selectively upregulated the expression of GABARAPL1, an ATG8 family gene, to induce the clearance of ubiquitinated proteins. Our findings highlight the discovery of an activation mechanism underlying NRF1-mediated aggrephagy through gene regulation when proteasome activity is impaired.
Take your pick...
1. mTOR Pathway Inhibition: The mammalian target of rapamycin (mTOR) pathway is a key regulator of autophagy. Inhibition of mTOR with compounds like rapamycin can enhance autophagy, including aggrephagy.
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2. AMPK Activation: AMP-activated protein kinase (AMPK) is another crucial regulator of cellular energy homeostasis and autophagy. Activating AMPK through various means, such as metformin, can enhance aggrephagy.
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3. Chaperone-Mediated Autophagy (CMA) Activation: CMA is a selective form of autophagy that targets specific protein substrates. Enhancing CMA can help clear aggregated proteins. Modulating CMA-specific chaperones like Hsc70 and LAMP-2A could be a potential strategy.
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4. Modulation of Autophagy Receptors: Autophagy receptors such as p62/SQSTM1 and NBR1 recognize protein aggregates and facilitate their degradation via autophagy. Enhancing the activity of these receptors or preventing their degradation can boost aggrephagy.
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5. Proteasomal Inhibition: Inhibition of the proteasome system can redirect misfolded/aggregated proteins toward autophagic degradation pathways, including aggrephagy.
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6. Ubiquitination and Deubiquitination: Ubiquitination marks proteins for degradation. Modulating the ubiquitination process, along with deubiquitinating enzymes, can influence the clearance of ubiquitinated protein aggregates via aggrephagy.
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7. Enhancement of Lysosomal Function: Lysosomes are the endpoint organelles for autophagic degradation. Boosting lysosomal function, either through lysosomal enzyme supplementation or lysosomal biogenesis, can enhance aggrephagy.
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8. Modulation of Autophagosome-Lysosome Fusion: Autophagosomes need to fuse with lysosomes for cargo degradation. Factors influencing this fusion process, such as Rab GTPases and SNARE proteins, can be targeted to enhance aggrephagy.
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9. Genetic Approaches: Gene therapy or gene editing techniques can be employed to modulate the expression of key autophagy-related genes, enhancing the cellular machinery responsible for aggrephagy.
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10. Small Molecule Compounds: Various small molecules that modulate autophagy, such as trehalose, spermidine, and carbamazepine, have been investigated for their potential to enhance aggrephagy.
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11. Nutrient Sensing Pathways: Nutrient sensing pathways like the AMPK and mTOR pathways can be targeted by specific nutrients or pharmacological agents to enhance aggrephagy.
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12. Exercise and Caloric Restriction: Both exercise and caloric restriction have been shown to enhance autophagy in general. Lifestyle interventions that promote autophagy could potentially enhance aggrephagy as well.
I'd pick once a week rapamycin, fasting, exercise, and supplements. One reason being that they are easily accessible, the other being that I don't have enough understanding of the other methods.
Thank you for taking the time to compile this excellent list!
I am not convinced this is unique enough to deserve special attention from me. I am just going to group it in with misfolded proteins and assume disposal mechanisms are similar, until proven otherwise.
I've changed my mind after just reading Ross Peltons rapamycin book. I now pick rapamycin but toss a lot of the supplements. Especially curcumin and quercetin. Not that these are not great supplements. He just pointed out that inhibiting Mtor too much ( say by taking rapamycin as well as natural inhibitors along with say intermittent fasting) can actually be proaging. I choose rapamycin but where to draw the line on other supplements or fasting protocols that might also inhibit mtor or promote autophogy??