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«Thesis submitted for the degree doctor of philosophy By Haya Kisos Submitted for the senate of Hebrew University June 2013 This work was carried out ...»

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Multiple System Atrophy and Parkinson’s

disease

Thesis submitted for the degree "doctor of philosophy"

By Haya Kisos

Submitted for the senate of Hebrew University

June 2013

This work was carried out by supervision of

Dr. Ronit Sharon and Prof. Tamir Ben Hur

Abstract:

The synucleinopathies are a diverse group of neurodegenerative disorders that share a

common pathologic intracellular lesion, composed primarily of aggregates of

insoluble α-Synuclein (α-Syn) protein in selectively vulnerable populations of neurons and glia. The term, “synucleinopathy,” was introduced in 1998 after it was recognized that filamentous α-Syn deposits might represent a link between Multiple system atrophy (MSA), Parkinson’s disease (PD), and Dementia with Lewy bodies (DLB). In this thesis I have focused on two of the synucleinopathies, PD and MSA.

-Syn is an abundant neuronal protein enriched in presynaptic nerve terminals, and it has been critically implicated in the genetics and neuropathology of synucleinopathies. α-Syn is a soluble protein, yet, under certain conditions it gradually oligomerizes and deposits in intra-cellular insoluble inclusions. These inclusions, when in neuronal cells, are called Lewy bodies. When in oligodendrocytes, the inclusions are called glial cytoplasmic inclusions (GCIs), and are characteristics of MSA histopatholgy. Specific point mutations in the α-Syn gene, as well as duplications and triplications at the locus for wild-type -Syn, increase its propensity to self-oligomerize, in addition to increasing its pathogenicity.

In recent years, extracellular -Syn became the focus of many studies due to its potential role in disease initiation and progression While secretion of -Syn may occur normally from healthy neurons, growing evidence indicates that enhanced secretion is associated with -Syn pathogenesis. The mechanisms involved in -Syn secretion are not yet fully understood.

The general aims of the thesis are:

1. To elucidate the mechanisms underlying the pathogenic accumulation of -Syn, a neuronal protein in oligodendroglia, as observed in Multiple System Atrophy.

2. To elucidate the mechanisms by which -Syn expression affects catalase, the anti- oxidative stress enzyme.

In the first part of the study, I tested the hypothesis that oligodendrocytes can take up neuronal-secreted -Syn as part of the pathogenic mechanisms leading to MSA. I reported that increases in the degree of soluble α-Syn oligomers and intracellular - Syn levels, enhance its secretion from cultured MN9D dopaminergic cells, stably expressing the protein. In accord, I showed that the oligodendroglial cell line, Oli- Neu, can take-up neuronal-secreted or exogenously-added -Syn from their conditioning medium. This uptake is concentration-, time-, and clathrin-dependent.

Utilizing the demonstrated effect of polyunsaturated fattyacids (PUFAs) to enhance α-Syn neuropathology, I showed in vivo that increases in neuronal -Syn levels enhance its localization to oligodendrocytes in the brains of a mouse model for synucleinopathies, transgenic for the human A53T -Syn mutant form. Thus, the pathogenic mechanisms leading to elevated levels of α-Syn in neurons underlie neuronal secretion, and the subsequent uptake of -Syn by oligodendrocytes in MSA.

In the second part of the study I aimed at investigating the mechanisms by which Syn expression affects catalase, the anti-oxidative stress enzyme. Previous studies in our lab showed evidence suggesting that -Syn specifically affects catalase expression levels and enzymatic activity. Searching for a mechanism through which -Syn expression affects catalase, I found that peroxisome proliferator-activated receptor (PPAR which is known to control catalase transcription, has inhibited transcription activity when -Syn is expressed. It is important to note that activating PPARα, PPARγ and RXR, but not PPARβ/δ, restored and enhanced catalase activity.

Based on these results, I have suggested that through its involvement in fatty acid metabolism, -Syn expression affects the pool of fatty acid metabolites, which normally act as activating ligands for PPAR. The affected PPAR activity inhibits catalase expression and results in the accumulation of oxidative damage that characterizes PD. I concluded that α-Syn down-regulates catalase expression and activity by interfering with the complex and overlapping network of nuclear receptor dimerization and transcription activation.

In summary, my results may contribute to the understanding of the pathogenic mechanisms involved in -Syn toxicity in the synucleinopathies. A role for brain lipids, and specifically for PUFAs, has been demonstrated.

List of abbreviation:

1-methyl-4-phenylpyridinium ion (MPP+).

2,4-dinitrophenylhydrazine (DNPH) 3′-Cyclic Nucleotide 3′-Phosphodiesterase (CNPase) 3-nitropropionic acid (3-NP) 4-hydroxynonenal (4-HNE) 6-hydroxydopamine (6-OHDA) carbonic anhydrase II (CAII) cerebrospinal fluid (CSF) clathrin-mediated endocytosis (CME) conditioned medium (CM) deep brain stimulation (DBS) Dementia with Lewy bodies (DLB) docosahexaenoic acid (DHA, 22:6) docosohexaenoic acid (DHA) eicosapentaenoic acid (EPA, 20:5) genome-wide association (GWA) glial cytoplasmic inclusions (GCI) Glial fibrillary acidic protein (GFAP) glial nuclear inclusions (GNIs) glutathione (GSH) hydrogen peroxide (H2O2) hydroxyeicosatetraenoic acid (HETE) Immunocytochemistry (ICC) Immunohistochemistry (IHC levodopa (L-dopa) Lewy bodies (LB), Lewy neurites (LN) linolenic acid (ALA, 18:3) Multiple System Atrophy (MSA) Muno unsaturated fatty acid (MUFA) myelin basic protein (MBP) neuronal cytoplasmic inclusions (NCIs) neuronal nuclear inclusions (NNIs) Neuronal Nuclei (NeuN) nuclear receptor related 1 (NURR1) Olivopontocerebellar Atrophy (OPCA) paraformaldehyde (PFA) Parkinson’s disease (PD) peroxisome proliferator- activated receptor  coactivator  (PGC-1-) peroxisome proliferator-activated receptor gamma(PPAR) polyunsaturated fatty acids (PUFAs) prostaglandin J2 (PGJ2) proteolipid protein (PLP) quinolinic acid (QA) reactive oxygen species (ROS) Retinoid X Receptor (RXR) Reverse transcription polymerase chain reaction (RT-PCR) saturated fatty acids (SFAs) Shy-Drager Syndrome (SDS) single nucleotide polymorphisms (SNPs) small hairpin RNA (shRNA) Striatonigral Degeneration (SND) substania nigra pars compacta (SNpc) succinate dehydrogenase inhibitor superoxide dismutase (SOD) superoxide dismutase (SOD1) transgenic (tg) tubulin polymerization promoting protein (TPPP/P25) wild type (wt) α-Synuclein (α-Syn)





List of publication:

1. The clathrin-dependent localization of dopamine transporter to surface membranes is affected by α-Synuclein" Haya Kisos, Tziona Ben-Gedalya and Ronit Sharon. Submitted.

2. -Synuclein expression inhibits catalase activity in brains of mice modeling Parkinson's disease.

Eugenia Yakunin, Haya Kisos, Willem Kulik,; Ronald J. A Wanders,and Ronit Sharon. Submitted.

3. Enhanced neuronal -Synuclein pathology associates with its accumulation in oligodendrocytes in mice modeling Synucleinopathies.

Haya Kisos, Katharina Pukaß, Tamir Ben-Hur, Christiane Richter-Landsberg and Ronit Sharon. PLoS One,2012

4. Docosahexaenoic acid controls α-synuclein neuropathology in a mouse model.

Eugenia Yakunin,Virginie Loeb,Haya Kisos,Yoav Biala,Shlomo Yehuda, Yoel Yaari, Dennis J. Selkoe and Ronit Sharon. Brain Pathol. 2012

5. Alpha-synuclein expression selectively affects tumorigenesis in mice modeling Parkinson's disease. αSynuclein Expression Selectively Affects Tumorigenesis in Mice Modeling Parkinson's Disease Eitan Israeli,Eugenia Yakunin,Yonaton Zarbiv,Amir HacohenSolovich,Haya Kisos,Virginie Loeb,Michal Lichtenstein,Tziona BenGedalya,Ofra Sabag,Eli Pikarsky,Haya Lorberboum-Galski,Ronit Sharon PLoS One. 2011 Introduction

1. Synucleinopathies

2. Multiple System Atrophy

2.1 Clinical presentation and diagnosis

2.3 Histopathology

2.4. α-Synuclein

2.5 Animal models of MSA

3. Parkinson's disease

3.1 Pathology

3.2 Therapeutic approaches for Parkinson's disease

3.3 Etiology of PD

3.4 Models of Parkinson's disease

3.5 Parkinson’s disease and oxidative stress

4. Alpha-synuclein:

4.1 -Syn in PD pathology

4.2 Protein structure

4.3 Post-translational modifications

4.5 Oligomerization and aggregation

4.6 Physiological function

5. Catalase

6. Nuclear receptors

6.1 Peroxisome proliferator-activated receptors (PPARs)

6.2 RXR

7. Working Hypothesis

8. Aims and Objectives

Materials and Methods:

Results

Chapter I

Increased neuronal -Synuclein pathology is associated with its accumulation in oligodendrocytes in mice modeling -Synucleinopathies.

Syn Secretion from Stably-Transfected Neuronal Cells

2. Oligodendroglial cell lines take-up α-Syn from their growth medium............ 33

3. Evidence for affected oligodendrocytes in the brains of A53T α-Syn tg mice modeling neuronal synucleinopathies

Chapter 2:

Synuclein and Oxidative Stress

1. Evidence for oxidative damage in brains of A53T -Syn tg mice.

2. -Syn specifically inhibits catalase activity by affecting PPAR transcription activity

Discussion

Concluding remarks

Bibliography…

Introduction

1. Synucleinopathies The synucleinopathies are a diverse group of neurodegenerative disorders that share a common pathologic intracellular lesion, composed primarily of aggregates of insoluble α-Synuclein (α-Syn) protein in selectively vulnerable populations of neurons and glia (Goedert, 1999; Spillantini et al., 2000; Galvin et al, 2001;

Trojanowski et al., 2003; Wakabayashi et al., 1998a). The term, “synucleinopathies,” was introduced after it was recognized that filamentous α-Syn deposits might represent a link between Multiple System Atrophy (MSA), Parkinson’s disease (PD), and Dementia with Lewy bodies (DLB) (Spillantini et al., 1998).

2. Multiple System Atrophy Multiple System Atrophy (MSA) was first described by Graham and Oppenheimer in 1969 as a general term for three disorders that had “neuronal atrophy in a variety of overlapping combinations” (Graham et al., 1969). MSA combines together the following three distinct clinicopathological disorders: Olivopontocerebellar Atrophy (OPCA) (Geary et al, 1956), Striatonigral Degeneration (SND) (Adams et al,

1964) and Shy-Drager Syndrome (SDS) (Shy et al., 1960). Pathologically, MSA is characterized by filamentous glial cytoplasmic inclusions (GCIs) (Papp et al, 1989).

The finding of misfolded, hyper-phosphorylated, fibrillar α-Syn as a main component of GCIs has classified MSA as a synucleinopathy (Wakabayashi et al, 1998b). At present, therapy for MSA only treats symptoms, mainly targeting Parkinsonism and autonomic failure (Stefanova et al, 2009).

2.1 Clinical presentation and diagnosis An accurate and final diagnosis of MSA is obtained at autopsy, with characteristic pathology consisting of widespread and abundant GCIs in association with neurodegenerative changes in striatonigral or olivopontocerebellar structures.

According to clinical signs, MSA is divided into two types: MSA-P with predominant Parkinsonism, and MSA-C with dominant cerebellar features (MSA-C).

Cases of probable or possible MSA are diagnosed based on the occurrence of the

following:

1. Autonomic failure involving urinary incontinence (with erectile dysfunction in males), or orthostatic decrease of blood pressure within 3 minutes of standing.

2. Poorly-levodopa-responsive Parkinsonism (bradykinesia with rigidity, tremor, or postural instability) for MSA-P, or a cerebellar syndrome (gait ataxia with cerebellar dysarthria, limb ataxia, or cerebellar oculomotor dysfunction) for MSA-C.

In addition, possible MSA-P is diagnosed upon rapidly-progressive Parkinsonism;

postural instability within 3 years of motor onset; dysphasia within 5 years of motor onset; atrophy (as visualized with MRI) of the putamen, middle cerebellar peduncle, pons, or cerebellum; and hypo-metabolism (as visualized with FDG-PET imaging) in the putamen, brainstem, or cerebellum. Atrophy (as visualized with MRI) of the putamen, middle cerebellar peduncle, or pons; hypometabolism (as visualized with FDG-PET imaging) in the putamen; and presynaptic nigrostriatal dopaminergic denervation (as visualized with SPECT or PET imaging) are often signs of possible MSA-C (Gilman et al., 1998; Gilman et al., 2008).

2.3 Histopathology The histopathology of MSA includes glial cytoplasmic inclusions (GCI) and gliosis, neuronal cell loss and axonal degeneration, and a reduction in myelin content.

The neuropathological hallmark of MSA is the presence of α-Syn in the GCIs (Papp et al., 1989). Several studies have described the regional distribution and severity of GCIs, with pyramidal, extrapyramidal, corticocerebellar and preganglionic autonomic systems being particularly vulnerable. The density of GCIs is lower in white matter structures with severe myelin pallor, and higher in those with only mild to moderate myelin loss (Ishizawa et al, 2008). Importantly, a study focusing on the nigrostriatal and olivopontocerebellar regions, found a correlation between the frequency of GCIs, the severity of neuronal cell loss, and disease duration, suggesting a link between neurodegeneration and GCIs in these particular regions (Ozawa et al., 2004).

In addition, pathogenic α-Syn accumulations have been detected in the nuclei of oligodendrocytes, forming glial nuclear inclusions (GNIs) (Papp et al., 1992); in the cytoplasm and nuclei of neurons, forming neuronal cytoplasmic inclusions (NCIs);



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