**6. Conclusions**

Molecular physiopathology of Parkinson's disease represents an intricate cascade of events that researchers have only begun to clarify (Fig. 1). The association that has been established between nigral degeneration and alpha-synuclein modifications has found its confirmation in a growing body of experimental evidences. Anyway, the primitive conditions that are responsible for the toxic gain of function of this protein, as well as the molecular properties of aberrant alpha-synuclein that are responsible for its deleterious effect on neuronal homeostasis, are mostly unknown and must be further explored. The precise assessment of the sequence of events leading to alpha-synuclein oligomerization and to neuronal death is undoubtedly an essential step in the research of neuroprotective tools; an ideal goal would consist in the identification of critical nodes in the molecular physiopathology of Parkinson's disease, which may provide novel promising targets of therapies aimed at blocking the degenerative process.

Mitochondrial impairment and oxidative stress seem to be early features responsible for alpha-synuclein modifications favoring protein misfolding and aggregation, but the same mechanisms can be induced by the same alpha-synuclein oligomers that they contribute to produce, so that a linear sequence of events cannot be established. Glutammatergic overstimulation of nigral neurons seems to exert a major role in the genesis of motor symptoms, whereas excitotoxicity probably plays a secondary role that only accelerates the death of neurons when these are exposed to energetic defects, oxidative stress and other toxic features. Therefore, it is possible to argue that a significant neuroprotective effect is unlikely to be obtained through pharmacologic interference with only one of these mechanisms, as it is confirmed by the failure of multiple selective strategies aimed at stimulating mitochondrial function or at contrasting oxidative stress or excitotoxicity.

improvement in motor symptoms, based on the increase of dopaminergic nigrostriatal transmission, so that it is difficult to distinguish symptomatic from neuroprotective effect. this confirms the need of a peripheral, pathology-related biomarker, useful as a surrogate endpoint in clinical trials of neuroprotective drugs. Anyway, molecular mechanisms different from MAO-B inhibition are supposed to contribute to the putative neuroprotective effect of selegiline and rasagiline: propargylamines have demonstrated to prevent mitochondrial permeabilization, cytochrome c release, caspase activation and nuclear translocation of glyceraldehyde 3-phosphate dehydrogenase; moreover, rasagiline induces the expression of anti-apoptotic proteins, such as Bcl-2 and glial cell-line derived

Drugs interfering with excitotoxic insult, such as the NMDA antagonist amantadine, produce little improvement in motor parkinsonian symptoms and significantly reduce motor side effects of L-dopa treatment. Although NMDA antagonists have been found to prevent nigral degeneration in animal models of Parkinson's disease (Blandini et al 2001), no

Dopaminergic drugs, such as L-dopa and dopamine agonists, as well as deep brain stimulation, might determine neuroprotective effects based on the hypothesis that an increase of dopaminergic transmission should inhibit the glutammatergic projection from

Molecular physiopathology of Parkinson's disease represents an intricate cascade of events that researchers have only begun to clarify (Fig. 1). The association that has been established between nigral degeneration and alpha-synuclein modifications has found its confirmation in a growing body of experimental evidences. Anyway, the primitive conditions that are responsible for the toxic gain of function of this protein, as well as the molecular properties of aberrant alpha-synuclein that are responsible for its deleterious effect on neuronal homeostasis, are mostly unknown and must be further explored. The precise assessment of the sequence of events leading to alpha-synuclein oligomerization and to neuronal death is undoubtedly an essential step in the research of neuroprotective tools; an ideal goal would consist in the identification of critical nodes in the molecular physiopathology of Parkinson's disease, which may provide novel promising targets of therapies aimed at blocking the

Mitochondrial impairment and oxidative stress seem to be early features responsible for alpha-synuclein modifications favoring protein misfolding and aggregation, but the same mechanisms can be induced by the same alpha-synuclein oligomers that they contribute to produce, so that a linear sequence of events cannot be established. Glutammatergic overstimulation of nigral neurons seems to exert a major role in the genesis of motor symptoms, whereas excitotoxicity probably plays a secondary role that only accelerates the death of neurons when these are exposed to energetic defects, oxidative stress and other toxic features. Therefore, it is possible to argue that a significant neuroprotective effect is unlikely to be obtained through pharmacologic interference with only one of these mechanisms, as it is confirmed by the failure of multiple selective strategies aimed at stimulating mitochondrial function or at

neurotrophic factor (GDNF).

subthalamus to the substantia nigra.

**6. Conclusions** 

degenerative process.

contrasting oxidative stress or excitotoxicity.

neuroprotective effect has been demonstrated in patients.

: genetic factors; : environmental factors; : therapeutic strategies.

Fig. 1. Scheme illustrating genetic and enviromental factors involved in alpha-synuclein (α-SYN ) toxicity and possible therapeutic targets. CMA: chaperone mediated autophagy

Therapeutic tools able to remove alpha-synuclein oligomers or to favor the protein refolding are not currently available. Anyway, several data support a critical role for the efficiency of the intracellular clearance machinery in the maintenance of neuronal integrity; in fact, strong links have been established between abnormal functioning of surveillance pathways and the pathogenesis of Parkinson's disease. Ubiquitin-proteasome system represents the first degradative pathway which has been investigated, however its importance has been downsized by the finding of its secondary role in the degradation of alpha-synuclein, which remains the most disease-specific pathogenetic factor. In this context, the scientific attention has switched to autophagy. Alpha-synuclein, UCH-L1, ATP13A2, DJ1 and PINK1 have all been demonstrated to regulate the clearance of proteins and mitochondria through autophagic-lysosomal pathway. Furthermore, the loss of a single allele of the glucocerebrosidase gene seems to be sufficient to increase the risk of developing the disease.

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The fact that the intraneuronal surveillance machinery has been demonstrated to contrast the onset of most pathogenetic mechanisms of Parkinson's disease makes the recovery and the improvement of this cell quality-control a priority in the development of new therapeutic strategies. Pharmacologic approaches aimed at promoting the removal of aberrant proteins and organelles could reveal as the most rationale and global solution applicable to delay the progression of Parkinson's disease and other neurodegenerative disease related to protein misfolding.

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An accurate knowledge of the wide range of mechanisms involved in the physiopathology of Parkinson's disease and, firstly, the definition of the complex interactions connecting these mechanisms represent basic requirements to develop diagnostic instruments and therapeutic tools able to modify the natural course of this disease.

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**7** 

*Italy* 

**Disease Therapy** 

*University of Brescia, Brescia (BS), 2IRCCS San Camillo Hospital, Venice,* 

Arianna Bellucci1 and PierFranco Spano1,2

*National Institute of Neuroscience –Italy, School of Medicine,* 

**Targeting** α**-Synuclein-Related Synaptic** 

**Pathology: Novel Clues for Parkinson's** 

*1Division of Pharmacology, Department of Biomedical Sciences and Biotechnologies and* 

Parkinson's disease (PD) is the most diffuse movement disorder, affecting approximately 6 milion individuals worldwide and presenting tremor, rigidity and bradykinesia as the main clinical features. The onset of PD typically occur in patients over the age of 50 years and its incidence slowly progresses with increasing age. Neuropathologically, it is characterized by loss of striatal-projecting dopaminergic neurons of the substantia nigra pars compacta, and by the presence of Lewy bodies (LB) and Lewy neurites (LN) (Forno, 1996). To date, LB and LN are the characteristic neuropathological alterations of another neurodegenerative disease: Dementia with Lewy bodies (DLB), a form of late-life dementia which eventually

It is noteworthy that, despite the staggering impact of PD on society, the available therapeutic armamentarium for this disease is still limited. Indeed, the gold-standard treatment for PD from the 60'- the dopamine precursor L-DOPA - induces severe motor side effects and its efficacy declines with the progression of the disease. The rest of the pharmacological treatments for PD mainly include drugs that are usually employed in association with L-DOPA such as dopamine agonists, which however fail to match L-DOPA's efficacy. Best results are currently achieved with invasive strategies via subcutaneous or intraduodenal delivery of apomorphine or L-DOPA, or deep brain stimulation of the subthalamic nucleus. Nonetheless, usually after 15 years of pharmacological and therapeutical interventions, most of the patients start to present several motor complications, thus requesting multiple adjuvant

For these reasons, in recent years, much effort has been made in order to outline novel therapeutical approaches to cure PD. In particular, interventions such as stem-cell based approaches have been tested as potential treatments for PD. Although results indicate that patients may gain a long-term clinical benefit from the intrastriatal transplantation of human embryonic mesencephalic tissue (Piccini et al., 1999), part of the graft-derived dopaminergic cells develop LB after 11-16 years (Li et al., 2008;Kordower et al., 2008a;Kordower et al., 2008b),

strategies such as physiotherapy, hospitalization or social assistance.

**1. Introduction** 

overlaps with Alzheimer's disease.

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