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.
Downstream
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Misfolded Polyglutamine Protein Aggregation
The elongated polyQ tract destabilizes the disease protein and drives misfolding and aggregation.
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.
Downstream
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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.
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.
Downstream
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Selective Neuronal Dysfunction and Loss
Loss of co-activator function and aberrant gene expression compromise neuronal survival programs.
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.
Downstream
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Selective Neuronal Dysfunction and Loss
Failure to clear misfolded polyQ protein accelerates accumulation and neuronal toxicity.
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.
Downstream
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Selective Neuronal Dysfunction and Loss
Bioenergetic failure and oxidative stress lower the threshold for neuronal dysfunction and death.
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.