Cell Biology and Pathways Flashcards
Define the term nuero-degenerative disorders?
Predominantly dementias and movement disorders of the elderly. Clinically and pathologically they are diverse however they share the basic property:
selective loss of a specific population of neurones
What features would manifest regarding neurodegenerative disorders of the cerebellum/basal ganglia/corticle?
Cerebellum = protein deposition and ataxic gait
Basal ganglia = extra-pyramidal disorder
Corticle = Cognitive and motor problems
Define Alzheimer’s disease and what is the current gold-standard diagnosis?
Progressive cognitive decline often with psychiatric features - gold standard diagnosis = post-mortem
Often caused by senile plaques (Amyloid-Beta deposits in brain)
Which two enzymes cut the chunk of B-amyloid plaque from out of the amyloid precursor protein which sits on the cell membrane?
Gamma secretase (outside bit) Beta secretase (inside bit)
Describe how the B-amyloid plaques accumulate and deposit on the brain?
As they sit in the cell membrane the AB plaques are hydroPHOBIC, therefore once leaked out of the cell it doesn’t like to sit in the watery environment so it clumps together and deposits on the brain
Which clinical condition is at increased susceptibility to Alzheimer’s?
Down syndrome - the gene is found on chromosome 21
What investigation can be carried out to look for AB deposition on the brain?
Pittsburgh compound B (a type of dye)
Describe how anti-amyloid-Beta therapy would work?
Give four examples of this therapy?
Passive immunisation due to monoclonal Ab = reduction of plaques: Bapinuezumab Aducanumab Solanezumab Ganterenerumab
Describe fronto-temporal lobar degeneration and which conditions it may also seen in?
Neurofibriallary tangles (Tau proteins) as well as AB plaques - Mutations of Tau and therefore accumulation Seen in Alzheimer's, PSP, cortico-basal degeneration
Name four clinical features associated with fronto-temporal lobar degeneration?
Speech problems Memory problems In-co-ordination Clumsyness NO extra-pyramidal features
Describe how Tau proteins aggregate?
Tau protein holds together the microtubule network. It is typically phosphorylated (comes off tubule) and then dephosphorylated (goes back on). In A.D and FTLD = hyperphosphorylation (reduced tubule binding) and aggregation of the hydroPHOBIC Tau molecules
Name the enzyme which phosporylates Tau, and describe why this may be of therapeutic significance?
Glycogen-synthase kinase 3.B (GSK3.B)
If this is inhibited it may prevent the hyperphosphorylation of Tau molecules leaving the microtubule network
Which investigations may be appropriate for diagnosing Alzheimer’s disease?
CSF analysis:
LOW amyloid-Beta plaque as they are deposited on the brain
HIGH Tau proteins as they leak of microtuble
Describe the pathophysiology behind Lewy-bodies?
a-synuclein sits on the surface of nerve cells (very hydrophobic). a-synuclein phosphorylation occurs at the C-terminus of the protein and the hydrophobic molecules stack together to form Lewy-bodies
Name three enzymes and two drugs that can help work to therapeutically target Lewy-body formation?
Polo-like kinase 2 and cABL = Dasatinib
PP2A = Metformin
Name two investigations that can be used as diagnostic markers for Lewy-body dementia?
Phosphorylated a-synuclein
Aggregated a-synulein
Describe lysosomal storage disorders?
Often autosomal recessive
‘Loss of function’ mutation leads to progressive accumulation of metabolite (sugar/lipid/glycan) within the lysosomes. Progressive dysfunction of phagocytes/macrophages/reticuloendothelium system
Describe Gaucher’s disease? (4)
Glucosidase-B gene mutation (AR) leading to:
- Skeletal problems (active bone growth)
- Throbocytopaenia and anaemia
- Pulmonary involvement
- Hepatosplenomegaly
Describe Hurler-Schieie syndrome? (5)
A-L-Idruronidase enzyme deficiency - mucopolysaccheride (hyuronic acid, chondroitan sulphate) accumulation leading to:
- Skeletal deformities
- Progressive developmental delay and regression
- Hepatosplenomegaly
- Corneal clouding
- Heart and lung abnormalities
How might ‘protein folding’ be targeted to treat lysosysmal storage disorders?
Occurs in the endoplasmic reticulum via chaperone proteins. In LSD - these may be deficient = pharmacological chaperones stabilise proteins in the ER and therefore provide adequate time for folding .
Name three protein folding drugs which may help treat LSD?
Diltiazem
Ambroxai
Ivacaftor (CFTR folding in CF)
Name three conditions that can cause transitional iron overload and name three complications that may occur as a result?
Thalasaemia
Sickle cell anaemia
Aplastic anaemia
(Cirrhosis, DM, cardiomyopathy)
What investigations would point to a diagnosis of haemachromatosis?
Elevated transferrin sats >43%
Elevated ferratin >200mls
Name four Iron related neurological disorders?
Neuronal Fe2+ brain accumulaton
Freidrich’s ataxia
Neuroferritinopathy - adult onset
Aceruloplasminaemia
Name a common cause of copper toxicity?
Denture creams = Increased levels of zinc (XS) and this inhibits copper metabolism
How is copper taken up in cells and how is it used?
ctr.1 transporter
Some used in mitochondria
Stored as metallothionein
What are the acute features of copper overload?
GI spasm
Haematemesis
Rhabdomyolysis
AKI
What are the chronic features of copper overload?
Cirrhosis
DM
Kidney damage
Describe Wilson’s disease?
Recessive with copper retention
Comes into cells normally however defective ATP7B transporter which normally shifts out XS cu out into bile and proteins is deficient. Therefore mitochondrial damage and cell death occurs
Name two investigative findings and one O/E finding that are indicative of Wilson’s disease?
LOW serum ceruloplasmin
HIGH urinary copper
O/E = Kayser-flesher rings
