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LECTURE 1: ALZHEIMER’S DISEASE ... 2

LECTURE 2: MOTOR NEURON DISEASE ... 6

LECTURE 3: PRION DISEASE ... 9

LECTURE 4: PARKINSON’S DISEASE ... 12

LECTURE 6: NEURODEVELOPMENTAL DISORDER ... 14

LECTURE 8: AUTISM SPECTRUM DISORDER ... 16

LECTURE 9: MODEL SYSTEM (NLGN1) ... 19

LECTURE 10: Type 2 Diabetes ... 21

LECTURE 11: ATHEROTHROMOSIS ... 25

LECTURE 12: LIPID METABOLISM ... 27

LECTURE 13: CARDIAC REGENERATION ... 30

LECTURE 16: System biology in cardiovascular disease ... 34

LECTURE 17: OBESITY ... 35

LECTURE 18: TYPE 1 DIABETES ... 37

LECTURE 19: RHEUMATOID ARTHRITIS ... 40

LECTURE 20: COVID FOG ... 43

LECTURE 21: Dengue Virus ... 48

LECTURE 22: ‘Horror autotoxicus’ ... 53

LECTURE 23: HTLV (human T-cell lymphotropic/leukemia virus) ... 55

LECTURE 24: Designer drugs/Clinical trials in oncology ... 58

LECTURE 25: Cancer immunotherapy ... 61

LECTURE 26: High throughput functional genomics technologies ... 64

LECTURE 27: Cancer Epigenetics ... 68

LECTURE 28: Tumour microenvironment ... 71

LECTURE 29: Tumour metastasis ... 74

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LECTURE 3: PRION DISEASE

- Also known as Transmissible Spongiform Encephalopathies - Invariably fatal

- Neurodegenerative disorder - Long incubation period - Rapid progression

- Symptoms = hunched, ruffled, withdrawn, weight loss, ataxia, paresis Pathology:

- degeneration and death of neurons -> cleaved (activated) caspase 3 - accumulation of abnormal form of host encoded prion protein (PrP)

- Astrocytosis = both hypertrophy and hyperplasia of astrocytes in gray matter Aeitiology:

- Sporadic (85%)

o No known aetiology o CJD, GSS, sporadic FI

§ Strains of sporadic CJD

• PrPSc isolated from patient with CJD has different

electrophoretic mobility following PK digestion (different shape) -> indicative of strains of CJD

- Familial (15%)

o Mutation of prion protein gene

§ Gerstmann-Straussler-Scheinker (GSS)

• Motor incoordination

• Cerebellar ataxia

§ Creutzfeldt Jakob Disease (CJD)

• Rapidly progressive dementia

§ Fatal Familial Insomnia (FFI)

• Intractable insomnia - Acquired (rare)

o Iatrogenic (surgical) o Zoonotic

Discovering infectious agent:

- Protein only hypothesis:

o o Initially thought to be an exogenous agent… but later shown to be a post- translational modification of normal cellular protein

- PrP and prion transmission

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o Absolute requirement of PrPC for transmission (prion protein knockout wont develop disease)

o Gene dosage effect

o Species specificity determined by sequence of prion protein gene

- Proving protein only hypothesis:

o Cell-free propagation of prion (PrPC + PrPSc -> PrPSc increase over time)

§ If given to knockout mouse… no conversion o Cell-free conversion assay

§ protein in presence of 50 fold excess of PrPSc derived from a prion- infected hamster

o RNA stimulated misfolding of mammalian PrPC -> prion disease

o RNA and lipid induced misfolding of recombinant PrP -> prion disease o Cell-free prions:

§ Propagation

• Partially prufieid PrPSc can induce conformational change in mammalian and recombinant PrPC

• Crude brain homogenates efficiently propagate prions

§ Infectivity

• Infectivity can be spontaneously generated from partially purified mammalian and recombinant PrPC

§ Efficient prion propagation requires PrPc and host derived ‘factors’

Pathogenesis:

- Prion protein (PrPC) misfolding -> PrPSc

o Protein sensitive, soluble, alpha-helix, many tissues, required for infection ->

protease resistant, insoluble, beta-sheet, disease specific, infectious o Physical association with clinical disease

o Major macromolecule which co-purifies with infectivity o Concentration of PrPSc is proportional to infectivity o Biophysical state correlates with infectivity profile o Mutations in PRNP linked to disease

- In presence of PrPSc, pathology only observed in tissue expressing PrPC - Despite presence of PrPSc, pathology can be reversed when PrPSc misfolding is

stopped by turning off/knocking down PrPC expression (RNAinterference targeting PrPC expression)

- Pathology is not observed when PrPSc propagation is not associated with membrane anchored PrPC (GPI-mice)

Prion strains:

- Characterised by:

o Clinical phenotype

o Where in brain damage occurs (lesion profile) o Incubation period

o Conformation of PrPSc

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- Hyper strain (HY)

o Short incubation

o Brain stem and cerebellar cortex o Hyperactivity

- Drowsy strain (DY) o Long incubation

o Pyramidal layer adjacent to hippocampus o Lethargy (lack energy)

- HY VS DY = different conformation of PrPSc associated with strain variation o different electrophoretic mobility after PK digestion & FTIR spectroscopy

profile - Applications:

o Cofactors in sporadic disease o Diagnosis

o Treatment o Prevention Treatment:

- Poor clinical translation is due to:

o Short clinical duration

o Limitations of pre-clinical diagnosis o Strain variation

- Anti-sense oligo (ASO) therapeutics:

o Alter function of target RNA

o Decrease total protein (therapeutic target for disease caused by single protein)… however, depletion of PrPC induce cancer

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Unduh sekarang ( PDF - 4 Halaman - 354.09 KB )

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