L8 - Frontotemporal Dementia

Question 1

What is FD?

Answer 1

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

Question 2

When is FD most common?

Answer 2

Pre-senile, 40 or 50

Question 3

What are the symptoms of FD?

Answer 3

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

Question 4

What are the symptoms of semantic dementia (SD)?

Answer 4

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

Question 5

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

Answer 5

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

Question 6

What can FTD sometimes overlap with?

Answer 6

ALS

Question 7

How can FTD be classified?

Answer 7

By neuronal protein inclusions

Question 8

What is the inheritance of FTD?

Answer 8

50% of cases show positive familial association

10-20% show autosomal dominant inheritance

Question 9

What proteins can be involved?

Answer 9

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

Question 10

How could the proteins involved in FTD possibly effect it

Answer 10

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

Question 11

What does tau do?

Answer 11

Stabilises and assembles microtubules

Question 12

What do mutations in tau cause?

Answer 12

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

Question 13

What do the mutations in tau do to the isoforms?

Answer 13

Decrease isoform 3 and increase in isoform 4

Question 14

What happens internally when tau is mutated?

Answer 14

Swollen cells with phosphorylated tau (pick podies)

Question 15

What can mutations in tau also cause (another disease)

Answer 15

Parkinsons

Question 16

What is the cascade of tau toxicity?

Answer 16

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

Question 17

What is IBMPFD?

Answer 17

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

Question 18

what does IBMPFD affect

Answer 18

muscle bone and brain

Question 19

What are the mutations in IBMPFD?

Answer 19

In ubiquitously expressed valosin-containing peptide

Question 20

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

Answer 20

Role of VCP in various cellular functions

Question 21

What cellular functions is VCP involved?

Answer 21

Endosomal trafficking
Handling aggregates
Mitochondria degradation

Question 22

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

Answer 22

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

Question 23

What parts of TDP-43 and FUS are mutated?

Answer 23

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

Question 24

What can mutations in tdp and fus cause?

Answer 24

FTD and ALS overlap

Question 25

What is CHMP2B?

Answer 25

Chromatin modifying protein 2B

Question 26

What is the mutation in CHMP2B?

Answer 26

G to C transition in splice acceptor site of exon 6

Question 27

What does the mutation in CHMP2B cause?

Answer 27

abberant mRNA splicing forming two abnormal transcripts

C terminal truncated proteins

Question 28

What does CHMP2B protein do usually?

Answer 28

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

Question 29

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

Answer 29

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

Question 30

What is the most common mutation found in FTD?

Answer 30

C9ORF72

Question 31

What mutation is C9ORF72?

Answer 31

Up to 100x Hexanucleotide repeat GGGGCC

Question 32

What is also included with C9ORF72 mutations?

Answer 32

TDP-43 and tau positive inclusions

Question 33

How can C9ORF72 result in neuronal cell death?

Answer 33

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