Parkinson disease - Dipartimento di Biotecnologie, chimica e farmacia

Parkinson’s Disease
PARKINSON’S DISEASE
1817
Il Morbo di Parkinson è una malattia neurodegenerativa cronica
caratterizzata dalla degenerazione e quindi dalla conseguente
riduzione del numero di neuroni dopaminergici nigrostriatali
Sintomatologia
• Quattro Sintomi principali: tremore a riposo, rigidità,
bradicinesia, alterazione della postura e della deambulazioneIPO o ACINESIA dovuta alla riduzione dell’azione della dopamina
sulle cellule striatali.
• Sintomi secondari: sintomi cognitivi (demenza), sintomi affettivi
(depressione)
Although treatment is available to achieve symptomatic improvement, its
management is both a challenge and an art.
DOPAMINA:
precursore
di
noradrenalina e adrenalina. Importante
per modulazione attività psichica e
motoria, ma anche per tono dell’umore,
secrezione alcuni ormoni ipofisari,
alcune componenti dei processi cognitivi.
Sintomi primari
13/01/2016
4
Sintomi secondari
13/01/2016
5
PARKINSON’S DISEASE
Malattia molto rara in individui < 40 anni
1% in individui > 60 anni
2% in individui > 85 anni
uomini > donne
• Malattia neurodegenerativa cronica molto diffusa
(The most common neurodegenerative movement disorder)
• Sintomi e aspetti neuropatologici ben caratterizzati
• Non ancora del tutto chiariti i meccanismi patogenetici
Eziopatogenesi
•
Degenerazione progressiva e selettiva
dei neuroni dopaminergici nigrostriatali
D2
D1
STAGES OF PARKINSON'S DISEASE
DOPAMINE
(% control)
100
80
ADAPTIVE
CAPACITY
60
40
20
DECOMPENSATION
0
COMPENSATION
-no symptoms
MILD SYMPTOMS
MARKED SYMPTOMS
While most clinical and pathological attention in PD
has focused on the dopamine system, it is important
to appreciate that cell loss and Lewy body pathology
can also be seen in multiple other sites, including
cholinergic, norepinephrine, and serotonin neurons in
selected regions of the cerebral cortex, olfactory
system, basal forebrain, brain stem, spinal cord, and
peripheral autonomic nervous system
Neuropathology of Parkinson’s Disease
Possibili fattori causali:
•Genetici
•stress ossidativo (alterazione
funzionalità mitocondri)
•sistema ubiquitina-proteasoma
•Ambientali
Degenerazione progressiva e
selettiva dei neuroni dopaminergici
nigrostriatali
PARKINSON’S DISEASE
Genetic Factors
• PD may be multifactorial in etiology with genetic contributions
• Familial cases are relatively rare (~10%)
• The younger the age of symptom onset, the more likely genetic
factors play a key role
• At least ten single gene mutations identified
Protein aggregation – Ubiquitin/proteasome system
PD è caratterizzato dalla presenza di proteine neuronali che
tendono ad assumere una conformazione anomala (PARK1=alphasynuclein) e polimerizzare formando aggregati intracellulari che
portano ad alterazioni dell’attività neuronale e morte neuronale.
Le proteine con conformazione anomala sono normalmente
degradate tramite il sistema dell’ubiquitina/proteasoma con un
meccanismo ATP-dipendente.
Disfunzione di questo sistema conduce all’accumulo di proteine
danneggiate/tossiche che portano a danno neuronale fino a
degenerazione/morte del neurone.
PARK1 = a-Synuclein
a-synuclein (PARK 1) is a 140-amino acid presynaptic
protein involved in synaptic vesicle recycling, storage
and release of neurotransmitters; it is associated with
vesicular and membranous structures
Three mutations in a-synuclein gene (A53T, A30P, E46K)
are associated with early onset PD
a-Synuclein has an increased propensity to aggregate
due to its hydrophobic domain. The presence of fibrillar
a-synuclein as a major structural component of Lewy
Bodies in PD suggests a role of aggregated a-synuclein
in disease pathogenesis.
A pathological modification involving phosphorylation of
Ser129 in a-synuclein promotes aggregation, and that
Ser129 phosphorylated a-synuclein is a major
component of LB
Mechanisms by which abnormal processing and accumulation of a-synuclein
disrupt basic cellular functions leading to dopaminergic neurodegeneration are
intensely studied. One of the earliest defects following a-synuclein
accumulation in vivo is blockade of endoplasmic reticulum to golgi vesicular
trafficking causing ER stress
Transgenic mice expressing human A53T a-synuclein develop mitochondrial
pathology providing a crucial role of a-synuclein in modulating
mitochondrial function in neurodegeneration.
This may be due to the fact that a-synuclein is a modulator of oxidative
damage, since mice lacking a-synuclein are resistant to mitochondrial toxins
a-synuclein has also been shown to activate stress-signaling protein kinases,
impair
microtubule-dependent
trafficking,
reduce
intercellular
communications at gap junctions to promote toxicity. These pathophysiological
aspects are detrimental to normal functioning of dopaminergic neurons and
provide implications for disease pathogenesis in a-synuclein-induced PD.
Park2= PARKIN gene = E3 ubiquitin ligases
Catalyzes the addition of ubiquitin chains to target misfolded proteins
before their degradation by the proteasome.
•Loss of its E3 ubiquitin ligase activity due to mutations lead to
early-onset PD. Patients suffer from motor symptoms similar to
idiopathic PD including rigidity, resting tremor, and bradykinesia. Patients
respond to L-DOPA therapy; however, they develop L-DOPA-induced
dyskinesias sooner than patients with idiopathic PD. Pathologically,
patients also have a degeneration of nigrostriatal DA neurons but most do
not develop Lewy bodies.
Oxidative Stress and mitochondrial dysfunction
• Alcuni dei geni coinvolti nelle forme di Parkinson familiare hanno
ruoli intracellulari associati alla funzione mitocondriale e/o
neuroprotezione da stress ossidativo (DJ-1; PINK1; LRRK2;
PARKIN)
• Gli inibitori del complesso mitocondriale 1 (MPTP, rotenone) sono
in grado di provocare Parkinsonismo con una selettiva
neurodegenerazione dei neuroni dopaminergici nigrostriatali sia
in vitro sia in modelli animali (roditori e scimmie).
• Numerose evidenze indicano la presenza di stress ossidativo in
cervelli di pazienti con PD (analisi post-mortem).
PARK6 = PINK1
Mutations in the PINK1 cause early-onset familial PD.
PINK1 contains an N-terminal mitochondrial targeting sequences and
a highly conserved protein kinase domain similar to ser/thr kinases.
Very little is known about the precise function of PINK1 although its
mitochondrial localization, presence of kinase domain with
identification of majority of mutations in the kinase domain suggest a
role in mitochondrial dysfunction, protein stability and kinase
pathways in pathogenesis of PD.
In vivo PINK1 disease-causing mutations leads to dopaminergic
degeneration as a consequence of mitochondrial dysfunction.
Interestingly, this degenerative phenotype was rescued by
overexpression of the ubiquitin E3 ligase parkin, implicating the
importance of both parkin and PINK1 in regulating mitochondrial
physiology and survival.
Models based on the genetic deficits associated with a small
percentage of sufferers demonstrate the pathological
accumulation of α-synuclein characteristic of the disease but
have few motor deficits and little neurodegeneration.
PARKINSON’S DISEASE
Possibili fattori ambientali
•
•
•
•
•
Vita rurale / lavoro nell’agricoltura
Fumo di sigaretta
MPTP (mitochondrial complex I inhibitor)
Pesticidi/erbicidi (rotenone, paraquat)
Metalli pesanti (ferro, manganese)
Rotenone
Rotenone è un pesticida di uso comune ampiamente
utilizzato anche per giardinaggio.
• It is a high-affinity and specific inhibitor of mitochondrial
complex I
• Chronic systemic low-dose rotenone exposure induces features of
PD in rats, including selective nigrostriatal dopaminergic
degeneration and formation of ubiquitin- and a-synuclein-positive
inclusions
• Marked microglial activation with minimal astrocytosis is another
pathological feature; progressive oxidative damage and caspasedependent cell death are also observed
PARKINSON’S DISEASE
1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine (MPTP)
•
Synthetic street drug ad azione neurotossica individuata per la prima volta nel 1983
•
Selettiva degenerazione delle cellule dopaminergiche della sostanza nera in uomini,
scimmie e roditori producendo i classici sintomi della malattia di Parkinson.
•
Attraversa BBB, entra negli astrociti dove MPTP viene convertito in MPP+ dalle MAO-B;
MPP+ entra nei neuroni dopaminergici attraverso il sistema di ricaptazione della
dopamina; porta a deplezione dei livelli intracellulari di ATP bloccando la “respirazione
mitocondriale”, in particolare il mitochondrial Complex I.
•
MPP+ ha una struttura chimica simile all’erbicida paraquat e altri derivati isochinolinici
ampiamente distribuiti nell’ambiente.
• Utile per la produzione di modelli animali dove studiare la disfunzione
dopaminergica
PARKINSON’S DISEASE
Fumo di sigaretta
• Oltre all’età, il fumo di sigaretta rappresenta il
•
•
•
più consistente studio epidemiologico effettuato
sul Parkinson con una associazione inversa tra
fumo ed insorgenza della malattia.
Diminuzione del 50% del rischio di insorgenza di
PD tra I fumatori.
Nicotina protegge il sistema mitocondriale da
alcuni tipi di danni (esperimenti in modelli
animali).
Nicotina riduce l’attività delle MAO-B.
Current drugs for Parkinson’s Disease
Therapy of PD: limitations of levodopa
Does not prevent the continuous degeneration of nerve cells in
the subtantia nigra, the treatment being therefore symptomatic.
Efficacy tends to decrease as the disease progresses.
Chronic treatment associated with adverse events
(motor fluctuations and dyskinesias).
Most dyskinesias occur in association with peak plasma L-dopa
concentration and maximal clinical response (peak-dose
dyskinesia).
Motor complications are most prominent in younger patients and
in those who take high dose of levodopa.
In the extreme, patients can cycle between ‘‘on’’ periods
complicated by severe dyskinesia and ‘‘off’’ periods when they are
severely Parkinsonian.
+
© TND 2005
Principali farmaci attivi sui recettori Dopamina
I principali farmaci presenti in commercio sono:

Pergolide mesilato(Nopar®), derivato semisintetico che agisce su D1 e D2 utilizzato in
ogni fase della malattia, ben assorbito per via orale, il cui dosaggio medio giornaliero è
di 2-3 mg.

Bromocriptina (Parlodel®) utile in tutti gli stadi della malattia e per tutti i principali
sintomi, solo o associato con la levodopa.

Lisuride (Dopergin®), utile negli stadi di maggiore gravità ma con frequenti effetti
collaterali psicotici (allucinazioni visive) dosaggio dipendenti, somministrato per via
orale e parenterale.

Ropinirolo (Requip®) e Pramipexolo (mirapexin®) recenti farmaci di sintesi con
struttura dopamino- simile, sono ben tollerati, hanno buona efficacia, minori effetti
collaterali.
© TND 2005
Inibitori enzimatici
Un altro approccio alla malattia
è quello di ripristinare la quota
di dopamina che non viene
prodotta andando a sfruttare il
meccanismo dell’inibizione
enzimatica di MAO e COMT
responsabili della
catabolizzazione della
dopamina.
Si distinguono in inibitori delle
MAO-B (selegilina) e delle
COMT (tolcapone, entacapone).
Cell-based therapies that involve transplantation into
the striatum of fetal dopaminergic cells have attracted
considerable interest as possible treatments for
Parkinson’s disease (PD).
Implanted fetal dopaminergic cells can survive, reinnervate
the striatum, and improve motor function in rodent and
primate models of PD
Long-term follow-up studies suggest that individual
transplantation patients have done very well and in some
instances can even be maintained with minimal or even no
levodopa.
However, all double-blind, sham-controlled, studies have
failed
to
meet
their
primary
endpoints,
and
transplantation of fetal dopamine cells is associated
with a potentially disabling form of dyskinesia that
persists even after withdrawal of levodopa.
50% of transplantation patients develop a novel and
previously unreported form of involuntary movement
referred to as “off-medication dyskinesia” : Graftrelated dyskinesias have been described L-DOPA
induced dyskinesias because they can persist for
prolonged periods of time (days to weeks) after dose
reduction or even complete withdrawal of levodopa.
The precise mechanism responsible for graftinduced
dyskinesias is not known, but their presence suggests
that transplantation of dopamine cells using current
transplant protocols does not restore dopamine in a
physiological manner.
At present, we lack an understanding of how to
prevent off-medication dyskinesia and this side
effect remains an obstacle to further clinical testing
of dopamine cell-based therapies in PD.
Fetal dopamine neurons transplanted 11 to 14 years earlier had decreased
staining for the dopamine transporter (DAT) and contained intracellular
inclusions identical to Lewy bodies, suggesting that they may have been
affected by the PD pathologic process.
Summary

1-2 % of the general population over the age of 65 y

Lewy bodies and Lewy neurites particularly in the substantia nigra
pars compacta dopaminergic neurons projecting to striatum

DA levels severely reduced in striatum.

Resting tremor, bradykinesia, muscle rigidity

Levodopa and other dopaminergic drugs

No treatment which would prevent the continuous degeneration of
nerve cells in the substantia nigra and resulting striatal DA loss