Reprogramming Proteostasis Networks to Delay Neurodegenerative Disease Progression in Aging Populations

The Proteostasis Network and Its Role in Neurodegeneration

The proteostasis network (PN) comprises a sophisticated cellular machinery responsible for maintaining protein homeostasis, ensuring proper folding, trafficking, and degradation of proteins. As organisms age, the efficiency of these mechanisms declines, leading to the accumulation of misfolded and aggregated proteins—a hallmark of neurodegenerative diseases such as Alzheimer's, Parkinson's, and Huntington's.

Key Components of the Proteostasis Network

• Chaperones: Heat shock proteins (HSPs) and other molecular chaperones assist in protein folding and prevent aggregation.
• Ubiquitin-Proteasome System (UPS): Tags damaged or misfolded proteins for degradation.
• Autophagy-Lysosome Pathway: Clears protein aggregates and dysfunctional organelles via macroautophagy, microautophagy, and chaperone-mediated autophagy.
• Unfolded Protein Response (UPR): Activates stress-responsive pathways in the endoplasmic reticulum (ER) to restore proteostasis.

Age-Related Dysregulation of Proteostasis

Aging disrupts proteostasis through multiple mechanisms:

• Declining Chaperone Activity: Reduced expression of HSP70 and HSP90 impairs protein refolding.
• Proteasome Dysfunction: Oxidative damage decreases proteasomal degradation efficiency.
• Impaired Autophagy: Lysosomal acidification defects and diminished autophagosome formation lead to aggregate accumulation.
• ER Stress Mismanagement: Chronic UPR activation in aging cells results in apoptosis rather than repair.

Strategies to Reprogram Proteostasis in Neurodegenerative Diseases

1. Enhancing Molecular Chaperone Function

Pharmacological activation of heat shock factor 1 (HSF1), the master regulator of chaperone expression, has shown promise in preclinical models:

• HSF1 Activators: Compounds like HSF1A and celastrol enhance HSP70/90 expression, reducing tau and α-synuclein aggregation.
• Small Molecule Chaperones: Chemical chaperones (e.g., trehalose, 4-phenylbutyrate) stabilize native protein conformations.

2. Restoring Ubiquitin-Proteasome System Efficiency

UPS impairment is a major contributor to proteinopathy. Therapeutic approaches include:

• Proteasome Activators: Compounds like PA28γ enhance proteasomal degradation of misfolded proteins.
• Deubiquitinase Inhibitors: Targeting USP14 and UCHL1 increases ubiquitin availability for protein tagging.

3. Augmenting Autophagy-Lysosomal Clearance

Autophagy induction is a key strategy for clearing toxic aggregates:

• mTOR Inhibitors: Rapamycin and its analogs (rapalogs) induce autophagy via mTORC1 inhibition.
• TFEB Activation: Transcription factor EB (TFEB) upregulates lysosomal biogenesis and autophagy genes.
• Lysosomal Enzyme Replacement: GBA1 gene therapy enhances glucocerebrosidase activity in Parkinson's models.

4. Modulating the Unfolded Protein Response (UPR)

Selective UPR modulation can alleviate ER stress without triggering apoptosis:

• IRE1α/XBP1s Pathway: Activators like IXA4 enhance adaptive UPR signaling.
• PERK Inhibitors: Compounds such as GSK2606414 prevent excessive PERK-mediated apoptosis in neurodegeneration.

Emerging Technologies in Proteostasis Reprogramming

Gene Therapy Approaches

AAV-mediated delivery of proteostasis-related genes (e.g., HSPB1, TFEB) shows potential in preclinical studies.

CRISPR-Based Interventions

Gene editing to enhance endogenous chaperone expression or remove aggregation-prone protein domains is under investigation.

Senolytics and Proteostasis

Clearing senescent cells with senolytics (e.g., dasatinib + quercetin) improves proteostasis in aged tissues.

Challenges and Future Directions

• Tissue-Specific Delivery: Crossing the blood-brain barrier remains a major hurdle for CNS-targeted therapies.
• Balancing Proteostasis Networks: Overactivation of certain pathways (e.g., excessive autophagy) may have detrimental effects.
• Biomarkers of Proteostasis Health: Developing reliable assays to monitor PN functionality in patients is crucial.

The Road Ahead: Personalized Proteostasis Medicine

Future interventions may involve:

• Patient-specific PN profiling to identify vulnerable pathways.
• Combination therapies targeting multiple proteostasis nodes simultaneously.
• AI-driven drug discovery for novel proteostasis modulators.