8 modules on Parkinson’s disease: substantia nigra biology, α-synuclein and Lewy bodies (cryo-EM structures), genetics (LRRK2, GBA, parkin, PINK1), MDS-UPDRS clinical, DaTscan imaging, the L-DOPA story (Carlsson Nobel) through deep brain stimulation, and the future of disease-modifying therapy.
Eight Modules
- Part I — Overview & Epidemiology: James Parkinson 1817 "Essay on the Shaking Palsy", prevalence ~1% over 60, the four cardinal features (TRAP), MDS criteria, fastest-rising of any neurological disease.
- Part II — Neuroanatomy: Substantia nigra pars compacta, nigrostriatal dopamine pathway, basal ganglia direct/indirect pathways, MPTP toxicity (Langston 1983), Cav1.3 vulnerability.
- Part III — α-Synuclein & Lewy Bodies: SNCA gene, α-synuclein structure (140 aa, intrinsically disordered → β-sheet aggregates), Lewy body pathology, Braak PD staging, prion-like spread, gut-brain (vagal) hypothesis. PDB: 6CU7 fibril.
- Part IV — Genetics: Autosomal dominant SNCA (PARK1), LRRK2 (PARK8 G2019S), recessive PRKN/parkin, PINK1, DJ-1, the GBA risk allele, GWAS hits. PDB: 7LHW LRRK2, 2NT0 GBA.
- Part V — Clinical Features & Phenotypes: TRAP, freezing, festination, non-motor (RBD, hyposmia, autonomic, depression, dementia), atypical parkinsonism (PSP, MSA, CBD, DLB) — distinguishing features.
- Part VI — Diagnosis: MDS criteria 2015, DaTscan (¹²³I-FP-CIT), MRI red flags (hummingbird sign in PSP, hot-cross-bun in MSA), genetic testing in young-onset, RBD as prodromal.
- Part VII — Therapy (flagship): The L-DOPA story (Carlsson 1957 Nobel; Cotzias 1967), levodopa-carbidopa, dopamine agonists, MAO-B inhibitors, COMT inhibitors, motor fluctuations & dyskinesias, ICDs, deep brain stimulation (Benabid 1987; PALLAS, EARLYSTIM), focused ultrasound. PDB: 6QRC dopamine D2 receptor.
- Part VIII — Future Directions: Prasinezumab/cinpanemab antibody attempts (failed), GBA-targeted (ambroxol, venglustat), LRRK2 inhibitors (BIIB122/DNL151), AAV-GDNF and AAV-AADC gene therapy, Kyoto/BlueRock stem-cell trials, exercise/microbiome.
The therapy module is structured around the 60-year arc from Cotzias 1967 levodopa to modern device therapies (LCIG, focused ultrasound, DBS) and the open frontier of disease-modifying interventions.