Mutant huntingtin in the extracellular matrix: A new perspective on Huntington's disease pathology

Huntington's disease (HD) is a monogenic neurodegenerative disorder characterized by extensive brain pathology. While its underlying cause has been attributed to intracellular mutant huntingtin (mHTT), growing evidence reveals that mHTT is also present, and biologically active, outside cells. Detected in cerebrospinal fluid, plasma, and brain tissue, extracellular mHTT can induce toxicity and spread between cells. This commentary explores a challenging, yet the largely overlooked possibility that the extracellular matrix (ECM) - a dynamic and highly structured network surrounding neurons and glia - may shape how mHTT aggregates form, accumulate and propagate in the brain. Drawing on parallels with other proteinopathies, we examine how ECM components could create a microenvironment that favors mHTT accumulation and pathogenicity. While direct evidence remains limited, we argue that the ECM may play a more active role in HD than previously recognized. This perspective invites a rethinking of HD pathology and may help guide the development of therapies that extend beyond targeting intracellular mHTT.