Parkinson's disease | EPFL Graph Search

Parkinson's disease (PD), or simply Parkinson's, is a chronic degenerative disorder of the central nervous system that affects both the motor system and non-motor systems. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms become more common. Early symptoms are tremor, rigidity, slowness of movement, and difficulty with walking. Problems may also arise with cognition, behaviour, sleep, and sensory systems. Parkinson's disease dementia becomes common in advanced stages of the disease. The motor symptoms of the disease result from the death of nerve cells in the substantia nigra, a region of the midbrain that supplies dopamine to the basal ganglia. The cause of this cell death is poorly understood, but involves the aggregation of the protein alpha-synuclein into Lewy bodies within the neurons. Collec

Towards elucidating the structural and cellular determinants of a-synuclein seeding and toxicity

Somanath Jagannath

Although it has been nearly two and half decades since the discovery of alpha-synuclein (aSyn) as the major component of Lewy bodies (LBs), our understanding of the involvement of different aSyn species, their seeding, spreading and toxicity in Parkinson's disease (PD) is limited. One of the major causes underlying this knowledge gap is the unavailability of adequate tools, techniques, and model systems to capture, monitor, and evaluate the role of different aSyn species in the disease process. In addition, our understanding of cell-type specific contributions to disease pathogenesis is limited. In this thesis, we systematically address the current knowledge gaps and elucidate the structural and cellular determinants of aSyn seeding and toxicity using cellular and animal model systems of PD. In the first chapter of this thesis, we describe an antibody characterization and validation pipeline to assess the specificity of antibodies to well-characterized preparations of various aSyn species, including monomers, fibrils, and different type of oligomers. Using an array of techniques, we demonstrate that that: i) none of the antibodies tested are specific for one particular type of aSyn species, including monomers, oligomers or fibrils; ii) all antibodies that were reported to be oligomer-specific also recognized fibrillar aSyn; and iii) a few antibodies (e.g., the antibody clone 26F1, 5G4) showed high specificity for oligomers and fibrils but did not bind to monomers. These findings suggest that most aSyn aggregate-specific antibodies cannot be used to differentiate between oligomers and fibrils, thus highlighting the importance of exercising caution when interpreting results obtained using these antibodies. In the second chapter of this thesis, we systematically addressed the current knowledge gaps on the role of aSyn oligomers in the initiation, seeding and pathology spreading. Towards this goal, we used different biophysical approaches to investigate aSyn seeding in vitro and in neurons and animal models of aSyn seeding and pathology spreading. we observed that oligomeric forms do not form in the PFF-based neuronal seeding model and we report that different types of oligomers do not seed pathology in vitro and primary hippocampal neurons, and their presence slows rather than accelerates aSyn fibrillization. Altogether, our work points to fibrils as the most seeding competent species and suggests that they are the critical mediators of pathology spreading in PD and other synucleinopathies.In the third chapter of this thesis, we used single-nuclei RNA-sequencing to investigate transcriptional changes in different cell types of the amygdala brain region, which is highly susceptible to developing pS129 positive aggregates in the PD brains. We identified that most of the top 100 differentially expressed genes (DEGs) are of neuronal rather than non-neuronal cell types. In addition, we report that the gene expression profile of a handful of PD risk genes such as Sncaip, Park7, Maob, Hspa8, Scl2a3 and Hsf3 and some pathways that have been associated with PD are differentially altered in specific cell types. Our study highlights the involvement of unique gene expression changes and their associated pathways in different cell types in driving the disease process at an early stage in a PFF-based mouse model of PD.

EPFL2022

Opportunities and challenges of alpha-synuclein as a potential biomarker for Parkinson's disease and other synucleinopathies

Hilal Lashuel, Pedro José Santana Ribeiro Magalhães

Parkinson's disease (PD), the second most common progressive neurodegenerative disease, develops and progresses for 10-15 years before the clinical diagnostic symptoms of the disease are manifested. Furthermore, several aspects of PD pathology overlap with other neurodegenerative diseases (NDDs) linked to alpha-synuclein (aSyn) aggregation, also called synucleinopathies. Therefore, there is an urgent need to discover and validate early diagnostic and prognostic markers that reflect disease pathophysiology, progression, severity, and potential differences in disease mechanisms between PD and other NDDs. The close association between aSyn and the development of pathology in synucleinopathies, along with the identification of aSyn species in biological fluids, has led to increasing interest in aSyn species as potential biomarkers for early diagnosis of PD and differentiate it from other synucleinopathies. In this review, we (1) provide an overview of the progress toward mapping the distribution of aSyn species in the brain, peripheral tissues, and biological fluids; (2) present comparative and critical analysis of previous studies that measured total aSyn as well as other species such as modified and aggregated forms of aSyn in different biological fluids; and (3) highlight conceptual and technical gaps and challenges that could hinder the development and validation of reliable aSyn biomarkers; and (4) outline a series of recommendations to address these challenges. Finally, we propose a combined biomarker approach based on integrating biochemical, aggregation and structure features of aSyn, in addition to other biomarkers of neurodegeneration. We believe that capturing the diversity of aSyn species is essential to develop robust assays and diagnostics for early detection, patient stratification, monitoring of disease progression, and differentiation between synucleinopathies. This could transform clinical trial design and implementation, accelerate the development of new therapies, and improve clinical decisions and treatment strategies.

NATURE PORTFOLIO2022

Dopaminergic fiber protection and regeneration by Wlds protein and GDNF in rodent models of Parkinson disease

Ali Etemad-Sajadi

Parkinson disease (PD) is a common neurodegenerative disorder characterized by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta. The resulting failure of the nigrostriatal pathway leads to profound dopamine deficiency, causing bradykinesia, tremor, rigidity and postural imbalance. The current therapeutic options for this disabling disorder remain symptomatic and are devoid of any impact on the neurodegeneration process per se. The development of neuroprotective and regenerative strategies constitute therefore an important challenge, in order to halt and possibly reverse the loss of the nigrostriatal pathway in PD. In the present study, we have investigated two different approaches to protect or restore the nigrostriatal dopaminergic system in rodent models of PD. In the first part, we examined the potential of a spontaneous dominant mutation in mice called slow Wallerian degeneration (Wlds) to confer protection of the dopaminergic pathway against the catecholaminergic toxin 6-hydroxydopamine (6-OHDA). Interestingly, the Wlds fusion protein proved capable to provide functional preservation of the nigrostriatal dopaminergic terminals. The observed Wlds-mediated protection of dopaminergic axons might help to further elucidate the mechanisms leading to the loss of dopamine axons in PD and conduct to the development of new therapeutic modalities for this disorder. In the second approach, we assessed the protective and regenerative potential of the neurotrophic factor glial cell line-derived neurotrophic factor (GDNF) delivered via capsules in a rat model of PD. GDNF delivery by encapsulated cells resulted in regeneration of dopaminergic fibers and behavioral improvement in a bilateral 6-OHDA model in the rat. Importantly, GDNF withdrawal did not affect the morphological and behavioral effects in our model. The sustainability of the striatal dopaminergic reinnervation and behavioral performances following GDNF washout has important implications. It suggests that GDNF needs to be delivered only transiently to allow prolonged functional regenerative effect, rendering the retrievable capsules attractive to achieve this purpose in PD patients. The promising potential of GDNF to protect and regenerate the nigrostriatal pathway has been hampered by several recent studies showing that long-term GDNF overexpression in the intact nigrostriatal pathway induces a downregulation of tyrosine hydroxylase (TH), the rate-limiting enzyme in the synthesis of dopamine. In the last part of this work, we aimed therefore at investigating the effect of GDNF on other enzymes of dopamine biosynthesis, using a lentiviral vector-mediated gene transfer technique, in order to overexpress GDNF in rat striatum. We showed that in addition to TH downregulation, long-term GDNF overexpression results in tetrahydrobiopterin upregulation, and importantly in dopamine decrease in the intact striatum of rats. In a clinical perspective, dose and treatment duration of the trophic factor will thus have to be established and optimized with the aim of achieving beneficial neuroprotective effects while circumventing undesirable pharmacologic effects on dopamine biosynthesis. The discovery of new protective molecules such as the Wlds protein, as well as a better understanding of cellular effects of the promising neurotrophic factor GDNF might lead to the establishment of neuroprotective and neuroregenerative strategies for PD in the close future.

EPFL2005