Alzheimer's Disease, Huntington's, Parkinson's & ALS - PDF

# Alzheimer's Disease - Part I ## Alzheimer's Disease (Symptoms, causes, pathology) * **Early:** Unable to solve problems, short term memory, altered mood and behavior * **Then:** DAM (disorientation, aphasia, memory loss) + DMI (disability, muteness, immobility) * Has a preference for females...

# Alzheimer's Disease - Part I ## Alzheimer's Disease (Symptoms, causes, pathology) * **Early:** Unable to solve problems, short term memory, altered mood and behavior * **Then:** DAM (disorientation, aphasia, memory loss) + DMI (disability, muteness, immobility) * Has a preference for females. * **Majority of cases are sporadic*, rest are genetic (APP, PSEN1/2) * APP, PSEN1/2 CAUSE Alzheimer's disease, high prevalence CAUSE, low prevalence and RISK * **Brain shrinks in size** - cortical atrophy, widening of s in frontal, temporal, parietal lobes. * AB produces plaques, tau produces tangles (tau is behind AB) ## AB peptide (APP, amyloids) * Natively unfolded/intrinsically disordered, AB to B AB42, Chelix to Bsheet + disease associated change * AB 42 is the unhealthy state, AP 40/42 are in equilibrium * **Formation of AP40** proteases cleave APP into smaller piece: soluble (domain w/ yellow) * **Formation of AB42** soluble (fray, Aß peptide, and domain w/ yellow) * **AB 40/AB42 ratio** more AB42 disease range for AD * **Plaques and tangles are considered disease causing** ## Tau tangles * **Tau:** MAPs stabilize MTs, doesn't have native form (unfolded) * **Early AD:** Ap plaques are deposited (low tau in dendrite) - becomes toxic. * **Later AD:** AB plaques damage the enzyme (high tau in dendrite) - hyper(P) and misfolds * **LoF:** tau gets corrected, can't stabilize MTs when it aggregates. * **GoF:** Introduces toxic functions not associated w/ MTs (unclear) * Both happen at the same time. * Both enhance each other. * **LoF:** Destabilizes MTs, protein disolutions are affected (tau aggregates faster) * **GoF:** More tau agg more Mis disfunction (accelerates tau agg) # Alzheimer's Disease - Part II ## Genes responsible for AD * **APP mutation** CAUSES Alzheimer's disease (rare) * **PSEN 1/2** also CAUSE Alzheimer's disease (genetically caused) * Clips APP and forms AP40/42 ## AB variants * **Amino acid substitutions** in AB40/42 * Variants can accelerate amyloid formation and aggregation. * Subs have ↑ propensity to form amyloids and efficiency of fiber formation of APPS. * **BACE1/2-secretase mutations here** ↑ formation of Af 40/42 (causes AD), more 42 aggregates. * Some secretases prefer certain cleavages, leads to ↑ processing of APP to AB42 peptides. * APP mutations alter processing by making more AB42 peptides. * **↑ secreatase/BACE/PSEN1/2** ↑ ratio of Ap42/AB40, causes ↑ in amyloid and plaque formation. ## ApoE * **Lipid binding protein involved in many cellular processes.** * **Very common genetic factor** - RISK not causative. * Mutations in ApoE increase the risk of AD. * High penetrance = causative mutation, low penetrance = risk factor. ## ApoE variants * **ApoE2 (protective)** homo (Cys, Cys), low risk of AD. * **ApoE3 (neutral)** hetero (Cys, Arg), no ↑ or ↓ risk. * **Apo E4 (deleterious)** - homo (Arg, Arg), high risk of AD. * Apo E4 is the worst case, more of it, early onset & more likely to develop AD. * **Apo E3 is the neutral form.** * **Apo E3 changes to ApoE4** so the a-helix is closer to the rest (compact) - can change functions. * ApoE4 can accelerate misfolding (non neural cells also) * **CAUSATION ≠ CORRELATION** # Huntington's Disease & other PolyQ expansion disorders ## HD Trinucleotide Repeat Expansions * **HD - monogenic disease, neuronal death in striatum, autosomal dominant.** * **TRE** * Occurs in promoter, UTR, introns (exons, doesn't make protein) - causes disease. * LoF - extension in 5' UTR (CGG), GoF - HD, CAG triplet * **PolyQ - CAG repeats in exons results into glutamine repeats.** * HD - if n < 35 no disease, if n > 35 disease. * SCAI - if n > 21 disease, if n < 21 no disease. - general rule if n > x disease, n < x no disease. * CAG expansions can be found in multiple spots (e.g. amino terminus, C terminus) - PolyQ is a disease causing mutation, longer the expansion - earlier onset. ## PolyQ Expansion Diseases ## Brain Regions * **Starts in very distinct regions in the brain, then spreads.** * **HD affects striatum** (first place showing ND), basal ganglia GONE. * **SCA affects neurons in spinal cord, defects in cerebellum** * Neuronal cell type most affected in HD, medium spiny neurons (die) * Most affected in SCAI, purkinje cells (makes connection) ## SCAI * **Ataxin 1 causes the disease,** patients show issues w/ coordination (cerebellum broken) * WT Ataxin 1 - interaction w Ataxin 7 CIC allows for full function, trans, inhibitor, ON/OFF. * PolyQ Ataxin 1 - interaction w ATX17 CIC happens different that doesn't allow for proper function (oligomer found), ON only. * **Can be both LoF + GoF.** ## Heat Shock Response * **HSR lets cells express quality control to fix damages.** * In represses HSR, doesn't allow cells to defend themselves. * **Accumulation of damaged cells cause HD** * **Early HD:** Hsp90 binds to HSFI, dissociates, HSFI gets P, binds to HSE, HSR activated * **Late HD:** Same thing but the aggregation is too much (toxic), can't bind to HSE, ASR. ## ER associated degradation (ERAD) * **ER can't do regular job, proteins misfold and accumulate triggering an unfolding response.** * **PolyQ in occupies the system that normally monitors and degrades proteins in ER.** * ERAD-polyQ over employs UPR, 2nd system is exhaustive. # Parkinson's Disease - Part I ## Parkinson's Disease * **Happens in the beginning,** dopamine neurons are affected. * Affects dopaminergic neurons in SNPC (found in midbrain, deteriorate quick). * Lewy bodies contain alpha-synuclein - ARJPD and synuclein, but no lewy bodies. * **Substantia nigra (SNPC)** makes the most dopamine in brains (starts here too) * Coordinates movement, no initiating, stamping - important for functioning but overregulation. ## Dopamine * **A precursor for 2 neurotransmitter (norep, serpinp), made of Phe and Tyr.** * **MAO degrades dopamine** and is the drug target for PD (treats depression by ↑ dopamine). * Formation of ROS might be an explanation to why there's an excess amount of degradation in PD. * **H2O + OH, H2O2 + H2O**, releases O2 group, ROS very damaging. * Formation of ROS always happens, cells need to regulate and get rid of it to an extent. * ROS at ↓[] is important for regular cell signaling and mito. function. ## Reactive oxidative species * **Oxidative damage** is a major driver of aging. * Contributing/risk factor. * **Ox. Phos is a major source - Complex III and IV (releases perioxide ion) + Complex I** * **Low-normal ROS:** NF2 interacts w Keap1, Keap1 regulates degradation of NF2. * **Alot of ROS:** Keap1 chemically modifies ROS, detaches from NF2, NF2 is free agent. * **NF2 binds to ARES** * SOD: Takes superoxide and stabilizes (no ub) to go to nucleus, in promoters of genes that become activated to fight ROS effect. * CAT: takes H2O2 → H2O + O2 not very reactive, fastest enzyme and limiting factor in availability of substrates. O2 + O2 + 2H+ → very reactive, O2 + H2O2 + lex reactive. ## Antioxidant Response * **6-Hydroxy dopamine, Rotenone, Paraquat, MPTP** damage same type of neurons and symptons. * **6-Hydroxy dopamine:** reacts with ROS alone and interferes w dopamine metabolism. * **Rotenone, MPTP, paraquat:** interferes with ox. phos and can cause DNA damage. * MPP paraquat only affects cells that have dopamine transporter and enters cell. * **Dopamine specific** (high degree), inject in brain and dopamine ones die. ## Chemical PD models ## Alpha-synuclein * **Natively unstructured,** important player in sporadic cases - H500 * **Most mutations found in N-term, a-helia struct. weakened by a.a sub, also duplication, triplication** * Can't pinpoint LoF since WT unknown. * **Soluble monomer prone to misfolding** then undergoes aggregation. # Parkinson's Disease - Part II ## Pink1 and Parkin * **Pink1 Kinase sits on mito, Parkin E3 ub. ligase (attaches Ub to molecules to mark degradation).** * Healthy mito: Pink1 becomes activated w Kinase that faces cytoplasm. * Damaged mito: Parkin bumps into Pink1, Pink1-parkin triggering mitophagy. * Of ubiquitin seems to activate Parkin, helps degrading mitochondria. * Pink1 sits on inner membrane then gets translated to outer membrane. * LoF in ARJPD no or E3 activity by mitophagy. * If Parkin Pink1 don't work, mito doesn't get degradation. * Pink and parkin mutants can block the functions, don't tag damaged mito - reads to ND. ## Ubiquitination (Ε1, Ε2, Ε3) * **Ubiquitin is normally attached to protein by E3 ligase.** * **E1 activates Ub to act w conjugating enzyme E2, E2 gives Ub over to E3 to transfer indirectly to the substrate.** * Some E3s only work w E2, parkin never gets modified, takes Ub transfers from E2 directly to substrate. ## Mitophagy and Autophagy * **Mitophagy: cells get rid of mitochondria by autophagy, genetically caused leads to ND.** * **Microautophagy:** mito enters vacuole of yeast to be degraded. * **Macroautophagy:** autophagosume recognizes damaged mito and engulfs them into a membrane. ## DJ1 (PARK7) * **Mutation causes PD and ARJPD.** * **As an antioxidant, regulates NF2 - can directly interact w oxidizing molecules.** * Might mitigate ROS produced bez it's localized to inner mitochondrial membrane. # ALS - Amyotrophic lateral sclerosis ## ALS * **Lack in muscle support, starts on one side (asymmetrical).** * **Not common bez low incident rate and die very quick.** * Death of lower motor neurons in spinal cord, brainstem and upper in motor cortex. * TDP43 (95% of ALS cases) and common pathology for ALS. ## Frontotemporal (FTD) Lobar Degeneration * **Normally mistaken for ALS bez of cognitive symptoms, now has a combo with ALS.** ## RNA Binding and SOD1 * **Fus: responsible for protein aggregates in the phase separation.** * **SOD1 - enzyme that gets rid of hydrogen perioxide (specific form of ALS).** * Loss of SOD1 ≠ cause ALS, ND caused by misfolding of SOD1 - toxic GoF. * RNA proteins involved in RNA binding and metabolism. * **TDP43, FUS** are cause of familial ALS cases (triple repeat expansion, HD) * C9Orf 72 causes majority, causing mutations. * ANG is a rare disease causing mutations. ## TDP43 * **Found in inclusions, aggregates inside the cell.** * **Found in other NDs** (later stages and brain regions). * Prone to misfolding (goes to cytoplasm). * Newly made TDP43 doesn't reach nucleus (put it back?) ## Prion-like domain * **Intrinsically disordered domain imp for TDP misfolding and aggregation (misfolding cytoplasm).** * Gly-rich region (PLD) is on N terminus in FUS, C terminus in TDP43. * Gly-rich domains are important for inclusion formation in yeast cells or make amyloid fibrils. * **TDP43 and FUS have 2 RNA binding domains.** ## LLPS * **Accumulation and misfolding of TDP43/FUS (diff phases mixes together)** * Heating up or adding molecules can speed up LLPS process (happens overtime/sporadically). * **Protein misfolding in soluble protein has a.a that glues diff peptides by causing LLPS.** * Macromolecules regulates other cell processes, not just disease (not always bad). * Driving forces: Ications, π-π bonds. ## DNA JC7 and molecular chaperones * **Mutations in gene cuding region causes rare familial ALS** * Contains J domain that regulates DNA folding outside cells (missense and nonsense spreads around). * Delivers misfolded proteins to HSP 70 and accelerates the ATP hydrolysis. * HSP 70 undergoes cycle involving I protein (delivers misfold alone but efficient with DCJ7) - interacts with HSP70 (has ATP binding and hydrolysis domain) - HSP 70 refold the protein, releases ATP and domain. * **Hsp90 functions as homodimer, has middle, dimerization of N domain that binds to ATP.** * Hsp70 + 90 work together; they can't function properly in cells. * A.a change led to destabilizing DJC7 mutations lead to LoF. ## Yeast model * **TDP43 + WT YFP → results in massive inclusions** * Grows slowly or can't form bigger colonies (easily tracked). * **TDP43-YFP + DJC7 → toxicity drops of colonies form (aggregate doesn't cause toxicity).** # Prion's Diseases ## PrPc $ PrPsc * **Prion protein solely causes the disease (no RNA/DNA needed), genetic info in protein.** * Normal form: PrPc, infectious form: PrPSc * Genetic (missense mutation in PrP), acquired (infection with PrPSc in diet, sporadic). ## Infectious Prp cycle * **Ppl with prions have big holes in brain to die, comes with aggregates made from prion protein.** * **A.a sub favor converting PrPc to PrPsc (both interact), PrPc (x-helix) PrPsc (B-sheet).** * Accumulation of PrPc to PrPSc causes prions, feed forward cycle. * PrPSc enters brain and cycle continues. * Sheet allows stacking that lets intermol. rxns to enter, a-helices are confined. ## Prion Strains * **All subs are disease causing mutations (genetic determinants - absolute diagnosis for prions).** * **Conformational variants of same prion protein (same a.a chain/peptide reg), diff biochem properties, cause diff. disease phenotypes/affect diff. neurons.** * Amyloids can form diff shapes/strains - some form larger oligomers & amyloid variants. ## Prion-like spreading * **Neuron to neuron all NDs associated w protein misfulding, share PLMs that spread in CNS.** * Neurons are connected, Spreading can happen many times (happens in other cells). * Other cells can contribute to spreading (spreads or removes - defense mech?). * **Inhibiting the spreading can become a very therapeutic intervention (slows down).** ## Yeast Prion * **Sup35 - prion form, makes aggregate (less soluble and functional), stop codan entered later.** * **Sup35 involved in translation termination.** * Weak [PSI+] less functional (red colony), color is dependent on shape of protein ONLY. ## Prion Conformation * **Transmission from mother to daughter, prion is always maintained** * Infected material gets transferred so prion resists, propagates spread. * **Can result to phenotypic changes alone, but doesnt determine enough.**