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 deambulazione
•
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.
Care of patients with advanced disease need clinical experience, patient cooperation and
utilization of all available treatment options.
Sintomi primari
21/12/2015
3
Sintomi secondari
21/12/2015
4
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
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.
…. a predominantly sporadic disease, the likely cause
of PD is currently considered to involve a combination
of genetically determined vulnerability and exposure
to toxins in the environment….
Emma Lane & Stephen Dunnett, 2008
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=alpha-synuclein) 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 ATPdipendente.
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.
Parkin functions as a multipurpose neuroprotective protein in a variety of toxic
insults crucial for dopamine neuron survival
Recent studies suggest that parkin mediates neuroprotection through activation of
IkappaB kinase/nuclear factor-kappaB signaling, whereas parkin mutants failed to
stimulate this pathway.
Parkin knockout mice show a reduction in weight gain, reduced mitochondrial
respiration, reduced antioxidant capacity, and increased oxidative damage in the
brain.
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).
•
L’inibizione del complesso mitocondriale 1 ha due conseguenze principali: deplezione del
contenuto di ATP del neurone (e quindi riduzione di tutti i processi cellulari ATP dipendenti)
e produzione di radicali liberi che causano stress ossidativo.
•
Numerose evidenze indicano la presenza di stress ossidativo in cervelli di pazienti con PD
(analisi post-mortem).
PARK7 = DJ-1
• Mutations in the DJ-1 locus are associated with rare forms of early-onset parkinsonism.
• Many lines of evidence suggest that DJ-1 functions as an antioxidant protein.
• DJ-1 may function as a scavenger of reactive oxygen species (ROS).
• Overexpression of wild-type DJ-1 both in cell culture and to dopaminergic neurons in vivo
protects against wide variety of toxic injury due to oxidative stress.
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.
Only few putative substrates to the kinase have been identified till date
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.
PINK1 mutations lead to increased lipid peroxidation and defects in mitochondrial complex I
activity.
PARK8=leucine-rich repeat kinase 2 (LRRK2)
Mutations in LRRK2 cause early PD.
LRRK2 gene encodes for a 280kDa protein that includes a Ras-like GTPase domain, a protein
kinase domain of the MAPKKK family.
Point mutations have been found in almost all of the identified domains. Mutations are
associated with increased kinase activity of LRRK2.
The precise physiological role of this protein is unknown but presence of multiple functional
domains suggesting involvement in wide variety of functions.
LRRK2 and it seems to be predominantly cytoplasmic especially in the golgi apparatus, synaptic
vesicles, plasma membrane, lysosomes and associates with the outer mitochondrial membrane.
LRRK2 modulates synaptic vesicle recycling, neurite outgrowth and functions inherent to golgi,
lysosomes and mitochondria, dysfunctions of which may compromise dopamine neuron 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 caspase-dependent cell death are also observed
•
Rotenone model links mitochondrial dysfunction/oxidative stress/
stress & pesticide exposure to the mechanism of sporadic PD
proteolytic
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
DOPAMINE
(% control)
100
STAGES OF
PARKINSON'S DISEASE
80
ADAPTIVE
CAPACITY
60
40
20
DECOMPENSATION
0
COMPENSATION
-no symptoms
MILD SYMPTOMS
MARKED SYMPTOMS
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
GENERAL TREATMENT STRATEGIES FOR
MOTOR COMPLICATIONS (Dyskinesias)
• Individualize treatment
• Adjust medication combination
• Substitute controlled-release with regular levodopa
• Dose levodopa regularly
• Smaller doses of levodopa; increase frequency
SPECIFIC TREATMENT STRATEGIES FOR
MOTOR COMPLICATIONS (Dyskinesias)
• Add Dopamine agonist
• Add COMT inhibitor (tolcapone) or a MAO-B
inhibitor (Rasagiline)
• Amantadine
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).
Unified Parkinson’s Disease Rating Scale (UPDRS)
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 “offmedication dyskinesia” : Graft-related 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