Neurogenetics Coursework Materials

Neurogenetics Dementia  Deterioration of intellectual capabilities, memory, judgement, and personality to the extent that daily functioning and quality of life are seriously impaired.  Generally affects the elderly.  There are a variety of circumstances that impair brain function and cause dementia. o Alzheimer’s disease. o Huntington disease. o Creutzfeldt-Jakob disease. o Multiple strokes (multi-infarct dementia). o Head injury. Alzheimer’s disease  Accounts for ≥2/3 of all diagnosed cases of dementia.  If diagnosed ≥65 years old, disease lasts 8 – 20 years.  If diagnosed <65 years, course of disease is rapid and death occurs within 5 – 10 years from diagnosis. Neuropathological features  Severe loss of synapses and neurons within the hippocampus and the entorhinal cortex.  Dense spherical structures (20 – 200mm in diameter), called senile plaques (SPs), are prevalent outside the neurons of the hippocampus and other regions of the brain.  Aggregations of neurofibrillary tangles (NFTs) accumulate within the cell bodies and dendritic processes of the neurons. Genetics  ~10% of cases occur as well-defined, fully penetrant autosomal dominant inheritance. o Onset of disease is 55 – 60 years in these families.  Approximately 90% of Alzheimer’s are late onset, and many of these are sporadic. o However, 25 – 40% with late onset Alzheimer’s have at least one close relative with the disorder. Amyloid precursor protein  Roles of APP: o Synaptic formation and repair. o Intracellular APP may be associated with the cytoskeletal system.  Processed by α-secretase and β-secretase.  Atypical processing of APP leads to excess Aβ42 isoform  destruction of synapses during early stages + formation of senile plaques  degradation of neurons.  The plaques are made up of 39 – 43 AA peptides (Aβ peptides), which are derived from proteolytic cleavage of APP. o Aβ43 isoform encompasses AA sites 672 to 714 of the APP molecule, and is made by cleaving actions of β-secretase and γ-secretase.  Chromosome site for APP gene is 21q21.2.    APP gene mutations. o Age of onset 45 – 60 years (10% of familial early onset). o Same phenotype as late onset Alzheimer’s, but no APP mutations have been found in late onset. o Depending on mutation, either β-secretase or γ-secretase activity is altered, increasing number of Aβ42/43 fragments. o Aβ42/43 is amyloidogenic; increasing its production might lead to formation of amyloid bodies. o Excess Aβ42 likely causes neurotoxicity and the initiation of a stepwise sequence of biochemical and structural events. Presenilin gene mutations. o Presenilin participate in γ-secretase cleavage of APP, which leads to an increased production of Aβ42 peptide. o Mutations in PSEN1 account for 40% of all familial early (30 – 55 years old) onset Alzheimer’s. o Mutations in PSEN2 account for 1% of all familial early onset Alzheimer’s. Together, APP, PSEN1 and PSEN2 mutations represent about 50% of all familial early onset Alzheimer’s. Genetic risk factors  Apolipoprotein E. o Synthesised primarily in the brain by astrocytes. o Apolipoprotein E sequesters cholesterol and triglycerides from cellular debris and transports these to the nucleus. o These are used for the formation of synaptic membranes.  Polymorphic for 3 common alleles; APOE*2, APOE*3 and APOE*4.  APOE*4 significantly associated with occurrence of Alzheimer’s, increasing risk:  o If one allele by 2 – 5 times. o If two alleles by 5 – 10 times. Thought to be a risk to Alzheimer’s because APOE*4 has high affinity for cholesterol, thus preventing cholesterol from moving into the neuron (needed for normal function). Risk factors and protection factors  Known risk factors: o Old age. o Family history of dementia. o ApoE genotype. o Down syndrome.  Disputed risk factors: o Ethnic group. o Head trauma. o Aluminium in drinking water.  Potential protective factors: o Anti-inflammatory drugs. o Oestrogen replacement therapy. o High education level. Huntington’s disease  Affects 1 in 10, 000.  First signs usually begin at 35 years, and worsens over time. o Initially, muscle coordination is slight impaired. o Eventually, both voluntary and involuntary movements become uncontrollable with jerking and writhing. o Later, patients become mute, cognitively non-functional and immobilised in contorted positions.  Usually die within 15 – 20 years.  Suicide is common.