Journal of Huntington's diseaseSep 3, 2026

Selective cleanup of damaged proteins with helper molecules in polyglutamine diseases: from how it works to possible treatments

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗

Updated Sep 4, 2026

Abstract

Chaperone-assisted selective autophagy (CASA) may play a crucial role in mitigating neurodegeneration linked to polyglutamine diseases.

CASA is essential for maintaining protein balance in neurons, which are particularly vulnerable to protein misfolding.
The process involves chaperones like HSPB8 and BAG3 that help direct misfolded proteins for degradation.
In conditions like Huntington's disease, the accumulation of mutant proteins can overwhelm the cellular quality control systems.
CASA components are upregulated as a compensatory response to enhance clearance of toxic aggregates.
Chronic stress can limit the efficiency of CASA, potentially contributing to the progression of polyQ diseases.
Therapeutic strategies are being explored to enhance CASA activity, including drugs that induce autophagy.

Simplified

Chaperone-assisted selective autophagy (CASA) is a crucial process aimed at maintaining proteostasis in several neurodegenerative diseases associated with protein misfolding, including polyglutamine (polyQ) diseases. Autophagy is a critical lysosome-mediated degradation pathway, particularly essential in neurons, which are highly susceptible to proteotoxic stress due to their post-mitotic nature. Selective autophagy pathways, including CASA, ensure the targeted removal of misfolded proteins and damaged organelles, thereby preserving cellular homeostasis. CASA is based on the intersection of chaperones and autophagy, where HSPB8 and BAG3 interact with HSPA and STUB1 forming a complex that identifies, ubiquitinates, and directs aberrant proteins toward autophagosomes for subsequent lysosomal degradation. In polyQ diseases, such as spinal and bul muscular atrophy (SBMA) and Huntington's disease (HD), mutant proteins accumulate, overwhelming the protein quality control systems. The CASA components are upregulated as a compensatory response, promoting toxic aggregates clearance and cellular damage mitigation. However, chronic proteotoxic stress and progressive impairment of autophagic and lysosomal pathways eventually limit CASA efficiency, contributing to disease progression. The review highlights how CASA exerts its protective activities in polyQ diseases and reports therapeutic strategies aimed at enhancing CASA activity, including pharmacological inducers and combinatorial approaches targeting autophagy and the ubiquitin-proteasome system. Overall, CASA emerges as a crucial adaptive mechanism and a promising therapeutic target in polyQ-related neurodegeneration.

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Selective cleanup of damaged proteins with helper molecules in polyglutamine diseases: from how it works to possible treatments

Abstract

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