Protein Waste Clearance in Aging and Neurodegeneration: Lorraine Kalia, MD, PhD

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"I think there's lots of exciting work in understanding the way that cells get rid of proteins through the proteasome, through the autophagy–lysosomal system, through the endosomal–lysosomal system, and also through these chaperones, and I think that we're starting to see a lot of uptake in drug development to try and enhance these systems."

In a plenary session on protein aggregate clearance in aging and neurodegeneration at the 2025 International Congress of Parkinson’s Disease and Movement Disorders (MDS), held October 5-9, in Honolulu, Hawaii, Lorraine Kalia, MD, PhD, delivered a comprehensive overview of the systems responsible for maintaining proteostasis in the aging brain. Her presentation, titled "Waste Clearance and the Aging Brain," underscored the growing relevance of protein clearance pathways as targets for therapeutic development in neurodegenerative diseases such as Parkinson’s disease (PD).

Kalia highlighted both intracellular and extracellular mechanisms that work to preserve protein homeostasis. Intracellularly, systems such as the proteasome, the endosomal-lysosomal pathway, autophagy, and molecular chaperones serve to identify, process, and degrade misfolded or toxic proteins, and she noted that these both diverse and redundant mechanisms are evolutionarily conserved, underscoring their importance for cell survival. On the extracellular front, Kalia discussed the role of glial cells in the uptake of protein aggregates and emphasized increasing scientific interest in the glymphatic system.

This recently characterized waste clearance mechanism involves the directional flow of cerebrospinal fluid (CSF) through the brain to remove metabolic waste, including aggregated proteins. Importantly, glymphatic activity appears to be enhanced during sleep, a link that may help explain emerging associations between sleep disturbance and the onset of neurodegenerative conditions. Kalia noted that enhancing glymphatic function or improving sleep quality may present novel opportunities for therapeutic intervention.

She also pointed to the potential of pharmacologic strategies aimed at boosting protein degradation—such as proteolysis-targeting chimeras (PROTACs)—which are already in use in oncology and could possibly be adapted for neurological applications. Although these technologies have not yet reached clinical trials for PD or related conditions, they represent a promising area of translational research. In that vein, Kalia emphasized the importance of moving beyond a single-protein framework for understanding neurodegeneration. As evidence mounts that multiple pathological proteins coaggregate in individual patients, broad-acting clearance strategies may offer a more effective approach than those targeting individual misfolded species.

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