ND disease- genetics

Question 1

4 molecular mechanisms underlying patholody of PD

Answer 1

Abnormal protein accumulation
Protein phosphorylation
Mitochondrial dysfunction
Oxidative damage

Question 2

Polymeropoulous (1997)

Answer 2

genetic linkage analysis of large italian kindred carrying the Ala53Thr mutation in SCNA gene. Autosomal dominant

Question 3

Spillatini (1997)

Answer 3

Immunolabelling of LBs shows contains alpha-synuclein

Question 4

Evidence that alpha synuclein adversely affects mitochondria

Answer 4

Stichel (2007) transgenic mice expressing A53T develop mitochondrial pathology
Kilvenyi (2006) AS deficient mice are resistant to mitochondrial toxins

Question 5

Harold (2009)

Answer 5

GWAS study for AD - no significance for APP, presenilin 1 or 2. BUT apoe4. Different mechanisms underly EOAD and LOAD.

Question 6

GWAS studies for PD

Answer 6

Simon-Sanchez and Satake (2009) Strong association between SCNA and sporadic parkinsonism. Satake also identified LRRK2.

Question 7

Tong (2010)

Answer 7

Impairment of autophagy-lysosomal pathway in LRRK2 absence, indicated by accumulation of lipofuscin granules, loss also increased apoptotic cell death and oxidative damage.

Question 8

Role of LRRK2

Answer 8

Kinase - abnormal protein phosphorylation seen in Lewy bodies. Adversely affects signalling pathways leading to mitochondrial damage.

Question 9

What is the ALS one?

Answer 9

C9ORF72

Question 10

Webster (2016)

Answer 10

miRNA knockdown of C9ORF72 in HeLa cells reduces basal levels of autophagy, essential in maintaining cellular homeostasis.

Question 11

How did C9ORF72 identification expand knowledge of ALS?

Answer 11

Helped verify link between ALS and FTD as same gene mutations associated with both diseases. Thought to represent a spectrum where different symptoms are derived from similar molecular processes occuring in different areas of the CNS

Question 12

Exner and Treske (2007)

Answer 12

In HeLa cells, RNAi mediated knockdown of PINK1 results in abnormal mitochondrial morphology and altered membrane potential. Phenotype rescued by parkin.

Question 13

What is parkin and what does it associate with?

Answer 13

E3 ligase. Tags protein with ubiquitin markers so they are directed to proteosome and broken down. Associates with DJ-1, antioxidant protein therefore common role in neuroprotection?