Category: disease_cascade
Parkinson disease (PD) progression centers on α-synuclein (SNCA) misfolding + aggregation in dopaminergic neurons. Step 1: α-synuclein expression — physiological role at presynaptic terminals (vesicle trafficking via SNARE-complex assembly). Step 2: misfolding — exposure to oxidative stress (rotenone, MPTP), mitochondrial dysfunction (complex I deficit), or genetic forms (SNCA point mutations A53T/A30P/E46K + duplications/triplications) → β-sheet conformer. Step 3: aggregation kinetics — monomer → oligomers (most toxic) → protofibrils → mature fibrils → Lewy bodies + Lewy neurites (the histopathologic signature). Step 4: prion-like spread — misfolded α-synuclein templates further misfolding cell-to-cell; staging via Braak hypothesis follows the olfactory bulb → brainstem → midbrain → cortex axis. Step 5: dopaminergic neurodegeneration — substantia nigra pars compacta loss → striatal DA depletion → motor symptoms (bradykinesia, rigidity, resting tremor) emerge at ~50-70% DA neuron loss. Step 6: cellular stress amplification — α-synuclein oligomers disrupt mitochondria, ER homeostasis (UPR — cross-link [[upr_er_stress_perk_ire1_atf6]]), lysosomes (CMA failure), and trigger microglial activation. Step 7: non-motor progression — autonomic dysfunction, REM sleep behavior disorder (often pre-motor), cognitive decline (PDD). Genetics: SNCA, LRRK2 (most common autosomal dominant), GBA (lysosomal — strongest single risk factor), PRKN/PINK1/DJ-1 (autosomal recessive — mitophagy defects). Therapeutics: levodopa + carbidopa — symptomatic gold standard; MAO-B inhibitors (selegiline, rasagiline) — DA preservation + possible neuroprotection; dopamine agonists; COMT inhibitors; deep brain stimulation. Disease-modifying programs in development (anti-α-synuclein mAbs, LRRK2 inhibitors, GBA gene therapy). Cross-links: [[catecholamine_synthesis]] (DA depletion), [[mitochondrial_peptide_signaling]] (complex I + mitophagy), [[autophagy_lc3_axis]] (lysosomal failure), [[neuroinflammation_microglia_priming]].