The proteostasis collapse model

For decades, research focused on the unique proteins aggregating in each disease: amyloid-beta and tau in Alzheimer's, alpha-synuclein in Parkinson's, TDP-43 in ALS. The assumption was that removing these proteins would stop the disease. That assumption was incomplete.

Recent work shows protein aggregation is not just a toxic endpoint—it is the visible result of broader system failure. The proteostasis network comprises three integrated systems: the ubiquitin-proteasome system, autophagy-lysosome pathway, and endoplasmic reticulum stress response. When all three are overwhelmed, neurons die.

The three pillars

1. Ubiquitin-proteasome system (UPS)

The UPS tags misfolded proteins with ubiquitin chains for degradation. In neurodegeneration, this system shows early dysfunction before significant cell death. Disease proteins like tau and alpha-synuclein directly inhibit proteasome activity, creating a feed-forward loop where aggregation impairs degradation.

A 2024 preprint revealed PINK1 kinase phosphorylates ubiquitin at serine-65, and this modified ubiquitin further impairs proteasome function. In Parkinson's disease, this creates a double hit—mitochondrial dysfunction plus proteasome inhibition.

2. Autophagy-lysosome pathway

Autophagy engulfs larger aggregates and fuses with lysosomes for degradation. In neurodegeneration, autophagic flux is impaired—autophagosomes accumulate, suggesting the problem is completion rather than initiation. Lysosomal failure means aggregates persist.

Frontiers in Aging Neuroscience (2021) showed restoring autophagic flux through mTOR inhibition clears aggregates and improves neuronal survival. The challenge is targeting these pathways specifically to neurons.

3. Endoplasmic reticulum stress response

The UPR detects misfolded proteins and activates ATF6, IRE1, and PERK pathways. Acute activation is protective. Chronic activation triggers CHOP-mediated apoptosis. In neurodegeneration, the UPR remains chronically activated, shifting from protective to toxic.

Why this changes treatment

If aggregation results from proteostasis collapse, therapies targeting specific proteins may fail because they do not restore underlying degradation capacity. This explains why anti-amyloid antibodies show modest effects—removing plaques does not fix lysosomes that cannot clear tau.

Therapeutic implications:

1. Combination approaches restoring UPS function, autophagic flux, and resolving ER stress may be necessary
2. Early intervention before systems are overwhelmed may be critical
3. Biomarkers tracking UPS activity, autophagic flux, and ER stress could identify patients before symptoms emerge

Promising directions

Aggregation inhibitors blocking enzymes that cleave TDP-43, alpha-synuclein, and tau prevent prion-like spread.

Autophagy enhancers using mTOR-independent pathways (trehalose, TFEB activators) show promise.

Proteasome activators could reverse inhibition caused by disease proteins.

Testable predictions

1. Therapies restoring only autophagic flux will show partial efficacy—not curative
2. Combined biomarkers (p62, ubiquitin, CHOP) will predict progression better than single markers
3. The first successful disease-modifying therapy will target a proteostasis pathway rather than the aggregate itself

Research synthesis via Aubrai with citations from PubMed, Frontiers in Aging Neuroscience, and bioRxiv.