Amyloidogenesis Module

Module amyloidogenesis 10 disorders Pathograph 6

A conserved pathophysiology module representing the formation of an amyloid deposit - the extracellular, highly ordered cross-beta-sheet fibrillar aggregate that recurs across systemic and localized amyloidoses and protein-misfolding diseases: light-chain (AL) amyloidosis, transthyretin (ATTR) amyloidosis, serum amyloid A (AA) amyloidosis, and the amyloid deposits of Alzheimer disease and type 2 diabetes. An amyloidogenic precursor protein, destabilized by mutation, overproduction, aging, or proteolysis, misfolds and converts from its native conformation into beta-sheet-rich oligomers. These nucleate and elongate into insoluble cross-beta amyloid fibrils that deposit in the extracellular space of tissues. Progressive fibril accumulation, together with proteotoxic soluble oligomers, disrupts tissue architecture and causes organ dysfunction. The module captures the shared core across the amyloidoses. Conforming disorder nodes substitute the disease-specific precursor protein (immunoglobulin light chain in AL, transthyretin in ATTR, serum amyloid A in AA, amyloid-beta in Alzheimer disease, islet amyloid polypeptide in type 2 diabetes) while preserving the precursor -> misfolding/oligomerization -> fibril formation/deposition -> tissue accumulation -> organ dysfunction causal chain.

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Pathophysiology Nodes

5 shared nodes are defined in this module.

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Cell Types

No cell types are annotated for this module.

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Biological Processes

Notes

This is a mechanism module, not a specific disease. It is a pathological structure-formation ("Xogenesis") module. Xogenesis anchor: the terminal output is an amyloid deposit, an OGMS:0000079 portion of pathological body substance produced by an OGMS:0000081 pathological derivation (a new extracellular fibrillar deposit); process genus OGMS:0000061 pathological bodily process. Amyloid deposits are extracellular and systemic/multi-organ, so no single UBERON site is bound. MPATH has no "amyloid" class, a noted OBO gap; SNOMED "Morphologically abnormal structure" (49755003) is used only as an external census/gap guide and is not bound here. Disorder entries reference individual nodes via conforms_to (for example, "amyloidogenesis#Amyloid Fibril Formation and Extracellular Deposition"). The module defines the expected pathophysiology structure; conforming nodes in disorder files should include the corresponding cell types, biological processes, and causal edges, specialized to their disease context. Key disease-specific substitutions: AL amyloidosis substitutes a clonal immunoglobulin light chain; ATTR substitutes wild-type or variant transthyretin; AA substitutes serum amyloid A driven by chronic inflammation; Alzheimer disease substitutes amyloid-beta. Modules bind GO and CL terms only and do not use chemical (CHEBI) or disease (MONDO) term bindings, except in the treatments block where the therapeutic agent carries an ontology identifier per the treatment schema.

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Used By Disorder Entries

AA Amyloidosis via Sustained Elevation of Circulating Serum Amyloid A → Amyloidogenic Precursor Protein , Proteolytic Processing and Beta-Sheet Misfolding of SAA → Protein Misfolding and Beta-Sheet Oligomerization , Glycosaminoglycan-Assisted Fibril Nucleation and Extracellular Deposition → Amyloid Fibril Formation and Extracellular Deposition , Progressive Multi-Organ Amyloid Accumulation → Progressive Tissue Amyloid Accumulation , Glomerular Filtration Barrier Disruption → Organ Dysfunction , Progressive Kidney Failure → Organ Dysfunction , Extrarenal Organ Dysfunction → Organ Dysfunction

ACys Amyloidosis via Destabilized L68Q Cystatin C Precursor → Amyloidogenic Precursor Protein , Domain-Swapped Dimerization and Oligomerization → Protein Misfolding and Beta-Sheet Oligomerization , Cystatin C Amyloid Deposition in Cerebral Arterial Walls → Amyloid Fibril Formation and Extracellular Deposition , Arterial Wall Matrix Accumulation and Thickening → Progressive Tissue Amyloid Accumulation , Recurrent Lobar Intracerebral Hemorrhage → Organ Dysfunction

ADan amyloidosis via Amyloidogenic ADan Precursor Peptide → Amyloidogenic Precursor Protein , ADan Misfolding and Beta-Sheet Oligomerization → Protein Misfolding and Beta-Sheet Oligomerization , ADan Fibril Formation and Extracellular Deposition → Amyloid Fibril Formation and Extracellular Deposition , Progressive Cerebral ADan Amyloid Accumulation → Progressive Tissue Amyloid Accumulation

Amyloidosis via Clonal Immunoglobulin Light-Chain Precursor Excess → Amyloidogenic Precursor Protein , TTR Tetramer Destabilization and Monomer Release → Amyloidogenic Precursor Protein , Sustained Serum Amyloid A Precursor Production → Amyloidogenic Precursor Protein , Protein Misfolding and Beta-Sheet Oligomerization , Amyloid Fibril Formation and Extracellular Deposition

Early-Onset Autosomal Dominant Alzheimer Disease via Altered Gamma-Secretase Processing of APP and Increased Abeta42 Fraction → Amyloidogenic Precursor Protein , Increased APP Substrate Dosage → Amyloidogenic Precursor Protein , Amyloid-beta Misfolding and Soluble Oligomer Formation → Protein Misfolding and Beta-Sheet Oligomerization , Fibrillar Amyloid-beta Plaque Formation and Deposition → Amyloid Fibril Formation and Extracellular Deposition , Progressive Cortical Amyloid Accumulation → Progressive Tissue Amyloid Accumulation , Progressive Dementia → Organ Dysfunction

Familial Visceral Amyloidosis via Variant Plasma Protein Amyloidogenic Precursor → Amyloidogenic Precursor Protein , Destabilization and Beta-Sheet Conversion of the Variant Precursor → Protein Misfolding and Beta-Sheet Oligomerization , Visceral Amyloid Fibril Formation and Extracellular Deposition → Amyloid Fibril Formation and Extracellular Deposition , Progressive Visceral Amyloid Accumulation → Progressive Tissue Amyloid Accumulation , Progressive Renal Excretory Failure → Organ Dysfunction

Finnish Type Amyloidosis via Two-Step Proteolysis Releasing 8 and 5 kDa Amyloidogenic Fragments → Amyloidogenic Precursor Protein , Systemic AGel Amyloid Deposition → Amyloid Fibril Formation and Extracellular Deposition , Corneal, Cranial Nerve and Dermal Dysfunction → Organ Dysfunction

Hereditary Transthyretin Amyloidosis via Amyloidogenic Variant TTR Precursor → Amyloidogenic Precursor Protein , TTR Tetramer Destabilization, Misfolding, and Oligomerization → Protein Misfolding and Beta-Sheet Oligomerization , TTR Amyloid Fibril Formation and Extracellular Deposition → Amyloid Fibril Formation and Extracellular Deposition , Progressive Multitissue TTR Amyloid Accumulation → Progressive Tissue Amyloid Accumulation , Peripheral and Autonomic Nerve Injury → Organ Dysfunction , Cardiac Amyloid Infiltration and Dysfunction → Organ Dysfunction , Ocular and Renal Involvement → Organ Dysfunction

Primary Cutaneous Amyloidosis via Keratinocyte Damage and Amyloidogenic Keratin Release → Amyloidogenic Precursor Protein , Keratin Misfolding and Beta-Sheet Oligomerization → Protein Misfolding and Beta-Sheet Oligomerization , Papillary Dermal Amyloid Fibril Deposition → Amyloid Fibril Formation and Extracellular Deposition , Impaired Amyloid Clearance and Progressive Cutaneous Accumulation → Progressive Tissue Amyloid Accumulation , Chronic Cutaneous Lesion Formation and Dysfunction → Organ Dysfunction , Local Plasma Cell Light-Chain Production → Amyloidogenic Precursor Protein

Systemic AL Amyloidosis via Amyloidogenic Monoclonal Free Light-Chain Production and Secretion → Amyloidogenic Precursor Protein , Light-Chain Misfolding and Beta-Sheet Oligomerization → Protein Misfolding and Beta-Sheet Oligomerization , Amyloid Fibril Formation and Extracellular Deposition , Progressive Systemic Tissue Amyloid Accumulation → Progressive Tissue Amyloid Accumulation , Systemic Multiorgan Dysfunction → Organ Dysfunction , Hepatic Amyloid Accumulation → Progressive Tissue Amyloid Accumulation , Myocardial Amyloid Accumulation → Progressive Tissue Amyloid Accumulation , Myocardial Stiffening and Diastolic Dysfunction → Organ Dysfunction , Renal Amyloid Accumulation → Progressive Tissue Amyloid Accumulation , Glomerular Filtration Barrier Dysfunction and Protein Loss → Organ Dysfunction , Peripheral and Autonomic Nerve Amyloid Accumulation → Progressive Tissue Amyloid Accumulation , Peripheral and Autonomic Nerve Dysfunction → Organ Dysfunction , Gastrointestinal Amyloid Accumulation → Progressive Tissue Amyloid Accumulation , Gastrointestinal Dysmotility and Nutritional Impact → Organ Dysfunction , Tongue Soft-Tissue Amyloid Accumulation → Progressive Tissue Amyloid Accumulation , Vascular Amyloid Accumulation and Fragility → Organ Dysfunction

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Pathograph

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Pathophysiology

Amyloidogenic Precursor Protein

trigger

The proximal trigger of amyloidogenesis is an amyloidogenic precursor protein whose native fold is destabilized - by a point mutation, by overproduction, by aging, or by proteolytic processing - so that it is prone to misfold. The identity of the precursor defines the amyloidosis type (transthyretin, immunoglobulin light chain, serum amyloid A, amyloid-beta), but the shared feature is a metastable precursor poised to depart its native conformation.

protein folding GO:0006457 ABNORMAL

Used by disorders

AA Amyloidosis as Sustained Elevation of Circulating Serum Amyloid A

ACys Amyloidosis as Destabilized L68Q Cystatin C Precursor

ADan amyloidosis as Amyloidogenic ADan Precursor Peptide

Amyloidosis as Clonal Immunoglobulin Light-Chain Precursor Excess

Amyloidosis as Sustained Serum Amyloid A Precursor Production

Amyloidosis as TTR Tetramer Destabilization and Monomer Release

Early-Onset Autosomal Dominant Alzheimer Disease as Altered Gamma-Secretase Processing of APP and Increased Abeta42 Fraction

Early-Onset Autosomal Dominant Alzheimer Disease as Increased APP Substrate Dosage

Familial Visceral Amyloidosis as Variant Plasma Protein Amyloidogenic Precursor

Finnish Type Amyloidosis as Two-Step Proteolysis Releasing 8 and 5 kDa Amyloidogenic Fragments

Hereditary Transthyretin Amyloidosis as Amyloidogenic Variant TTR Precursor

Primary Cutaneous Amyloidosis as Keratinocyte Damage and Amyloidogenic Keratin Release

Primary Cutaneous Amyloidosis as Local Plasma Cell Light-Chain Production

Systemic AL Amyloidosis as Amyloidogenic Monoclonal Free Light-Chain Production and Secretion

Downstream

Protein Misfolding and Beta-Sheet Oligomerization

Protein Misfolding and Beta-Sheet Oligomerization

amplifier

The destabilized precursor undergoes a conformational change from its native fold into beta-sheet-rich, aggregation-prone species. These misfolded monomers self-associate into soluble oligomers that both seed further aggregation (nucleation) and are themselves proteotoxic. This misfolding and oligomerization is the amplifying step that commits the precursor to the amyloid pathway.

protein folding GO:0006457 ABNORMAL

Used by disorders

AA Amyloidosis as Proteolytic Processing and Beta-Sheet Misfolding of SAA

ACys Amyloidosis as Domain-Swapped Dimerization and Oligomerization

ADan amyloidosis as ADan Misfolding and Beta-Sheet Oligomerization

Amyloidosis

Early-Onset Autosomal Dominant Alzheimer Disease as Amyloid-beta Misfolding and Soluble Oligomer Formation

Familial Visceral Amyloidosis as Destabilization and Beta-Sheet Conversion of the Variant Precursor

Hereditary Transthyretin Amyloidosis as TTR Tetramer Destabilization, Misfolding, and Oligomerization

Primary Cutaneous Amyloidosis as Keratin Misfolding and Beta-Sheet Oligomerization

Systemic AL Amyloidosis as Light-Chain Misfolding and Beta-Sheet Oligomerization

Downstream

Amyloid Fibril Formation and Extracellular Deposition

Amyloid Fibril Formation and Extracellular Deposition

central effector

The rate-limiting central effector of amyloidogenesis. Beta-sheet oligomers nucleate and elongate into insoluble amyloid fibrils bearing the characteristic highly ordered cross-beta structural motif, which deposit in the extracellular space of affected tissues. Fibril formation and tissue deposition are the disorder-agnostic convergence step - the central event common to all amyloidoses - and the key conformance target of the module.

amyloid fibril formation GO:1990000 INCREASED

Used by disorders

AA Amyloidosis as Glycosaminoglycan-Assisted Fibril Nucleation and Extracellular Deposition

ACys Amyloidosis as Cystatin C Amyloid Deposition in Cerebral Arterial Walls

ADan amyloidosis as ADan Fibril Formation and Extracellular Deposition

Amyloidosis

Early-Onset Autosomal Dominant Alzheimer Disease as Fibrillar Amyloid-beta Plaque Formation and Deposition

Familial Visceral Amyloidosis as Visceral Amyloid Fibril Formation and Extracellular Deposition

Finnish Type Amyloidosis as Systemic AGel Amyloid Deposition

Hereditary Transthyretin Amyloidosis as TTR Amyloid Fibril Formation and Extracellular Deposition

Primary Cutaneous Amyloidosis as Papillary Dermal Amyloid Fibril Deposition

Systemic AL Amyloidosis

Downstream

Progressive Tissue Amyloid Accumulation

Progressive Tissue Amyloid Accumulation

effector

Continued fibril deposition accumulates as amyloid within the extracellular matrix of affected organs, progressively expanding the interstitium and physically disrupting normal tissue architecture. This accumulation - the growing amyloid burden - is the effector step that converts molecular fibril formation into an organ-level structural lesion.

Used by disorders

AA Amyloidosis as Progressive Multi-Organ Amyloid Accumulation

ACys Amyloidosis as Arterial Wall Matrix Accumulation and Thickening

ADan amyloidosis as Progressive Cerebral ADan Amyloid Accumulation

Early-Onset Autosomal Dominant Alzheimer Disease as Progressive Cortical Amyloid Accumulation

Familial Visceral Amyloidosis as Progressive Visceral Amyloid Accumulation

Hereditary Transthyretin Amyloidosis as Progressive Multitissue TTR Amyloid Accumulation

Primary Cutaneous Amyloidosis as Impaired Amyloid Clearance and Progressive Cutaneous Accumulation

Systemic AL Amyloidosis as Gastrointestinal Amyloid Accumulation

Systemic AL Amyloidosis as Hepatic Amyloid Accumulation

Systemic AL Amyloidosis as Myocardial Amyloid Accumulation

Systemic AL Amyloidosis as Peripheral and Autonomic Nerve Amyloid Accumulation

Systemic AL Amyloidosis as Progressive Systemic Tissue Amyloid Accumulation

Systemic AL Amyloidosis as Renal Amyloid Accumulation

Systemic AL Amyloidosis as Tongue Soft-Tissue Amyloid Accumulation

Downstream

Organ Dysfunction

Organ Dysfunction

consequence

The clinical end state of the module. Amyloid infiltration and proteotoxic soluble oligomers impair the function of the affected organs - producing restrictive cardiomyopathy and heart failure (cardiac amyloidosis), peripheral and autonomic neuropathy, nephrotic-range proteinuria and renal failure, or neurodegeneration - the consequence of the conserved amyloidogenesis chain.

Used by disorders

AA Amyloidosis as Extrarenal Organ Dysfunction

AA Amyloidosis as Glomerular Filtration Barrier Disruption

AA Amyloidosis as Progressive Kidney Failure

ACys Amyloidosis as Recurrent Lobar Intracerebral Hemorrhage

Early-Onset Autosomal Dominant Alzheimer Disease as Progressive Dementia

Familial Visceral Amyloidosis as Progressive Renal Excretory Failure

Finnish Type Amyloidosis as Corneal, Cranial Nerve and Dermal Dysfunction

Hereditary Transthyretin Amyloidosis as Cardiac Amyloid Infiltration and Dysfunction

Hereditary Transthyretin Amyloidosis as Ocular and Renal Involvement

Hereditary Transthyretin Amyloidosis as Peripheral and Autonomic Nerve Injury

Primary Cutaneous Amyloidosis as Chronic Cutaneous Lesion Formation and Dysfunction

Systemic AL Amyloidosis as Gastrointestinal Dysmotility and Nutritional Impact

Systemic AL Amyloidosis as Glomerular Filtration Barrier Dysfunction and Protein Loss

Systemic AL Amyloidosis as Myocardial Stiffening and Diastolic Dysfunction

Systemic AL Amyloidosis as Peripheral and Autonomic Nerve Dysfunction

Systemic AL Amyloidosis as Systemic Multiorgan Dysfunction

Systemic AL Amyloidosis as Vascular Amyloid Accumulation and Fragility