Experimental evidence for the diseases

Question 1

With prion disease, tell me about a pathological hallmark, in particular for CJD. Give the author and year

Answer 1

• Prion infected transgenic mice replicate prions, but they mainly develop PrP amyloid plaques, which are not seen in prion-inoculated Wt mice

Hackl and Becker, 2019

Question 2

What are some structural techniques?

Answer 2

NMR

X-ray crystallography

Cryo-EM

Question 3

What is genetic prion caused by?

Answer 3

Point mutations in the prion gene

Question 4

What is it thought that PrP^c maintains?

Answer 4

Cu2+ and Zn2+ in the CNS

Question 5

Is prion a rapid ND?

Answer 5

yes

Question 6

Give a study that support AD TAU

Answer 6

• In vitro
• Tau seed added to a culture medium and is taken up into cells via endocytosis and form new intracellular aggregates of Tau
• This provided theoretical evidence for interneuronal transfer of Tau as a mechanism underlying Tau propagation

Frost et al., 2009

Question 7

Give a study that supports AD Abeta

Answer 7

• Brains of 3 marmosets were injected intracerebrally 6-7 years earlier with brain tissue from patients with early onset AD, then it was noticed that the marmoset brains then contained a moderate number of amyloid plaques but no neurofibrillary tangles
• The plaques were positively stained with antibodies to beta A4 protein
• The control marmosets did not show these features
• The results suggested that cerebral Beta-amyloidosis may be induced by introduction of exogenous Abeta

Baker et al., 1993

Question 8

Give examples of studies that showed that axon regeneration does not occur in the CNS

Answer 8

Kim et al., 2003: NOGO-66 limits axon regeneration in vivo

Bartsch et al., 1995: MAG inhibits neurite outgrowth in vitro. This is the least important in stopping regenerations that the others

Kottis et al., 2002: OMgp interacts with NgR1 and PirB and limits neuro outgrowth in vitro

Question 9

Give a study that supports glial cells role in neurodegeneration

Answer 9

• Used mouse model of prion disease to study microglial proliferation
• Results showed that proliferation of resident microglial cells accounts for expansion of population during disease development
• Pathway regulation by the activation of CSF1R and the transcription factors PU.1 and C/EBPalpha for CJD and AD
• Target CSF1R to inhibit microglial proliferation and to slow neuronal damage and disease progression

Gomez-Nicola et al., 2013

Question 10

Give an example of a study which discusses MPTPs role as a toxin in PD

Answer 10

• MPTP is a toxin that causes PD in humans
• MPTP molecule is selectively neurotoxic for human and nonhuman primates
• Used to induce PD in monkeys
• In vitro, has shown that once in the cell MPTP becomes oxidsed to MPP via monoaminooxidase B
• MPP is the form that is toxic to dopaminergic neurons

Question 11

Present a study to test the prion-like manner fo Alpha-synuclein

Author and year

Answer 11

Luk et al., 2012

Aim: Test that A-syn has a prion-like spread

Method:

• Intracerebral inoculation of brain lysates containing aggregated A-syn into Transgenic mice expressing human a-syn brearing the familial PD-related A53T mutation
• Also had control Wt mice

Result: Accelerated formation of A-syn pathology observed in animals inoculated with pathogenic form of protein

correlated with biochemical and PTMs of A-syn that are characteristic of PD