Across nearly all neurodegenerative diseases, the same molecular pattern recurs: a normally-soluble protein misfolds, aggregates into insoluble fibrils, spreads cell-to-cell in a prion-like fashion, and kills the cells in which it accumulates. Amyloid-β and tau in Alzheimer's. α-synuclein in Parkinson's and Lewy-body dementia. Huntingtin in Huntington's. TDP-43 and SOD1 in ALS. Prion protein in Creutzfeldt-Jakob. The diseases are clinically different because each targets different neuron populations; the underlying machinery is suspiciously similar.
Huntington's disease gave the cleanest entry point: an autosomal-dominant CAG-repeat expansion in the huntingtin gene, fully penetrant, with onset typically in middle age and characteristic chorea (involuntary dance-like movements), cognitive decline, and psychiatric features; the misfolded huntingtin kills medium spiny neurons in the striatum. ALS (amyotrophic lateral sclerosis, Lou Gehrig's disease) is heterogeneous: motor-neuron degeneration with TDP-43 pathology in most sporadic cases; SOD1 in 1–2% (the discovery that founded the field's molecular era in 1993); C9orf72 hexanucleotide repeat expansion as the most common genetic cause, also linked to frontotemporal dementia. Frontotemporal dementias (FTD) — behavioral, semantic, and progressive nonfluent variants, with tau or TDP-43 pathology — overlap clinically and pathologically with ALS. Prion diseases (CJD, kuru, fatal familial insomnia) are the limit case: misfolded prion protein directly catalyzes the misfolding of normal prion protein, producing rapid progression and death within months. The prion-like spread hypothesis (Spillantini, Braak, others, 2010s) generalized this mechanism to all the others — providing the long-missing explanation of why each disease has a characteristic anatomical progression.
Therapeutic strategy across the field has converged on the misfolded-protein target. Tofersen (2023) is an antisense oligonucleotide that lowers SOD1 in the small fraction of ALS patients with that mutation; the effect is modest. Antisense oligonucleotide trials targeting huntingtin (tominersen) have failed. Anti-tau antibodies and anti-α-synuclein antibodies are in trials with mixed results. Brain organoid and iPSC-derived neuron models, and AI-driven drug discovery focused on misfolded-protein structures, are accelerating the pipeline. The deeper puzzle — why specific diseases target specific neurons, when the misfolded-protein machinery is so similar across diseases — remains the central unsolved question. ALS, Huntington's, FTD, and prion diseases together still have no disease-modifying therapy worth the name.