L8 - Frontotemporal Dementia Flashcards
What is FD?
clinically, pathologically and genetically heterogenous condition associated with atrophy of frontal lobe and temporal lobe
When is FD most common?
Pre-senile, 40 or 50
What are the symptoms of FD?
Lethargy, loss of social inhibition, loss of speech fluency, aphasia, loss of planning and organising
What are the symptoms of semantic dementia (SD)?
Loss of semantic memory in verbal and non verbal domains, loss of factual meanings
What are the symptoms of progressive non-fluent aphasia (PNFA)
Loss of speed production, stutters, hesistance, sound errors, use of wrong tense
What can FTD sometimes overlap with?
ALS
How can FTD be classified?
By neuronal protein inclusions
What is the inheritance of FTD?
50% of cases show positive familial association
10-20% show autosomal dominant inheritance
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)
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
What does tau do?
Stabilises and assembles microtubules
What do mutations in tau cause?
Damage MT stabilisation
aberrant phosphorylation of tau
Affects alternative splicing (altered ratios of isoforms)
What do the mutations in tau do to the isoforms?
Decrease isoform 3 and increase in isoform 4
What happens internally when tau is mutated?
Swollen cells with phosphorylated tau (pick podies)
What can mutations in tau also cause (another disease)
Parkinsons
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
What is IBMPFD?
Inclusion Body Myopathy with Pagets disease of bone and frontotemporal dementia
Part of FTD-VCP
what does IBMPFD affect
muscle bone and brain
What are the mutations in IBMPFD?
In ubiquitously expressed valosin-containing peptide
what explains the pleitropy of mutations in -FTD-VCP?
Role of VCP in various cellular functions
What cellular functions is VCP involved?
Endosomal trafficking
Handling aggregates
Mitochondria degradation
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)
What parts of TDP-43 and FUS are mutated?
TDP-43 = rgg rich domain FUS = Gly rich domain
What can mutations in tdp and fus cause?
FTD and ALS overlap
What is CHMP2B?
Chromatin modifying protein 2B
What is the mutation in CHMP2B?
G to C transition in splice acceptor site of exon 6
What does the mutation in CHMP2B cause?
abberant mRNA splicing forming two abnormal transcripts
C terminal truncated proteins
What does CHMP2B protein do usually?
Encodes component of ESCRT-III (multivesicular body biogenesis)
Important in endosomal-lysomal trafficking
What is lost in CHMP2B mutation and what does this lead to?
mir124 expression (regulator of AMPA receptor subtype abundance), dyregulation of AMPA receptors
What is the most common mutation found in FTD?
C9ORF72
What mutation is C9ORF72?
Up to 100x Hexanucleotide repeat GGGGCC
What is also included with C9ORF72 mutations?
TDP-43 and tau positive inclusions
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
