Proteinopathies

Proteinopathies (protein misfolding diseases; proteopathies) are disorders in which specific proteins misfold and/or aggregate, leading to cellular dysfunction and tissue damage. The pathogenic mechanism is typically a combination of toxic gain-of-function (e.g., oligomers/aggregates) and/or loss of normal protein function.

Pathogenesis / pathophysiology

Cells normally maintain proteostasis (protein homeostasis) using molecular chaperones, the ubiquitin–proteasome system (UPS), and autophagy–lysosomal pathways. When misfolded proteins accumulate due to various different reasons that include: mutations, aging, oxidative stress, post-translational modifications, or increased production, clearance pathways may become overwhelmed and aggregates can form. In secretory cells, misfolded proteins in the endoplasmic reticulum trigger ER stress and the unfolded protein response (UPR). Persistent ER stress can contribute to cell injury and death.

Main forms / examples

Neurodegenerative proteinopathies

• Alzheimer disease – amyloid-β plaques and tau tangles
• Parkinson disease – α-synuclein (Lewy bodies)
• ALS / FTLD – TDP-43 (and other proteins depending on subtype)
• Prion diseases – misfolded prion protein with “seeding” properties

Systemic / extracellular proteinopathies (amyloidoses)

Amyloidosis refers to extracellular deposition of misfolded proteins as amyloid fibrils. Common clinically important forms:

• AL (light-chain) amyloidosis
• AA (serum amyloid A) amyloidosis
• ATTR (transthyretin) amyloidosis (wild-type or hereditary)

Clinical significance

Proteinopathies are clinically important because aggregated proteins can disrupt cellular function (synapses, mitochondria, axonal transport), trigger stress pathways, and impair protein quality control, leading to cell death. In amyloidosis, deposition can cause organ dysfunction (e.g., cardiomyopathy, nephrotic syndrome, neuropathy) depending on the amyloid type.

Diagnosis (principles)

• Depends on disease type (clinical phenotype + targeted tests)
• In suspected amyloidosis: tissue biopsy with amyloid confirmation and typing (to guide therapy)

Treatment (principles)

• Disease-specific (e.g., remove/stop production of pathogenic protein when possible)
• Supportive care + prevention of complications
• In amyloidosis, therapy is guided by amyloid type (e.g., AL vs AA vs ATTR)

Diagram

References

• BAYER, T. A. Proteinopathies, a core concept for understanding and ultimately treating degenerative disorders? Acta Neuropathologica. 2015.
• RAO, R. V.; BALACHANDRAN, S. Misfolded proteins, endoplasmic reticulum stress and neurodegeneration. Trends in Neurosciences. 2004.
• CIECHANOVER, A.; KANNER, S.; et al. Degradation of misfolded proteins in neurodegenerative diseases: therapeutic targets and strategies. Experimental & Molecular Medicine. 2015.
• SIPE, J. D.; BENSON, M. D.; BUXBAUM, J. N.; et al. Amyloid fibril proteins and amyloidosis: International Society of Amyloidosis (ISA) nomenclature guidelines. Amyloid. 2016.