Cell death and neurodegeneration

Question 1

What does SOD1 mutations cause

Answer 1

Familial MND

Question 2

What does TDP-43 mutations cause

Answer 2

familial MND and prefrontal temporal dementia

Question 3

What does hexanucleotide repeat in C9ORF72 cause

Answer 3

most common cause of familial MND

Question 4

What is Huntington’s Chorea

Answer 4

Disease of mid-adult life: onset 38-42 years, personality disturbance, twist and turn in dance like motion, death
Massive degeneration in striatum in HD due to the loss of GABAergic neurons
Autosomal dominant
>40 CAG repeats

Question 5

What is MND

Answer 5

Excessive loss of motor neurones in the spinal cord, brainstem, and/or motor cortex
Age of onset typically 50-60, with life expectancy 5 years after onset

Question 6

What happens when a motor neuron die

Answer 6

others take over the territory by a process called compensatory sprouting, and this increases the size of the motor unit. However, capacity to do this is limited and motor units are eventually lost (catastrophic decline below certain threshold). The disease state is characterised by the excessive loss of motor units and severe muscle atrophy.

Question 7

What happens when microglia is activated

Answer 7

release toxic factors that can drive neuroinflammation

Question 8

What happens when EAAT2 is lost

Answer 8

no clearance of excitatory glutamate from extra cellular disease

Question 9

What happens when astrocytes are activated

Answer 9

Release toxic factors (e.g. NO and TNFa), and lose their ability to recycle glutamate resulting in excitotoxicity.

Question 10

What is excitotoxicty

Answer 10

glutamate accumulates at synapses
NMDA, AMPA and Kainate recetpros are permeable to Ca2+ and/or Na+
Na+ influx will depolarise cells and open voltage gated calcium channels
Calcium has normal functions e.g. regulating receptor activity by phosphorylation to control synaptic plasticity
Too much calcium is very toxic

Question 11

What is used to treat excitotoxcity

Answer 11

Glutamate receptor antagonists (AMPA, NMDA)
Na channel antagonists
Voltage gated-calcium channel antagonists

Question 12

What happens with hypercalcaemia

Answer 12

damage mitochondria and in addition can activate proteases, endonucleases, stress activated kinases, phospholipases, and NO synthase