In trinucleotide repeat disorders, anticipation (worsening severity across generations) depends on which strand and which parent transmits the expanded allele. In Huntington disease (CAG repeat expansion in HTT), what is the pathological mechanism by which mutant huntingtin causes neuronal death in the striatum?

• A Mutant Htt activates caspase-9 exclusively in medium spiny neurons by directly binding APAF-1
• B Mutant Htt causes trinucleotide repeat RNA toxicity (foci) that sequesters splicing factors without protein aggregation
• C Gain of toxic function by enhanced interaction of mutant Htt with N-methyl-D-aspartate receptors causing glutamate excitotoxicity via direct receptor activation
• D Polyglutamine (polyQ) tract of mutant Htt forms intranuclear aggregates that sequester transcription factors (e.g., CBP/p300) and impair CREB-dependent gene transcription ✓

Explanation

Mutant huntingtin with expanded polyglutamine (>36 repeats) forms misfolded oligomers and nuclear/cytoplasmic aggregates that sequester transcriptional co-activators including CREB-binding protein (CBP/p300), which have short polyQ regions themselves. This impairs CREB-mediated transcription of pro-survival genes (BDNF, PGC-1α). Additionally, mutant Htt impairs proteasomal function and mitochondrial transport. The medium spiny neurons (MSN) of the striatum are most vulnerable because of their low BDNF (Htt normally facilitates BDNF transcription and transport). RNA toxicity is the mechanism in myotonic dystrophy, not HD.

Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.

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