Download Neurodegenerative disorders

Neurodegenerative disorders
Bart Dermaut
Center for Medical Genetics Ghent
Postgraduate Course Human Genetics 13-11-2015
Outline
Introduction
Alzheimer disease (AD)
Triplet repeat disorders
Diseases of mitochondrial DNA (mt DNA)
General introduction
Chronic and progressive disorders
Progressive and selective loss of neurons
Motor, sensorial and cognitive system
Nosological classification following pattern of
neuronal loss and disease specific cellular markers
AD:
PD:
ALS:
HD:
senile plaques, neurofibrillar y ‘tangles’
neuronal loss
Lewy bodies, depletion of dopamine
cellular inclusions, axon swelling of
motor neurons
nuclear inclusions, loss of striatal neurons
Martin J.B., NEJM 340:1970-1980 (1999)
General introduction
Causes
Genetic factors
-Mendelian inheritance – monogenic:
rare familial forms of common disorders
classic monogenic e.g. repeat expansion disorder
-Multifactorial - common disorders:
several genes contribute to disease
variation in age of onset and progression point to
different pathogenetic mechanisms
e.g. AD
Environment: toxic or metabolic processes, infection, unknown
Outline
Introduction
Alzheimer disease (AD)
Triplet repeat disorders
Diseases of mitochondrial DNA (mt DNA)
Alzheimer disease
40
Cases / 100
30
Prevalence strongly increases with age
Dementia
20
70% are Alzheimer’s disease cases
(860,000 cases in France in 2005)
CVD
10
Parkinson
0
60
70
80
90
100
Age (years)
Alzheimer’s disease (AD) => characterised in the brain by :
Neurofibrillary degeneration
Intraneuronal accumulation of
hyperphosphorylated Tau
Amyloid deposition
Extracellular
accumulation of amyloid
peptides
Alzheimer disease
Alois Alzheimer (1864-1915)
Described AD in 1907
http://www.whonamedit.com/doctor.cfm/177.html
Alzheimer A.
Über eine eigenartige Erkrankung der Hirnrinde
Allgemeine Zeitschrift fur Psychiatrie und Psychisch-gerichtliche Medizin.
1907 Jan ; 64:146-8.
“Die Sektion ergab ein gleichmäßig atrophisches Gehirn ohne
makroskopische Herde. Die größeren Hirngefäße sind
arteriosklerotisch verändert.
An Präparaten. die mit der Bielschowskyschen Silbermethode
angefertigt sind, zeigen sich sehr merkwürdige Veränderungen
der Neurofibrillen. Im Innern einer im übrigen noch normal
erscheinenden Zelle treten zunächst eine oder einige Fibrillen
durch ihre besondere Dicke und besondere Imprägnierbarkeit
stark hervor. Im weiteren Verlauf zeigen sich dann viele
nebeneinander verlaufende Fibrillen in der gleichen Weise
verändert. Dann legen sie sich zu dichten Bündeln zusammen
und treten allmählich an die Oberfläche der Zelle. Schließlich
zerfällt der Kern und die Zelle, und nur ein aufgeknäueltes
Bündel von Fibrillen zeigt den Ort, an dem früher eine
Ganglienzelle gelegen hat.
Da sich diese Fibrillen mit anderen Farbstoffen färben lassen als
normale Neurofibrillen, muß eine chemische Umwandung der
Fibrillensubstanz stattgefunden haben. Diese dürfte wohl die
Ursache sein, daß die Fibrillen den Untergang der Zelle
uberdauern. Die Umwandlung der Fibrillen scheint Hand in Hand
zu gehen mit der Einlagerung eines noch nicht näher
erforschten pathologischen Stoffwechselproduktes in die
Ganglienzelle. Etwa 1/4 bis 1/3 aller Ganglienzellen der
Hirnrinde zeigt solche Veränderungen. Zahlreiche
Ganglienzellen, besonders in den oberen Zellschichten. sind
ganz verschwunden.”
“Über die ganze Rinde zerstreut, besonders
zahlreich in den oberen Schichten, findet
man miliare Herdchen, welche durch
Einlagerung eines eigenartigen Stoffes in
die Hirnrinde bedingt sind. Er läßt sich
schon ohne Färbung erkennen. ist aber
Färbungen gegenüber sehr refractär.”
Alzheimer disease
Disease characteristics
• adult-onset slow progressive dementia (memory,
cognition, personality)
• most frequent form of dementia
• >60 y: 5-10%, >85 y: 45%
• 4 mill/y, 100.000 +/y in US, cost 60 miljard US dollar
• 25% of cases familial
- mostly late onset
- < 2% early-onset familial AD (EOFAD)
symptoms always < 65 y
Alzheimer disease
Clinical features
• dementia, typically begins with subtle and poorly recognized
failure of memory
• slowly becomes more severe and, eventually, incapacitating
• other common symptoms: anxiety, confusion, poor judgment,
language disturbance, agitation, withdrawal, and hallucinations
• occasional symptoms: seizures, Parkinsonian features, increased
muscle tone, myoclonus, incontinence, mutism
• death usually results from general inanition, malnutrition,
pneumonia
• typical clinical duration of the disease: 8-10 yrs range: 1- 25 yrs
• post mortem: macroscopic - microscopic
Alzheimer disease
Near and connected to hippocampus
Learning processes, short term
memory and conversion to long
term memory in other parts
(olfactory bulb, amygdala,
nucleus basalis)
Alzheimer disease - neuropathology
Diagnosis/testing
histological findings (neuropathological hallmarks) in brain
tissue of ß-amyloid (senile) plaques and intraneuronal
neurofibrillary tangles
Alzheimer disease - tau
Although tau neurofibrillary tangles appear to be one of the causes of
the neuronal degeneration in AD, mutations in the tau gene are
associated not with AD, but with another autosomal dominant dementia,
FTD
Alzheimer disease - genetics
mid-80s:
• older patients with Down syndrome have
neurofibrillary tangles and senile plaques
• suggests that extra copies of a gene on chromosome
21 induce the pathologic spectrum of AD
finding of a protein fragment, -amyloid, in senile
plaques led to cloning of the -amyloid gene
-amyloid gene (chromosome 21q21.2):
• encodes large protein, amyloid precursor protein
(APP)
• -, - and -secretases (proteases) cleave APP into
smaller fragments A40 (normal) en A42 (toxic amyloid)
Alzheimer disease - APP
•
APP: transmembrain protein
-amyloid motif extracellular to the middle of membrane
•
mutations cause increased production of specific
-amyloid fragment (A42)
•
APP mutations in less than 1% of all early-onset cases
Alzheimer disease - APP
normal AA
AA substitutions
normal function APP:
neuronal survival,
neurite outgrowth,
synaptic plasticity,
cell adhesion
Alzheimer disease - APP
mutations in APP influence proteolytic - and -secretases
Alzheimer disease - genetics
• < 1% of EOFAD caused by APP mutations, other genes ???
• linkage to locus 14q in 50% of all EOFAD!!
• positional cloning PS-1 on 14q24.3
• identification PS-2 on 1q31-q42
through sequence homology with PS-1
• mostly missense mutations in PS-1
• rare missense mutations in PS-2
• new protein family, transmembranary, 450 AA, 8
transmembranary domains
• genomic organization of PS genes is similar (10 exons)
Alzheimer disease - genetics
APOE gene
apolipoprotein E variant 4
•
•
•
•
•
•
•
4th locus on 19q
involved in late-onset AD
homozygotes develop AD 10-20 years earlier than carriers of 2, 3
mainly produced in astrocytes
uptake in neurons through LDLR
part of LDL particle
apolipoprotein E4 increases deposition of -amyloid
AD – genetic testing
Presenile
Familial AD
Presenilin 1
gene
(chr 14)
Age: 25-60 y
Senile
Familial AD
Presenilin 2
gene
(chr 1)
Age: 45-84 y
Sporadic
AD
Inheritance of e4 allele
of ApoE
gene
(chr 19)
Age: > 50 y
APP
gene
(chr 21)
Age: 40-65 y
2° lic Biomedische
Wetenschappen
2006 - recently
2007
Other
risk genes
identified
AD risk loci
Meta-analysis: 74.000 individuals!
Consortium: > 200 authors, >250 collaborators!
Lambert et al, Nat Genet 2013
AD risk loci: causal gene, causal variant?
Clear!
Unclear!
Genetics of Alzheimer’s disease: a paradigm
APP, PS1
PS2
APOE
TREM2
ABCA7, APOE, BIN1,
CASS4, CD2AP, CELF1,
CLU, CR1, EPHA1,
FERMT2, HLA-DRB1,
INPP5D, MEF2C, MS4A6A,
NME8, PICALM, PTK2B,
SLC24A4, SORL, ZCWPW1
Less than 1% of the cases are monogenic forms.
The majority of other forms are defined as without obvious mendelian inheritance.
The genetic attributable risk has been estimated between 60 and 80% and to date, 22 loci have
been associated with AD risk.
AD – genetic counseling
Genetic counseling
• first degree relatives of individuals with sporadic AD
have about a 20% lifetime risk of developing AD
• presumably, when several individuals in a family have
AD, the risk is further increased
• EOFAD is inherited in an autosomal dominant manner
The risk to offspring of individuals with EOFAD is
50%
AD genes – therapy
Current (symptomatic) therapy
• cholinergic replacement (cholinesterase inhibitors)
Therapies under development
• inhibit of -secretases (PS1)
• inhibit -secretase
• stimulate -secretase
• Inhibit fibril formation and disaggregate amyloid
-Immunization against -amyloid
Outline
Introduction
Alzheimer disease (AD)
Triplet repeat disorders
- Class I: non-coding repeat, loss of protein function
- Class II: non-coding repeat, novel protein function
- Class III: coding repeat expansions
Diseases of mitochondrial DNA (mt DNA)
Triplet repeat expansions
5’UTR
coding
3’UTR
Dynamic mutations in NDD
10 hereditary NDD have polyglutamine expansions
different genes but specific neuropathological characteristics: same
pathogenesis ?
new paradigm for genetic disease - anticipation
repeats in non-coding regions of disease genes
3’ UTR in myotonic dystrophy,
5’ in fragile X mental retardation
intronic in Friedreich ataxia (FRDA)
putative antisense sequences in SCA8
CAG repeats in coding regions of following disease genes:
Huntington disease
dentatorubropallidoluysian atrophy (DRLPA)
spinal and bulbar muscular atrophy
SCA 1,2,3,6,7,12 and 17
Dynamic mutations in NDA
often autosomal dominant or X-linked inheritance
FRDA: autosomal recessive
somatic and germline instability
rather prone to expansions than contractions during transmission
increase in severity phenotype associated with repeat expansion
parental origin can influence degree of anticipation
increased risk for anticipation in male carriers
exception: FRAXA, FRDA, MD en SCA8
Triplet repeat disease
Unique for humans (repeat stable in transgenic mice)
Disease
Inher
Triplet
(*)
Location
Gender
bias
Nl
Unstable
Affected
Huntington AD
CAG
exon
pat
<36
27-35
>35
Fragile X
XL
CGG
5’UTR
mat
<60
59-200
(premut)
>200
Myotonic
dystrophy
AD
CTG
3’UTR
mat
<38
38-49
50-2000
(premut)
Friedreich
ataxia
AR
AAG
intron
mat
<34
36-100
>100
(*) 64 possible trinucleotide sequences; however only 10 different ones if you take into
account permutations (CAG)n=(AGC)n=(GCA)n and reading from either strand
5’(CAG)n=5’(CTG)n
Huntington disease (HD)
“On Chorea” 1872 – Huntington’s chorea
Latin ‘choreus’ = dance
Uncontroled, dance-like movements
Chorea not obligate, a lot of other features
Correct name: Huntington disease (HD)
Clinical characteristics
progressive disorder with motor,
cognitive and psychiatric symptoms (www.genetests.org)
first signs mostly in 4° decade
movement- and behavioural changes
progressive chorea, abnormal eye movements
Huntington disease (HD)
Clinical characteristics
end stage: dementia, personality changes,
irritability, depression, hearing loss
death due to swallowing problems, infection, suicide…
(15-18 y after ‘onset’)
juvenile form, first symptoms before age of 20
Huntington disease (HD) – basal ganglia
1. Gyrus cinguli
2. Gyrus frontalis superior
3. Gyrus frontalis medius
4. Gyrus frontalis inferior
5. Corpus callosum
6. Cornu frontale ventriculi
lateralis
7. Nucleus caudatus
8. Capsula interna
9. Putamen
10. Polus temporalis
11. Septum pellucidum
12. Corpus striatum
13. Arteria cerebri media
14. Gyri orbitales
http://www.neuropat.dote.hu/anastru/anastru.htm
Huntington disease (HD)
From disease to gene: a long journey…
Linkage
IT15 gene
HD – IT15 gene
CAG triplet repeat expansion in coding region, exon 1
10-26 CAGs : normal
27-35 CAGs : intermediary allele, carrier normal, next generation
‘at risk’
36-39 CAGs : ‘reduced penetrance’, check family history
> 40: 40-150 glutamine residues: HD
>70 repeats: juvenile HD (children, adolescents)
protein: 348 kDa, huntingtin, ubiquitously expressed
anticipation: increase of repeats and severity disease
in successive generations
HD – genetic testing
Slipped mispairing mechanism
Gain-of function due to CAG repeat mutations
Pathogenesis: toxic gain-of-function due to nuclear inclusions
Fragile-X syndrome
frequent cause of X-linked mental retardation (males)
clinical diagnosis: long face with prominent ears, chin,
ogival palate; macroorchidism, mild joint hyperlaxity.
Behavioural changes in children. MR milder in women
than men
1 in 4.000 males. 30% of female mutation carriers: mild
to moderate retardation (1/8.000)
“fragile site”: chromatin does not condense adequately
during meiosis (visible when X chromosome cultured in
folium-deficient medium)
Fragile-X syndrome
FMR1-gene (Fragile-X Mental Retardation-1) (Xq27.3)
expanding CGG-repeat in 5’ UTR (promotor region) FMR1
normal alleles: 6-43 CGG
premutation alleles: 59-200 CGG.
-premutation carriers: normal intelligence
full mutation: > 200 CGG
-hypermethylation of FMR1 promotor, leading to loss of function
-male mutation carriers: Fragile-X syndrome
-females: 30% mild to moderate mental retardation and 50%-70% IQ <
85
deletion or point mutation in FMR1, also leading to loss-of-function
FXTAS: Fragile X associated Tremor-Ataxia syndrome
FXTAS






25-30% of male carriers premutation: FXTAS
> 50 years
intentional tremor
ataxia
Parkinson-like manifestations
MRI: white matter lesions in cerebellum
Fragile-X syndrome vs FXTAS
Fragile-X syndrome
meiotic instability: maternal
transmission
premutation > mutation: in female
premutation carriers
risk of expansion premutation to
mutation: ~ number CGG-repeats
male premutation carriers: transmission
premutation to daughters without
expansion (normal transmitting males or
NTM)
Sherman paradox (anticipation)
Myotonic dystrophy (MD1, Steinert disease)
• multisystem disorder
• multi-organ involvement: muscles, eye, heart, endocrine
system, CNS
• variable expression: mild to severe (congenital)
mild:
classic:
cataract and mild myotonia
muscle weakness and dystrophy,
myotonia, cataract, cardiac conduction
abnormalities
congenital: severe hypotonia and muscle weakness
neonatal respiratory insufficiency
with early death
mental retardation
Myotonic dystrophy
CTG expansion in 3’ UTR of DMPK gene: genotype-phenotype correlation
Myotonic dystrophy
CTG expansion in 3’ UTR of DMPK gene: genotype-phenotype correlation
mild form
60 CTG
adult form
150 CTG
adult form
180 CTG
congenital form
2000 CTG
juvenile form
500 CTG
Outline
Introduction
Alzheimer disease (AD)
Triplet repeat disorders
Diseases of mitochondrial DNA (mt DNA)
Diseases of mt DNA
mitochondrial genome (mt DNA): circular, ds
16.5 kb, intronless, 37 genes, transcription
in mitochondria
-13 encode enzymes < 5 enzyme complexes
involved in oxydative phosphorylation and
apoptosis
-22 encode tRNAs and 2 rRNA’s necessary for
synthesis of these enzymes
energy supply (ATP) of nearly all systems
dependent of oxydative phosphorylation
-mutations in mitochondrial genome: a wide
variety of symptoms (pleiotropy)
-affect mainly organs that are highly energydependent: brains, skeletal muscles, eye (retina),
ears (inner ear), kidney, heart
Diseases of mt DNA
- 900 gene products
- mtDNA: 37 genes, no introns, very
compact, 16.6 kb, 22 tRNAs, 2 rRNAs,
13 subunits of the RC
- each cell contains hundreds to
thousands of mitochondria, 3-10
genomes per mitochondrion
Diseases of mt DNA
one mitochondrion: several mt DNA-molecules; most cells: more than
1000 mt DNA-molecules divided over 100 mt; in mature oocytes:
number is higher
mt DNA: higher mutation frequency than nuclear genome (10 x)
cause: no repair mechanisms
inheritance: maternal (mt DNA exclusively maternally transmitted)
- female with mutation in mt DNA: transmitted to 100% of offspring
- male: no transmission of mt DNA mutations
Diseases of mt DNA
mt DNA mutation: in 1 mt DNA-molecule
mitochondrial division: replication of each mt DNA-molecule. At random
division of new mt DNA-molecules over new organels
cell division: at random division of mitochondria over daughter cells
homoplasmy: cell contains same mt DNA-molecules (normal or
mutant mt DNA)
heteroplasmy: cell contains mixed mt DNA-molecules (normal
and mutant)
proportion normal/mutant underlies phenotypic expression
and variability of mt DNA disorders
Genotype-phenotype correlations
Mutations in tRNA genes: MELAS
Mitochondrial Encephalopathy Lactic Acidosis and Stroke-like lesions
Mutation in mitochondrial tRNALeu (3243)
Mutations in tRNA genes: MELAS and MERFF
mutations leading to MELAS
mutation leading to MERFF