L8 - Frontotemporal Dementia Flashcards Preview

Brain in Health & Disease > L8 - Frontotemporal Dementia > Flashcards

Flashcards in L8 - Frontotemporal Dementia Deck (33):
1

What is FD?

clinically, pathologically and genetically heterogenous condition associated with atrophy of frontal lobe and temporal lobe

2

When is FD most common?

Pre-senile, 40 or 50

3

What are the symptoms of FD?

Lethargy, loss of social inhibition, loss of speech fluency, aphasia, loss of planning and organising

4

What are the symptoms of semantic dementia (SD)?

Loss of semantic memory in verbal and non verbal domains, loss of factual meanings

5

What are the symptoms of progressive non-fluent aphasia (PNFA)

Loss of speed production, stutters, hesistance, sound errors, use of wrong tense

6

What can FTD sometimes overlap with?

ALS

7

How can FTD be classified?

By neuronal protein inclusions

8

What is the inheritance of FTD?

50% of cases show positive familial association
10-20% show autosomal dominant inheritance

9

What proteins can be involved?

Microtubule associated protein tau (MAPT)
Progranulin (GRN)
Valosin containing protein (VCP)
TAR-DNA binding protein (TARDP)
Fused in sarcoma (FUS)
C9ORF72 (FTD + ALS)

10

How could the proteins involved in FTD possibly effect it

TARDP, and FUS may work together as a complex and regulate mRNA
Others involved in endocytosis/autophagy

11

What does tau do?

Stabilises and assembles microtubules

12

What do mutations in tau cause?

Damage MT stabilisation
aberrant phosphorylation of tau
Affects alternative splicing (altered ratios of isoforms)

13

What do the mutations in tau do to the isoforms?

Decrease isoform 3 and increase in isoform 4

14

What happens internally when tau is mutated?

Swollen cells with phosphorylated tau (pick podies)

15

What can mutations in tau also cause (another disease)

Parkinsons

16

What is the cascade of tau toxicity?

- Alterations in phosphorylation
- Tau truncation and seeding of aggregates
- Aggregates block transport
- Loss of connectivity and cell death

17

What is IBMPFD?

Inclusion Body Myopathy with Pagets disease of bone and frontotemporal dementia
Part of FTD-VCP

18

what does IBMPFD affect

muscle bone and brain

19

What are the mutations in IBMPFD?

In ubiquitously expressed valosin-containing peptide

20

what explains the pleitropy of mutations in -FTD-VCP?

Role of VCP in various cellular functions

21

What cellular functions is VCP involved?

Endosomal trafficking
Handling aggregates
Mitochondria degradation

22

What are the two proteins involved in FTD that are part of RNA regulation?

TAR domain binding protein (TDP-43) and fused in sarcoma (FUS)

23

What parts of TDP-43 and FUS are mutated?

TDP-43 = rgg rich domain
FUS = Gly rich domain

24

What can mutations in tdp and fus cause?

FTD and ALS overlap

25

What is CHMP2B?

Chromatin modifying protein 2B

26

What is the mutation in CHMP2B?

G to C transition in splice acceptor site of exon 6

27

What does the mutation in CHMP2B cause?

abberant mRNA splicing forming two abnormal transcripts
C terminal truncated proteins

28

What does CHMP2B protein do usually?

Encodes component of ESCRT-III (multivesicular body biogenesis)
Important in endosomal-lysomal trafficking

29

What is lost in CHMP2B mutation and what does this lead to?

mir124 expression (regulator of AMPA receptor subtype abundance),
dyregulation of AMPA receptors

30

What is the most common mutation found in FTD?

C9ORF72

31

What mutation is C9ORF72?

Up to 100x Hexanucleotide repeat GGGGCC

32

What is also included with C9ORF72 mutations?

TDP-43 and tau positive inclusions

33

How can C9ORF72 result in neuronal cell death?

Reduced levels of transcript, loss of function
Formation of RNA foci, compromises protein function
Production of five repeat proteins, GOF protein toxicity