This is a mechanism module, not a specific disease. Disorder entries reference individual nodes via conforms_to (for example, "polyglutamine_expansion_proteotoxicity#Misfolded Polyglutamine Protein Aggregation"). The module is intended for the translated/coding CAG-polyQ diseases — Huntington disease (HTT), dentatorubral-pallidoluysian atrophy (ATN1), spinocerebellar ataxia type 17 (TBP), and Machado-Joseph disease / SCA3 (ATXN3) — and is readily extensible to the other classical polyQ disorders (SCA1, SCA2, SCA6, SCA7, SBMA). It is intentionally distinct from the fame_pentanucleotide_repeat_rna_toxicity module: that module models untranslated intronic pentanucleotide repeats acting through repeat RNA toxicity, whereas this module models protein-level proteotoxicity from a translated polyQ tract. Friedreich ataxia (intronic GAA expansion causing frataxin loss of function) is explicitly out of scope because it is not a toxic-gain-of-function polyQ disease. The precise toxic species (soluble mutant conformers versus mature aggregates) remains debated and is captured at the aggregation node.
Translated CAG / Polyglutamine Repeat Expansion
trigger
The shared initiating lesion is an expanded CAG trinucleotide repeat within the coding region of the disease gene, which is translated into an abnormally long polyglutamine tract in the respective disease protein. Repeat length correlates with severity and inversely with age at onset, and the expansion confers a dominant toxic gain of function rather than simple loss of the host protein.
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Misfolded Polyglutamine Protein Aggregation
The elongated polyQ tract destabilizes the disease protein and drives misfolding and aggregation.
Show evidence (3 references)
"In mutation carriers, huntingtin is produced with abnormally long polyglutamine sequences that confer toxic gains of function and predispose the protein to fragmentation, resulting in neuronal dysfunction and death."
The Huntington disease Primer establishes the conserved initiating logic: a translated CAG expansion yields an elongated polyglutamine tract that confers a toxic gain of function on the disease protein.
"They include at least nine disorders, including Huntington's disease (HD), dentatorubral pallidoluysian atrophy (DRPLA), spinal and bulbar muscular atrophy (SBMA), and the spinocerebellar ataxias SCA1, SCA2, SCA3 (also known as Machado-Joseph disease), SCA6, SCA7, and SCA17."
Confirms that this conserved mechanism spans the nine classical CAG-polyQ disorders, including the module's flagship diseases (HD, DRPLA, SCA17, and SCA3/Machado-Joseph disease).
"The underlying disease mechanism in the polyQ diseases is thought principally to reflect dominant toxic properties of the disease proteins which, when harboring a polyQ expansion, differentially interact with protein partners and are prone to aggregate."
Supports the dominant toxic-gain-of-function model and the propensity of polyQ-expanded proteins to aggregate as the shared mechanistic core.
Misfolded Polyglutamine Protein Aggregation
central effector
The expanded polyglutamine tract destabilizes the native fold of the disease protein, promoting a beta-sheet-rich misfolded conformation that self-associates into oligomers and amyloid-like aggregates. Across polyQ diseases this is accompanied by characteristic neuronal intranuclear inclusions and cytoplasmic deposits. Whether the principal toxic species is a soluble mutant conformer or a mature aggregate remains debated, and visible inclusions may represent a late stage of a longer toxic cascade.
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Transcriptional Dysregulation
Nuclear accumulation of misfolded polyQ protein sequesters transcriptional co-activators and disrupts gene expression.
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Proteostasis Network Overload
Misfolded and aggregated polyQ protein burdens the ubiquitin-proteasome and autophagy clearance systems.
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Mitochondrial and Bioenergetic Dysfunction
Mutant polyQ protein impairs mitochondrial function and energy metabolism.
Show evidence (3 references)
"The aggregates usually consist of fibers containing misfolded protein with a beta-sheet conformation, termed amyloid."
Establishes the shared structural basis of polyQ aggregation: misfolded protein adopting beta-sheet amyloid conformation.
"human brains affected by CAG repeat diseases share several polyglutamine-related changes in their neuronal nuclei and cytoplasm including the formation of intranuclear inclusions."
Human neuropathology confirms neuronal intranuclear inclusions as a conserved feature shared across CAG-polyQ diseases.
"Recent data suggest that the toxic species of protein in these diseases may be soluble mutant conformers, and that the protein context of expanded polyglutamine is critical to understanding disease specificity."
Partially qualifies the node: misfolding of the polyQ protein is central, but the toxic species may be soluble conformers rather than mature aggregates, and host-protein context shapes disease specificity.
Transcriptional Dysregulation
amplifier
Nuclear polyQ-expanded protein directly binds and sequesters transcriptional co-activators — notably CREB-binding protein (CBP) and other acetyltransferases — reducing histone/protein acetylation and broadly altering transcription of neuronal survival and homeostasis genes. For some disease proteins (e.g., atrophin-1 in DRPLA and TBP in SCA17) the host protein is itself a transcriptional regulator, so the polyQ expansion corrupts a normal transcriptional function.
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Selective Neuronal Dysfunction and Loss
Loss of co-activator function and aberrant gene expression compromise neuronal survival programs.
Show evidence (3 references)
"the polyglutamine-containing domain of Htt, Htt exon 1 protein (Httex1p), directly binds the acetyltransferase domains of two distinct proteins: CREB-binding protein (CBP) and p300/CBP-associated factor (P/CAF)."
Cell-free and cell-based assays show the polyQ domain physically engages and inhibits CBP-class acetyltransferases, the molecular basis of polyQ transcriptional co-activator sequestration.
"In vivo, HDAC inhibitors arrest ongoing progressive neuronal degeneration induced by polyglutamine repeat expansion, and they reduce lethality in two Drosophila models of polyglutamine disease."
Drosophila polyQ models show that pharmacologically restoring histone acetylation balance rescues neurodegeneration, causally linking transcriptional/acetylation dysregulation to the disease phenotype.
"The nuclear deposition of polyQ proteins correlates with rearrangements of nuclear matrix, transcriptional dysregulation, and cell death."
Links nuclear deposition of polyQ proteins to transcriptional dysregulation and downstream cell death.
Proteostasis Network Overload
amplifier
Misfolded and aggregated polyQ protein engages, and ultimately overwhelms, the cellular protein-quality-control machinery — molecular chaperones, the ubiquitin-proteasome system, and macroautophagy. Several polyQ proteins (e.g., the deubiquitinase ataxin-3) normally participate in this machinery, so the expansion both burdens and corrupts clearance pathways, leading to accumulation of misfolded substrates and progressive neuronal compromise.
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Selective Neuronal Dysfunction and Loss
Failure to clear misfolded polyQ protein accelerates accumulation and neuronal toxicity.
Show evidence (2 references)
"accumulating reports have demonstrated the functions of ataxin-3 protein in the chaperone system, ubiquitin-proteasome system, and aggregation-autophagy, all of which suggest a role of ataxin-3 in the clearance of misfolded proteins."
In SCA3 the disease protein ataxin-3 is itself a proteostasis factor; polyQ expansion disrupts chaperone, proteasome, and autophagy-mediated clearance of misfolded proteins.
"the same conditions increased the formation of inclusion bodies from nonproteasomal substrates such as huntingtin with long polyglutamine repeats."
Demonstrates that polyQ-expanded huntingtin depends on autophagic rather than proteasomal clearance, so perturbing the proteostasis balance increases polyQ inclusion-body formation.
Mitochondrial and Bioenergetic Dysfunction
amplifier
Mutant polyQ proteins impair mitochondrial dynamics, oxidative phosphorylation, and calcium handling, producing an early bioenergetic deficit and increased oxidative stress. Because neurons are highly energy-dependent, this bioenergetic failure is implicated as an early contributor to the selective regional neurodegeneration of polyQ disease.
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Selective Neuronal Dysfunction and Loss
Bioenergetic failure and oxidative stress lower the threshold for neuronal dysfunction and death.
Show evidence (1 reference)
"Research has identified mitochondrial failure as an early pathogenic mechanism contributing to HD's selective neurodegeneration."
Supports mitochondrial/bioenergetic failure as an early contributor to the selective neurodegeneration seen in Huntington disease, the prototype polyQ disorder.
Selective Neuronal Dysfunction and Loss
effector
The convergent effects of transcriptional dysregulation, proteostasis overload, and bioenergetic failure produce the defining feature of polyQ disease: region-specific, selective neuronal dysfunction and loss despite near-ubiquitous expression of the disease protein. Each disorder targets a characteristic neuronal population and brain region — striatal medium spiny neurons in Huntington disease, cerebellar and brainstem circuits in SCA3 and SCA17, and pallidal/dentate systems in DRPLA — yielding the corresponding motor, cognitive, and psychiatric phenotypes.
Show evidence (2 references)
"These disorders all share features including: delayed onset; selective neuronal vulnerability, despite widespread expression of disease-related proteins during the whole lifetime; abnormal protein processing and aggregation; and cellular toxic effects involving both cell autonomous and cell-cell..."
Directly supports selective neuronal vulnerability despite widespread protein expression as the shared end-stage feature of polyQ neurodegeneration.
"Spinocerebellar ataxia 17 (SCA17) is caused by polyglutamine (polyQ) repeat expansion in the TATA-binding protein (TBP) and is among a family of neurodegenerative diseases in which polyQ expansion leads to preferential neuronal loss in the brain."
SCA17 knock-in mouse work frames preferential (selective) neuronal loss as the shared outcome of polyQ expansion across this disease family, generalizing the effector node beyond Huntington disease.