Pathological protein deposits

Pathological protein deposits, also known as protein aggregates or amyloids, are insoluble clusters of misfolded proteins that accumulate in tissues and organs, disrupting cellular function and leading to progressive disease [1, 2]. These deposits are the defining histopathological hallmarks of various proteopathies, including neurodegenerative conditions like Alzheimer's (amyloid-beta and tau) and Parkinson's (alpha-synuclein), as well as systemic diseases like transthyretin amyloidosis [4, 6]. The proteins typically adopt a highly stable, cross-beta sheet fibrillar structure that is resistant to normal proteolytic clearance [1, 8]. In drug discovery, these deposits are treated as physical targets for clearance by monoclonal antibodies or for diagnostic detection by specialized radioligands [10, 13]. Because the term 'Protein deposits' is a broad descriptive category for diverse structures rather than a single molecular entity, specific therapeutic programs typically focus on the individual protein components involved to ensure therapeutic selectivity and safety [5, 11]. Monitoring the accumulation and clearance of these deposits via imaging and fluid biomarkers is essential for diagnosing patients and evaluating the efficacy of anti-amyloid therapies [3, 13].

Other names

Protein aggregatesAmyloid depositsAmyloid fibrilsInclusion bodiesProteopathic aggregatesPlaques and tangles

Drugs typically target pathological protein deposits through passive immunization, where monoclonal antibodies bind to specific epitopes within the insoluble aggregate to trigger microglia-mediated clearance via antibody-dependent cellular phagocytosis [10, 11]. Other strategies include the use of small-molecule ligands that bind with high affinity to the cross-beta sheet structure of fibrils to enable diagnostic imaging of the deposit burden in vivo [1, 13].