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Degenerative Disorders

Protein misfolding diseases
  1. In many cases, misfolded proteins are recognised to be undesirable by a group of proteins called heat shock proteins, and consequently directed to protein degradation machinery in the cell.
  2. This involves conjugation to the protein ubiquitin, which acts as a tag that directs the proteins to proteasomes, where they are degraded into their constituent amino acids.
  3. Hence many protein misfolding diseases are characterised by absence of a key protein, as it has been recognised as dysfunctional and eliminated by the cell’s own machinery.
  4. Diseases caused by lack of a particular functioning protein, due to its degradation as a consequence of misfolding, include:
    1. Cystic fibrosis (misfolded CFTR protein),Q
    2. Marfan syndrome (misfolded fibrillin),
    3. Fabry disease (misfolded alpha galactosidase),
    4. Gaucher’s disease (misfolded beta glucocerebrosidase) and
    5. Retinitis pigmentosa (misfolded rhodopsin).
    6. Some cancers may be associated with misfolding, and hence ineffective functioning, of tumour suppressor proteins such as von Hippel Lindau protein or p53.
  • Many protein misfolding diseases are characterised not by disappearance of a protein but by its deposition in insoluble aggregates within the cell. Diseases caused by protein aggregation include:
    1. Alzheimer’s disease (deposits of amyloid beta and tau),Q
    2. Type II diabetes (depositis of amylin),
    3. Parkinson’s disease (deposits of alpha synuclein),Q
    4. Spongiform encephalopathies such as Creutzfeldt-Jakob disease (deposits of prion protein).Q
    5. Hereditary transthyretin amyloidosis (deposition of transthyretin in heart or the nerves).Q
  • The diagnostic feature common to the protein aggregation diseases is the deposition of insoluble protein aggregates called amyloid fibrils, hence the generic term amyloidosis.
  • Multiple sclerosis is not associated with misfolding/abnormal folding of proteins.Q
Alzheimer disease Q
  1. is comm. cause of dementia in elderly
  2. 47% → ≥ 85 yrs.
L/M (i) Neurofibrillary tangles
     Bundles of filaments Q in cytoplasm that displace or encircle the nucleus
ii. (globose tangles)  Q (in cortical neurons) (ghost/tombstone tangles)
iii. Contain helical filament & stromal filaments
  1. MAP 2, ubiquitin A β (also found in progressive supranuclear Palsy, amyotrophic lateral sclerosis, Parkinson’s disease  Q
  2. Neuritic plaques: focal. spherical collection of dilated, tortuous neuritic processes seen; central amyloid core A β & others.
  3. Amyloid angiopathy
  4. Hirano bodies: elongated, glassy, eosinoplastic, beaded figments. In hippocampus
Genetic of ALZH. Disease
Presenilin 1
Presenilin 2
Apolipoprotein Σ

Pick disease:
Lobar atrophy
  1. Progressive dementia
  2. Thin wafer atrophy of gyri (Knife edge atrophy)
L/M: Severe neuronal loss         
Swollen pick cells contains Pick bodies - round Cytoplasmic inclusions (obtain neurofil; ER, painted helical filaments) Q

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