The Foundational Concept: Huntington's disease selectively destroys striatal neurons despite mutant huntingtin being expressed everywhere. The killing zone is the synapse where cortical glutamate meets cortical mutant huntingtin fragments delivered together.

The Mechanism:

Cortical Origin: Mutant huntingtin is expressed in cortical neurons projecting to striatum. Within these neurons, proteases (calpains, caspases) cleave mutant huntingtin into N-terminal fragments containing the polyglutamine tract.

Anterograde Delivery: These toxic fragments enter the axonal transport system, traveling along corticostriatal projections inside vesicles and along microtubules toward striatal terminals.

Co-Release: When cortical neurons fire, they release glutamate from synaptic vesicles. Simultaneously, mutant huntingtin fragments are released either packaged in exosomes or directly released with neurotransmitter.

Striatal Uptake: Striatal medium spiny neurons internalize these fragments via endocytosis at postsynaptic sites. The polyglutamine fragments enter cytoplasm and nucleus.

Glutamate Synergy: Cortical firing also delivers glutamatergic excitation to striatal neurons. This creates calcium influx through NMDA receptors activating calpains that further cleave internalized mutant huntingtin into more toxic fragments.

Synaptic Specificity: Only striatal neurons receiving both glutamate excitation and mutant huntingtin fragments from cortex experience this dual insult. Other brain regions missing one component are relatively spared.

The Selectivity Explained:

Cortical neurons project massively to striatum

Striatal neurons express high levels of NMDA receptors

Excitotoxicity and mutant protein toxicity synergize at synapse

Interneurons lacking cortical input partially protected

The Evidence:

Mouse models show cortical mutant huntingtin in striatal synapses

Corticostriatal silencing protects striatal neurons

NMDA receptor blockade reduces huntingtin fragment toxicity

Therapeutic Implications:

Cortical silencing (DREADDs, deep brain stimulation) reducing glutamate release

NMDA receptor modulators (memantine) dampening excitotoxicity

Exosome release inhibitors blocking fragment transfer

Cortical-specific antisense oligonucleotides reducing huntingtin at source

This reframes Huntington's as synaptopathy dual insult delivered directly to striatal doorstep.