Molecular neurology Parkinson's disease

Molecular neurology Parkinson's disease

Molecular neurology Parkinson's disease Matthias Georg Ziller R4 neurology January 30th 2008 Parkinson's disease Clinical picture first described in 1817 Motor features

Resting tremor Bradykinesia Rigidity Postural instability Non motor features Autonomic Cognitive psychiatric Burden of Parkinson's disease ~ 500.000 patients in US

1 % of > 50 yo. 2nd most common MD Lifetime risk 2 % for men, 1.3 % for women Projected increase Patient numbers will double to 8-9 million worldwide in 2030 Dorsey et al., NEUROLOGY 2007;68:384-386 Projected number of people with Parkinson disease in the most populous nations, 2005 through 2030

PD: A history of understanding For a long time assumed to be a non hereditary disorder but : 140 years ago description of early familial cases 90 years ago link between parkinsonism and cases of encephalitis and formation of inclusion bodies was exlored 45 years ago demonstration of dopamine deficiency, discovery of nigro-striatal pathway and first symptomatic use of dopamine 25 years ago observation of MPTP-induced toxicology 10 years ago The molecular genetic revolution monogenic forms a "Nature versus nurture" debate Pathophysiology of motor manifestations

D1 Result of the direct circuit is activation of cortex and facilitation of movement Pathophysiology of motor manifestations D2 Result of the indirect circuit is inhibition of thalamus, decreased activation of cortex and inhibition of movement Action of SNpc is antagonistic to this Pathophysiology of motor manifestations Loss of dopaminergic stimulation of striatum results in greater inhibition of thalamus and decreased cortical activation bradykinesia

Neuropathology Loss of dopaminergic pigmented neurons in substantia nigra pars compacta Neuropathology Cell loss in other pigmented nuclei Ventral tegmental area Locus coeruleus Raphe nucleus Intraneuronal eosinophilic inclusion bodies (Lewy) Brainstem Diffuse distribution in cortex

Staining + for alpha-synuclein Reactive gliosis Lewy body and Lewy neurites -SYNUCLEINE +SYNUCLEINE + 2003 Braak et al.: Staging of PD pathology Allows to understand presymptomatic disease and non motor manifestations

Inclusion bodies ascend in the brainstem Stage 2: coeruleus Sleep, mood At stage 3 reach SNpc Motor manifestations > stage 4 cortex involved Dementia Behavioural symptoms Progression of a-synuclein

immunopositive labelling from stages 3 to 6, Braak 2006 "Nurture": environmental contribution Factors that increase the risk Influenza epidemic - van Economos disease Being raised on a farm with well water Pesticide / herbicide / manganese exposure MPTP toxin exposure Factors that modify (maybe decrease) the risk Regular tobacco use and recent smoking Caffeinated beverages (but not EtOH) Physical exercise Some NSAIDs (Ibuprofen, but not ASA)

Increased risk with high dairy intake in men Higher levels of uric acid in peripheral blood "Nature": Genetic forms Discovered during past 10 years Monogenic forms may be clinically indistinguishable from "sporadic PD" 2-3 % of sporadic cases probably monogenic May lead to understanding of pathophysiology Genetic forms Familial forms - Summary

PARK 1-13 5 autosomal dominant: PARK 1 (=4), 4 is the triplication form of PARK1 3, 5, 8, 13 4 recessive: PARK 2,6,7,9 1 X-linked: PARK 12

2 with unknown mode of transmission: 10,11 additional mutations in small families without assigned PARKnumbers Alpha-synuclein (PARK1+4) First described + associated with familial parkinsonism 1997 SNCA gene, chrom 4q

3 known point mutations single-allele duplication or triplication in some families initially named PARK4 Penetrance low, 33 % Severity depends on gene dosage, patients with duplication resemble idiopathic PD more than triplication cases Mutations and multiplications are rare

Increased expression of wild type SNCA copies may play a role in "idiopathic disease" What is SNCA ? 140-residue cytosolic and lipid-binding protein Natively unfolded, presynaptic protein synaptic vesicle recycling, storage of transmitters negative coregulator of transmitter release

Identical with Non-amyloid component precursor Oligomer-forming SNCA in LBs truncated, oxidized and phosphorylated variants Mutants have greater nuclear targeting in cell culture

Speculative Model of the Interactions among Proteins Implicated in Parkinson's Disease Feany M. N Engl J Med 2004;351:1937-1940 LRRK-2 (PARK8) Leucin-rich repeat kinase 2 gene, identified by 2 groups in 2004 Mutations often associated with late-onset disease contrary to previous beliefs

Large gene, 51 exons encoding 2.527 AA- protein with several functional domains Certain genotypes may be susceptibility factors 16 sequence changes clearly pathogenic, in only 10 of 51 exons clustering in C-terminal region of protein pathology linked to kinase function but unclear* most frequent mutation is c.6055G A, 1.5 % of index cases with late-onset idiopathic PD same mutation found in 40% of Arab PD patients and 20 % of Ashkenazi Jewish PD likely founder effect

homozygous forms of this mutation exist, but are not more severe than heterozygous *Greggio et al., Neurobiol Dis 2006, Kinase activity is required for the toxic effects of mutant LRRK2/dardarin Parkin (PARK2) Identified 1998, earlier age at onset, slower progression most common factor (10-20%) for early onset disease, all ethnic groups large number of known mutations

12 exons, chrom 6 Gene product Parkin: 465 aa protein, ubiquitin ligase, activity disrupted in mutants Mediates ubiquitilation of target proteins loss of ligase activity leads to pathology May lead to accumulation of substrates

Parkin essential in formation of Lewy bodies ? Possible role in mitochondrial integrity Effector mechanisms Rescues mitochondrial dysfunction in flies after inactivation of PINK SNCA induced dysfunction is enhanced due to lack of Parkin activity Posttranslational modification of Parkin due to oxidative or nitrosative stress compromises ligase activity Speculative Model of the Interactions among Proteins Implicated in Parkinson's Disease Feany M. N Engl J Med 2004;351:1937-1940 Ubiquitin Proteasome System Ubiquitine-Proteasome System in PD

Parkin, E3-UB ligase Loss of function in mutants Mediates ubiquitylation of synphilin, SNCA-interacting protein UCHL-1 (PARK5), deubiquitylating enzyme Impaired UB-hydrolysis Alpha-synuclein inhibits proteasome But no generalized dysfunction in brain regions with LBs

Precise mechanism of UPS dysfunction in PD unclear Decreased function with toxin exposure ? MPTP inhibits proteasome Changes linked to mitochondrial function, aging ? PINK1(PARK6) =PTEN-induced kinase 1, mutations found in 2004 3 families with consanguinity and autosomal recessive parkinsonism 1-8 % of populations, considerable variation between ethnic groups

Mutations near kinase domain loss of function in vivo 581 aa-protein, mitochondrial localization Highly conserved kinase domain, mitochondrial targeting motif no known substrate for kinase activity Mutations lead to different phosphorylation patterns

Proteasomal stress enables altered cleavage of PINK and possible accumulation in LBs Interaction with DJ-1: recruited to pathway after oxidative damage due to PINK dysfunction DJ-1 (PARK7) Described 2003, chrom 1, 1-2 % of early onset cases Localization:

ubiquitous expression cytosolic, may translocate to mitochondria with pH changes Function: chaperone-like activity, intracellular sensor of oxidative stress regulates D2 receptor signaling Direct action as antioxidant ? DJ-1 mutants show increased vulnerability to energy metabolism changes

Overexpression of DJ-1 protects against mitochondrial complex 1 inhibitors effect is abrogated by mutants Speculative Model of the Interactions among Proteins Implicated in Parkinson's Disease Feany M. N Engl J Med 2004;351:1937-1940 Oxidative stress and mitochondrial dysfunction Mitochondrial complex 1 inhibitors MPTP rotenone, paraquat Reproduce parkinsonism with dopaminergic neuron loss Absence of LB in these cases

Chronic infusion reproduces all features, including LBs Supports theory of environmental toxin interaction by inhibition respiratory chain Inhibition of complex I: Depletion of ATP, impairment of dependent processes Generation of free radicals causing oxidative stress Post-mortem evidence of ox stress in PD brains Elevated lipid peroxidation and nitration levels in SN and LBs

Reduced levels of glutathione and oxidized glutathione (antioxidants) Reduced complex 1 activity in muscle, brain, platelets of PD patients More questions: Role of susceptibility genes 1. Exact role is controversial: - genes connected to monogenic forms may also act as susceptibility genes Single mutations in recessive genes are common (Parkin, DJ-1, PINK1) 2. Heterozygous mutations - may be associated with PET, MRI, ultrasound changes Subtle motor signs in asymptomatic carriers Unclear if these are developmental changes, early disease

markers or adaptive 3. Are modifications of wild-type forms linked to parkinsonism ? ubiquitylation studies of wild-type Parkin linked to sporadic PD 4. Genetic polymorphisms may be associated with disease pG2385 increases risk in Chinese population References

Continuum 2004, No.3 Movement Disorders, Suchowersky and Furtado Schlossmacher & Klein, Neurology, 2007, 69, 2093, PD 10 years after its genetic revolution Lim et al, BMC Biochemistry 2007, 8, S1, Role of ubiquitin proteasome system in Parkinson's disease Thomas & Flint Beal, Parkinson's disease, Human Molecular Genetics 2007, Vol 16, Review Issue 2, 183-194 Gandhi & Wood, Molecular pathogenesis of PD, Human Molecular Genetics 2005, 14, 18, 2749-2755 Braak et al., Stanley Fahn Lecture: The staging procedure for Inclusion Body Pathology, Mov Disorders 21, no.12, 2006, 20422051 Feany M. N Engl J Med 2004;351:1937-1940 16th Annual National Residents Seminar on Movement Disorders

Course Notes, Ottawa 2008

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