Here's the deeper picture—and why this reframing matters for therapy development.

The proteostasis collapse hypothesis

Neurons are professional secretors with high metabolic demands, making them dependent on two quality control systems: the ubiquitin-proteasome system (UPS) for short-lived proteins and the autophagy-lysosome pathway for larger aggregates. When either fails, misfolded proteins accumulate.

Cross-disease evidence

In Alzheimer's, amyloid-beta oligomers directly inhibit the proteasome (Gregori et al., 1995; Oddo et al., 2005). Tau pathology spreads faster when autophagy is genetically suppressed (Bolton et al., 2020).

In Parkinson's, alpha-synuclein aggregates impair chaperone-mediated autophagy (Cuervo et al., 2004). LRRK2 mutations—found in familial PD—disrupt lysosomal function. The GBA mutations that raise PD risk encode a lysosomal enzyme.

In ALS, TDP-43 and SOD1 aggregates sequester proteasome components. Importantly, ALS-linked mutations in ubiquilin-2 and p62 directly damage the protein degradation machinery—not the proteins being degraded.

Why this reframes therapeutic strategy

If plaques and tangles are end-stage garbage piles, clearing them (anti-amyloid antibodies, for example) treats a symptom. The upstream failure is proteostasis network collapse.

Emerging approaches now target this directly: proteasome activators, autophagy inducers like trehalose and rapamycin analogs, and TFEB activators that boost lysosomal biogenesis. Some are in Phase 2 trials.

Testable prediction

Patients with early proteasome or autophagy dysfunction markers (reduced Rpt6 ATPase activity, elevated p62) should show faster disease progression regardless of which specific protein aggregates in their disease.

Limitations

Aggregation and proteostasis failure likely form a feedback loop—oligomers themselves impair degradation. Also, some genetic forms of these diseases have primary aggregation drivers (APP duplication in early-onset Alzheimer's) where proteostasis may be secondary.

Research synthesis via established literature in proteostasis and neurodegeneration.

Extending this: the ubiquitin-proteasome system (UPS) and autophagy-lysosome pathway (ALP) are the two garbage disposal systems, and they fail in distinct ways with different therapeutic implications.

UPS handles short-lived, soluble proteins. It fails when misfolded proteins overwhelm proteasome capacity or when ubiquitin tagging becomes less specific (age-related decline in E3 ligase specificity). ALP handles larger aggregates and damaged organelles. It fails when lysosomal pH rises and cathepsin activity drops.

The treatment implication: For early-stage neurodegeneration (before visible aggregates), UPS enhancement is the target — proteasome activators like USP14 inhibitors or PA28γ overexpression. For late-stage (after aggregate formation), ALP enhancement is needed — TFEB activation plus lysosomal acidification.

The failure mode also differs by disease: Alzheimer's is predominantly an ALP failure (lipofuscin and lysosomal dysfunction in neurons). Parkinson's involves both (α-synuclein overwhelms both systems). ALS is primarily UPS failure (TDP-43 and FUS are normally UPS substrates).

This means "fix the garbage disposal" is the right framework, but it needs disease-specific and stage-specific implementation.