Loss of Proteostasis Module

Module loss_of_proteostasis 3 disorders Pathograph 4

A conserved mechanism module for the hallmark of aging (Lopez-Otin et al.) termed loss of proteostasis: the age-associated decline of the protein homeostasis (proteostasis) network and the resulting accumulation of misfolded and aggregated proteins. In healthy cells a complex proteostasis network - molecular chaperones, the ubiquitin-proteasome system, and autophagy, with their regulators - coordinates protein synthesis, folding, conformational maintenance, and degradation. Chronic external and endogenous stresses erode this network's capacity during aging; as folding and clearance fail, non-native proteins misfold and aggregate. The aggregates (often beta-sheet-rich amyloid) accumulate, disproportionately burdening postmitotic cells such as neurons, driving proteotoxic dysfunction and the age-associated proteinopathies. This is the conserved core shared by the major neurodegenerative diseases. Individual disorder entries declare conformance via conforms_to on their pathophysiology nodes, substituting the disease-specific aggregating protein (e.g. amyloid-beta and tau in Alzheimer disease, alpha-synuclein in Parkinson disease, polyglutamine huntingtin in Huntington disease, TDP-43/SOD1 in ALS) while preserving the conserved network-decline -> misfolding -> aggregation -> proteotoxicity chain.

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Pathophysiology Nodes

4 shared nodes are defined in this module.

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Cell Types

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Biological Processes

Notes

This is a mechanism module, not a specific disease. Disorder entries reference individual nodes via conforms_to (e.g., "loss_of_proteostasis#Misfolded-Protein Aggregation"). Conforming nodes in disorder files should include the corresponding biological processes and causal edges, specialized to their disease context, substituting the disease-specific aggregating protein and vulnerable cell type. The module is intentionally kept lean: it captures the conserved proteostasis-network decline and its convergence on protein aggregation and proteotoxicity, but deliberately does NOT embed disease-specific aggregate species, seeding/prion spread models, or contested cell-non-autonomous theories, which belong on the relevant disorder entry. Complements deregulated_nutrient_sensing (mTORC1 suppression of autophagy is one contributor to failing clearance) and cellular_senescence. Key conformance target: "loss_of_proteostasis#Misfolded-Protein Aggregation".

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Used By Disorder Entries

Hutchinson-Gilford Progeria Syndrome via Progerin proteotoxic aggregation → Misfolded-Protein Aggregation

Inclusion body myopathy with Paget disease of bone and frontotemporal dementia via VCP-dependent proteostasis failure → Loss of Proteostasis , Ubiquitin-positive aggregate accumulation → Misfolded-Protein Aggregation

VCP-Associated Multisystem Proteinopathy via VCP Dysfunction and Proteostasis Failure → Loss of Proteostasis

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Pathograph

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Pathophysiology

Proteostasis Network Decline

trigger

The proteostasis network - molecular chaperones, the ubiquitin-proteasome system, and the autophagy-lysosome pathway, together with their regulators - normally maintains proteome integrity by coordinating folding, conformational maintenance, and degradation. Chronic external and endogenous stresses that accumulate during aging erode the capacity of this network, the initiating lesion of the hallmark.

Protein Folding GO:0006457 DECREASED Proteasome-Mediated Ubiquitin-Dependent Protein Catabolism GO:0043161 DECREASED Macroautophagy GO:0016236 DECREASED

Downstream

Loss of Proteostasis

Loss of Proteostasis

central effector

As the network's folding and clearance capacity falls below demand, protein homeostasis is lost: the cell can no longer keep its proteome correctly folded and turned over. This age-associated collapse of proteostatic control is the central effector state and is a common feature of aging and age-related disease across tissues.

Protein Folding GO:0006457 DECREASED

Used by disorders

Inclusion body myopathy with Paget disease of bone and frontotemporal dementia as VCP-dependent proteostasis failure

VCP-Associated Multisystem Proteinopathy as VCP Dysfunction and Proteostasis Failure

Downstream

Misfolded-Protein Aggregation

Misfolded-Protein Aggregation

effector

With folding and degradation failing, non-native proteins misfold and self-associate into aggregates - frequently beta-sheet-rich amyloid fibrils and inclusion bodies. This is the conserved central node that disease-specific aggregating proteins (amyloid-beta, tau, alpha-synuclein, polyglutamine huntingtin, TDP-43) converge upon; conforming disorder nodes substitute their particular aggregate species.

Used by disorders

Hutchinson-Gilford Progeria Syndrome as Progerin proteotoxic aggregation

Inclusion body myopathy with Paget disease of bone and frontotemporal dementia as Ubiquitin-positive aggregate accumulation

Downstream

Proteotoxic Cell Dysfunction and Neurodegeneration

Proteotoxic Cell Dysfunction and Neurodegeneration

consequence

Accumulating misfolded and aggregated proteins are proteotoxic, especially to long-lived postmitotic cells such as neurons that cannot dilute the burden by division. The resulting cellular dysfunction and death underlies the age-associated proteinopathies, most prominently the neurodegenerative diseases. The specific clinical phenotype is supplied by the conforming disorder.

Neuron CL:0000540