Parkinson’s Disease

PARKINSON’S DISEASE

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-IPO 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.

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DOPAMINA: precursore dinoradrenalina e adrenalina. Importanteper modulazione attività psichica emotoria, ma anche per tono dell’umore,secrezione alcuni ormoni ipofisari,alcune componenti dei processi cognitivi.

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Sintomi primari

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Sintomi secondari

PARKINSON’S DISEASEMalattia 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

D1

D2

STAGES OF PARKINSON'S DISEASE

DOPAMINE(% control)

ADAPTIVECAPACITY

0

20

40

60

80

100

DECOMPENSATION

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

Degenerazione progressiva e selettiva dei neuroni dopaminergici

nigrostriatali

Possibili fattori causali:

•Genetici

•stress ossidativo (alterazione funzionalità mitocondri)

•sistema ubiquitina-proteasoma

•Ambientali

Neuropathology of Parkinson’s Disease

PARKINSON’S DISEASEGenetic 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

PD è caratterizzato dalla presenza di proteine neuronali chetendono ad assumere una conformazione anomala (PARK1=alpha-synuclein) e polimerizzare formando aggregati intracellulari cheportano ad alterazioni dell’attività neuronale e morte neuronale.

Le proteine con conformazione anomala sono normalmentedegradate tramite il sistema dell’ubiquitina/proteasoma con unmeccanismo ATP-dipendente.Disfunzione di questo sistema conduce all’accumulo di proteinedanneggiate/tossiche che portano a danno neuronale fino adegenerazione/morte del neurone.

Protein aggregation – Ubiquitin/proteasome system

PARK1 = a-Synuclein

a-synuclein (PARK 1) is a 140-amino acid presynapticprotein involved in synaptic vesicle recycling, storageand release of neurotransmitters; it is associated withvesicular 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 aggregatedue to its hydrophobic domain. The presence of fibrillara-synuclein as a major structural component of LewyBodies in PD suggests a role of aggregated a-synucleinin disease pathogenesis.A pathological modification involving phosphorylation ofSer129 in a-synuclein promotes aggregation, and thatSer129 phosphorylated a-synuclein is a majorcomponent of LB

Mechanisms by which abnormal processing and accumulation of a-synucleindisrupt basic cellular functions leading to dopaminergic neurodegeneration areintensely studied. One of the earliest defects following a-synucleinaccumulation in vivo is blockade of endoplasmic reticulum to golgi vesiculartrafficking causing ER stress

Transgenic mice expressing human A53T a-synuclein develop mitochondrialpathology providing a crucial role of a-synuclein in modulatingmitochondrial function in neurodegeneration.This may be due to the fact that a-synuclein is a modulator of oxidativedamage, 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 intercellularcommunications at gap junctions to promote toxicity. These pathophysiologicalaspects are detrimental to normal functioning of dopaminergic neurons andprovide implications for disease pathogenesis in a-synuclein-induced PD.

Park2= PARKIN gene = E3 ubiquitin ligases

Catalyzes the addition of ubiquitin chains to target misfolded proteinsbefore their degradation by the proteasome.

•Loss of its E3 ubiquitin ligase activity due to mutations lead toearly-onset PD. Patients suffer from motor symptoms similar toidiopathic PD including rigidity, resting tremor, and bradykinesia. Patientsrespond to L-DOPA therapy; however, they develop L-DOPA-induceddyskinesias sooner than patients with idiopathic PD. Pathologically,patients also have a degeneration of nigrostriatal DA neurons but most donot develop Lewy bodies.

Oxidative Stress and mitochondrial dysfunction

• Alcuni dei geni coinvolti nelle forme di Parkinson familiare hannoruoli intracellulari associati alla funzione mitocondriale e/oneuroprotezione da stress ossidativo (DJ-1; PINK1; LRRK2;PARKIN)

• Gli inibitori del complesso mitocondriale 1 (MPTP, rotenone) sonoin grado di provocare Parkinsonismo con una selettivaneurodegenerazione dei neuroni dopaminergici nigrostriatali siain vitro sia in modelli animali (roditori e scimmie).

• Numerose evidenze indicano la presenza di stress ossidativo incervelli 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 anda highly conserved protein kinase domain similar to ser/thr kinases.

Very little is known about the precise function of PINK1 although itsmitochondrial localization, presence of kinase domain withidentification of majority of mutations in the kinase domain suggest arole in mitochondrial dysfunction, protein stability and kinasepathways in pathogenesis of PD.

In vivo PINK1 disease-causing mutations leads to dopaminergicdegeneration as a consequence of mitochondrial dysfunction.

Interestingly, this degenerative phenotype was rescued byoverexpression of the ubiquitin E3 ligase parkin, implicating theimportance of both parkin and PINK1 in regulating mitochondrialphysiology and survival.

Models based on the genetic deficits associated with a smallpercentage of sufferers demonstrate the pathologicalaccumulation of α-synuclein characteristic of the disease buthave few motor deficits and little neurodegeneration.

PARKINSON’S DISEASEPossibili fattori ambientali

• Vita rurale / lavoro nell’agricoltura

• Fumo di sigaretta

• MPTP (mitochondrial complex I inhibitor)

• Pesticidi/erbicidi (rotenone, paraquat)

• Metalli pesanti (ferro, manganese)

RotenoneRotenone è un pesticida di uso comune ampiamente

utilizzato anche per giardinaggio.

• It is a high-affinity and specific inhibitor of mitochondrialcomplex I

• Chronic systemic low-dose rotenone exposure induces features ofPD in rats, including selective nigrostriatal dopaminergicdegeneration and formation of ubiquitin- and a-synuclein-positiveinclusions

• Marked microglial activation with minimal astrocytosis is anotherpathological feature; progressive oxidative damage and caspase-dependent cell death are also observed

PARKINSON’S DISEASE1-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 delladopamina; porta a deplezione dei livelli intracellulari di ATP bloccando la “respirazionemitocondriale”, in particolare il mitochondrial Complex I.

• MPP+ ha una struttura chimica simile all’erbicida paraquat e altri derivati isochinoliniciampiamente distribuiti nell’ambiente.

• Utile per la produzione di modelli animali dove studiare la disfunzionedopaminergica

PARKINSON’S DISEASEFumo di sigaretta

• Oltre all’età, il fumo di sigaretta rappresenta ilpiù consistente studio epidemiologico effettuatosul Parkinson con una associazione inversa trafumo ed insorgenza della malattia.

• Diminuzione del 50% del rischio di insorgenza diPD tra I fumatori.

• Nicotina protegge il sistema mitocondriale daalcuni tipi di danni (esperimenti in modellianimali).

• Nicotina riduce l’attività delle MAO-B.

Current drugs for Parkinson’s Disease

© TND 2005

Therapy of PD: limitations of levodopa

Does not prevent the continuous degeneration of nerve cells inthe 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-dopaconcentration and maximal clinical response (peak-dosedyskinesia).

Motor complications are most prominent in younger patients andin those who take high dose of levodopa.

In the extreme, patients can cycle between ‘‘on’’ periodscomplicated by severe dyskinesia and ‘‘off’’ periods when they areseverely Parkinsonian.

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© 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 inogni fase della malattia, ben assorbito per via orale, il cui dosaggio medio giornaliero èdi 2-3 mg.

Bromocriptina (Parlodel®) utile in tutti gli stadi della malattia e per tutti i principalisintomi, solo o associato con la levodopa.

Lisuride (Dopergin®), utile negli stadi di maggiore gravità ma con frequenti effetticollaterali psicotici (allucinazioni visive) dosaggio dipendenti, somministrato per viaorale e parenterale.

Ropinirolo (Requip®) e Pramipexolo (mirapexin®) recenti farmaci di sintesi construttura dopamino- simile, sono ben tollerati, hanno buona efficacia, minori effetticollaterali.

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, reinnervatethe striatum, and improve motor function in rodent andprimate models of PDLong-term follow-up studies suggest that individualtransplantation patients have done very well and in someinstances can even be maintained with minimal or even nolevodopa.However, all double-blind, sham-controlled, studies havefailed to meet their primary endpoints, andtransplantation of fetal dopamine cells is associatedwith a potentially disabling form of dyskinesia thatpersists even after withdrawal of levodopa.

50% of transplantation patients develop a novel andpreviously unreported form of involuntary movementreferred to as “off-medication dyskinesia” : Graft-related dyskinesias have been described L-DOPAinduced dyskinesias because they can persist forprolonged periods of time (days to weeks) after dosereduction or even complete withdrawal of levodopa.

The precise mechanism responsible for graftinduceddyskinesias is not known, but their presence suggeststhat transplantation of dopamine cells using currenttransplant protocols does not restore dopamine in aphysiological manner.

At present, we lack an understanding of how toprevent off-medication dyskinesia and this sideeffect remains an obstacle to further clinical testingof dopamine cell-based therapies in PD.

Fetal dopamine neurons transplanted 11 to 14 years earlier had decreasedstaining for the dopamine transporter (DAT) and contained intracellularinclusions identical to Lewy bodies, suggesting that they may have beenaffected 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