Frontotemporal Dementia Flashcards
Name the 3 types of FTD
Behavioural variant FTD
Progressive non-fluent aphasia
Semantic dementia
What are the main symptomatic differences between FTD and AD?
Episodic memory, navigation, general intellect preserved
What are the symptoms of behavioural variant FTD?
Decline in interpersonal and executive skills Lack of empathy Abnormal behaviours (e.g. obsessions, stereotypies)
What are the symptoms of progressive non-fluent aphasia?
Effortful non-fluent speech
Apraxia of other orofacial movements
What are the symptoms of semantic dementia?
Decline of semantic memory
Initially affects knowledge of word meanings
How can CSF protein markers be used to molecularly distinguish AD from FTD?
In AD increased ratio of tau:AB42
What is the pathological name for FTD?
Frontotemporal lobar degeneration (FTLD)
What are the 3 macroscopic features of FTD brains?
Frontal and temporal lobe atrophy
Enlarged lateral ventricles
Hippocampal atrophy
What is the effect of hippocampal atrophy?
Spatial navigation difficulties - later in disease
Name the 4 molecular subtypes of FTLD and their relative rarities
FTLD-TDP - most common
FTLD-tau - common
FTLD-FET - rare
FTLD-UPS - very rare
What is the physiological role of tau and why is this important?
Promotes microtubule stability
Key for neuronal integrity and axonal transport
Which gene encodes tau?
MAPT
How many tau isoforms can be formed by alternative splicing?
6
What are the microscopic features of FTLD-tau?
Pick bodies in temporal lobe
Tufted astrocytes - tau deposition within
What is the physiological role of TDP-43 and why is this important?
Binds multiple RNAs
Key for RNA processing
What is the main microscopic feature of most FTLD-TDP cases?
Cytoplasmic inclusion bodies - TDP43+, ubiquitin+, tau-
Where is TDP-43 normally localised to?
Nucleus
Which abnormal modifications are found on pathological TDP-43?
Hyperphosphorylation
Ubiquitination
N-terminal truncation
How do the 4 FTLD-TDP subtypes vary?
Different inclusion morphology
Different inclusion cortical layer distribution
What is the physiological role of FET and why is this important?
Binds RNA/DNA
Key for DNA and RNA processing
Which markers label inclusions in FTLD-UPS and what does this suggest?
UPS markers
Problem with protein degradation systems
Mutations in which gene cause FTLD-UPS?
CHMP2B
What are the inclusions in FTLD-UPS composed of?
Ubiquitin
p62
Which gene is linked to both ALS and FTD?
C9orf72
Which mutation type in C9orf72 causes FTD and ALS?
Hexanucleotide repeat expansions
Give the main component of inclusions in ALS and their frequency
TDP-43 - 97%
SOD-1 - 2%
Give the main component of inclusions in FTD and their frequency
Tau - 45%
TDP-43 - 45%
FUS - 9%
Name 3 major autosomal dominant causes of FTD
MAPT
GRN
C9orf72
What is seen in neurons from MAPT mutant FTD patient-derived iPSCs and what does this suggest?
Endosome accumulation, decreased lysosomes
Impaired endocytic trafficking
Where is GRN expressed?
Mature neurons
Microglia
What does GRN encode?
Progranulin
What is the disease mechanism of FTD due to a GRN mutation?
GRN haploinsufficiency - loss-of-function
What is the effect of an absence of progranulin in neurons?
Decreased neurite outgrowth
Which condition does a homozygous-null GRN mutation result in and what does this involve?
Neuronal ceroid lipofuscinosis (NCL)
Storage of abnormal lipopigment in lysosomes
What is the sequence of a hexanucleotide repeat in C9orf72?
GGGGCC
Are the hexanuclotide repeats in C9orf72 intronic or exonic?
Intronic
How many hexanucleotide repeats are usually in C9orf72?
2-24
How many hexanucleotide repeats are in C9orf72 in FTD-ALS?
100s/1000s
What are the 3 possible disease mechanisms for C9orf72 in FTD/ALS?
Decreased C9orf72 levels
Bidirectional transcription of repeats - forms sense and antisense RNA foci - sequester RNA-binding proteins
Dipeptide repeat proteins (DPRs) - toxic - from sense and antisense RNA RAN translation
What the physiological role of C9orf72?
Associated with autophagosomes - role in autophagy
Where do the C9orf72 repeat RNA foci form?
Nucleus
Cytoplasm
How do C9orf72 repeat RNAs sequester RNA-binding proteins?
G bases in repeat RNAs bind - via atypical pairing
Form square planar structures
Stack - form G-quadruplex
Traps RNA-binding proteins
Where are C9orf72 dipeptide repeat proteins (DPRs) found?
Cytoplasm
Nucleus
How does RAN translation differ from normal translation?
Non-canonical - no AUG start codon
How many dipeptide repeat proteins (DPRs) are generated from C9orf72 hexanucleotide expanded repeats?
5
What enables the formation of so many dipeptide repeat proteins (DPRs) from the C9orf72 hexanucleotide repeat expansion?
Bidirectional transcription - sense and antisense mRNA
Translation in 3 reading frames
Name 3 minor genetic FTD causes
CHMP2B
VCP
TARDBP
What is the physiological role of CHMP2B?
Part of endosomal sorting complex
Sorts proteins to late endosome and lysosome - for degradation
Where in CHMP2B does the FTD-causing mutation occur and how does affect the protein?
In splice site
C-terminal truncation
What can be seen in the neurons of FTD patients caused by CHMP2B mutation and what does this suggest?
Abnormally high lipoprotein deposition in neurons
Suggests lysosomal storage pathology
Which diseases does VCP mutation cause?
FTD and inclusion body myopathy - IBMFTD
What is the inheritance pattern of IBMFTD?
Autosomal dominant
What is the physiological role of VCP?
Protein homeostasis
What does TARDBP encode?
TDP-43
Name a gene with an FTD risk variant
TMEM106B
What is the effect of the TMEM106B FTD risk variant?
Increases TMEM106B levels
What is the physiological role of TMEM106B?
Lysosome size, acidification, function, transport
What are the advantages of Drosophila as neurodegenerative disease models?
Cheap Short lifespan Complex behaviour - e.g. learning, memory Fewer genes than humans Widely-available molecular genetic tools
What are the disadvantages of Drosophila as neurodegenerative disease models?
Not as complex as humans - may lack relevant pathology
Lack some genes
What are the advantages of cell lines as neurodegenerative disease models?
Immortal
Cheap
No ethical issues
What are the disadvantages of cell lines as neurodegenerative disease models?
Not neuronal
Altered morphology to tissue origin
What are the advantages of mice as neurodegenerative disease models?
Genetically malleable
Fairly short lifespan
What are the disadvantages of mice as neurodegenerative disease models?
Lack complex neuron circuits
Lack full complement of glia
Lack vascular and immunologic components
What are the advantages of iPSCs as neurodegenerative disease models?
Contain mutation from patient derived from
Can be differentiated into multiple cell types
No ethical issues
What are the disadvantages of iPSCs as neurodegenerative disease models?
In dish - lack supporting glia
Demanding - require daily attention
