molecular genetics & neuropathology of frontotemporal dementia · molecular genetics &...

Molecular Genetics & Neuropathology of

Frontotemporal Dementia

Ian MackenzieProfessor, Neuropathology

University of British ColumbiaVancouver, Canada UBC

Neurodegenerative diseases

slow, progressive, permanent loss of neurologic function.cause unknown.sporadic, familial or inherited.degeneration of specific brain region → clinical syndrome.pathology: abnormal accumulation of disease specific protein.


Alzheimer’s disease

dementia

Parkinson’s disease

movement disorder

ALS weakness

β-amyloid (senile plaques)

disease protein deposits anatomy clinical

α-synuclein (Lewy bodies)

TDP-43 (skeins)

cerebral cortex

brainstem & basal ganglia

spinal cord


early-onset fAD

↑ senile plaques

protein depositsgene

↑ β-amyloid

disease biochemistry

late-onset fAD

●APP ●PS1 ●

PS2

●ApoE

Frontotemporal dementia (FTD)

Clinical syndrome:progressive change in behaviour, personality and/or language.often associated with movement disorder (parkinsonism or ALS). 25-50% have family history, most autosomal dominant.

selective atrophy of frontal & temporal lobes

Neuropathology of FTD

Neuropathology of FTDfrontal lobe (behaviour)

temporal lobe (language)

selective atrophy of frontal & temporal lobes

Neuropathology of FTDMicroscopic pathology:

Pick’s diseasecorticobasal degeneration (CBD)progressive supranuclear palsy (PSP)frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U)FTD with ALSatypical FTLD-Uneuronal intermediate filament inclusion diseasebasophilic inclusion body diseasedementia lacking distinctive histopathology (DLDH)

Neuropathology of FTDMicroscopic pathology:

Pick’s diseasecorticobasal degeneration (CBD)progressive supranuclear palsy (PSP)frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U)FTD with ALSatypical FTLD-Uneuronal intermediate filament inclusion diseasebasophilic inclusion body diseasedementia lacking distinctive histopathology (DLDH)

tau

TDP-43

FUS

none

protein


FTLD-TDP

FTLD-tau

FTLD-FUS

●FTLD-U ●FTD+ALS

● aFTLD-U ● NIFID ● BIBD

●PiD ●CBD ●PSP

other

Tau protein

a microtubule associated protein.gene on chromosome 17.forms cytoskeleton of neurons, important for axonal transport.abnormal tau accumulates in neurons and glial cells (inclusion bodies).

Pick’s diseaseusually presents as FTD.

Pick bodies.

HE silver tau

hippocampus cerebral cortex

silver silver

Corticobasal degeneration (CBD)may present as parkinsonism or FTD.

abnormal accumulation of tau in neurons and glia.

cortex, subcortical grey and white matter.

HE silver silvertau

tau tau

cerebral cortex white matter

swollen neuron neuronal tangle astrocytic plaque coiled body

Progressive supranuclear palsy (PSP)most often presents as parkinsonism but may cause FTD.

HE silver silver

tau tau

abnormal accumulation of tau in neurons and glia.

cortex, subcortical grey and white matter.

neurofibrillary tangle tufted astrocyte thorny astrocyte

subcortical grey matter cerebral cortex

P301L/S

9 10 11 13

R406W

12

G272VI260V

G389R

S320F

K257TL266V

K369IV337M

E342V

1

R5H/L

MAPT mutations44 mutations in >130 families.10-20% familial FTD.FTD + parkinsonism.FTLD-tau pathology.

ΔK280

N279KL284L

ΔN296N296N/H E10 RNA splicing

mutations (internal)

-1 -2 +3 +11 +12 +13 +14 +16

E10 RNA splicing mutations (5’SS)

U (+12)

U

ACU

C

GA U

G

GUG

C

CA

AC

GU

U (+16)

G (+13)U (+14)

AC

U

(+3) A

(S305N/-2) A(S305S/-1) C

Exon10 5’- SS

Exon 10

C (+11)

aag GUGCAGAUAAUUAAUAAGAAGCUGGAUCUUAGCAA...AAUAUCAAA

GN279K (+)

CL284L (+)

ΔK280 (-)Exon10 3’- SS

ΔN296 (+)

N296N/H (+)

Exons

FTLD with ubiquitinated inclusions

originally identified as cerebral pathology in patients with ALS and dementia.now recognized as most common FTD pathology.neuronal inclusions only recognized with immunohistochemistry for ubiquitin (non-specific).TDP-43 recently identified as abnormal (ubiquitinated) protein in most FTLD-U and ALS.

abnormal protein deposits in neurons.stain for ubiquitin but not tau or other proteins.

HC-dentate

ubiquitin

FTLD-U

ubiquitin

neocortex

nuclear protein involved in mRNA processing. abnormally fragments accumulate in neurons and glia.

TDP-43 TDP-43

FTLD-U ALS

cerebral cortex spinal cord

type 1

type 3a

type 2

type 3b

• neurites & NCI in layer II.• 32%.• bvFTD or PNFA.

• neurites in layer II.• 27%.• SD.

• NCI in neocortex.• 20%.• ALS-FTD.

• NCI in HC.• 22%.• bvFTD or ALS-FTD.

FTLD-U subtypes

ubiquitin

1145delC

1232_1233insGT

1 2 3 4 5 6 7 8 10 12119

p G F B A C D E PGRN mRNA593 codons

1157G>A

388_391delCAGT1252C>T

933+1G>A1402C>T

0

UTR

-8+5G>C 2T>C3G>A

90_91insCTGC102delC

138+1G>A234_235delAG 380_381delCT

463-1G>A

675_676delCA708+1G>C

759_760delTG

836-1G>C

910_911insTG

1395_1396insC

1477C>T

26C>A(A9D)

UTR

154delA

911G>A63_64insC

835_835+1insCTGA

UTR

708+1G>A

1231_1232delGT

243delC

709-2A>G 1414-15_1590del

813_816delCACT

-8+3A>T361delG

384_387delTAGT

373C>T468_474delCTGCTGT

942C>A998delG

1095_1096delCT

1201C>T

1294C>T (R432C)743C>T (P248L)

1243C>T

909delC

GRN mutations in FTD

progranulin = secreted neuronal growth factor.GRN gene on chromosome 17.68 mutations in 226 families.all cause ↓ functional PGRN.12-25% of familial FTD.clinical = bvFTD or PPA, no ALS.pathology = FTLD-TDP type 1 with neuronal intranuclear inclusions.

1A>G 328C>T 350delG

1009C>T

1069delC

1144_1145insA

multiple families reported with combination of FTD and ALS showing genetic linkage to region on chromosome 9.

FTD/ALS linked to chromosome 9

FTLD-TDP type 3 and ALS.

UBC-20

Inclusion body myopathy with Paget’s disease of bone and FTD

rare autosomal dominant syndrome. myopathy (80%), Paget’s disease of bone (50%), early-onset FTD (30%). mutations in the gene for valosin-containing protein (VCP). FTLD-TDP type 4.

TARDBP mutations in ALS

38 missense mutations in 78 families.~3% FALS and ~1.5% SALS.clinically and pathologically typical ALS. rare mutations in familial and sporadic FTD +/- ALS.


FTLD-TDP

FTLD-tauother

●FTLD-U (type 1, 2, 3)●FTD+ALS ●GRN ●VCP ● chrom 9p

● aFTLD-U ● NIFID ● BIBD ● DLDH ● CHMP2B

●PiD ●CBD ●PSP ●MAPT

fused in sarcoma / translocated in liposarcoma. RNA/DNA binding protein with similar function to TDP-43. mutations → ~4% FALS and <1% SALS.pathology = TDP-43-negative, FUS-positive inclusions.

Science, Feb. 27, 2009


FTLD-TDP

FTLD-tauother

●FTLD-U (type 1, 2, 3)●FTD+ALS ●GRN ●VCP ●chrom 9p

● aFTLD-U ● NIFID ● BIBD ● DLDH ● CHMP2B ●PiD

●CBD ●PSP ●MAPT

FUS?

FTLD-FUS“Atypical” FTLD-U

most tau/TDP-negative FTLD is FUS+.

Basophilic inclusion body disease

Neuronal intermediate filament inclusion disease

FUS

FUS

HC-dentate

ubiquitin FUS

ubiquitin+ inclusions do not label for tau, TDP-43 or FUS.

single Danish family with FTD caused by mutation in CHMP2B gene.

FTD linked to chromosome 3


FTLD-TDPFTLD-tau

FTLD-FUS

FTLD-U (type 1, 2, 3)●FTD+ALS ●GRN ●VCP ● chrom 9p ●(TARDBP)

● aFTLD-U ● NIFID ● BIBD ● (FUS)

●PiD ●CBD ●PSP ●MAPT

other● DLDH ● CHMP2B

molecular genetics & neuropathology of frontotemporal dementia · molecular genetics &...

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