**7. Conclusion**

210 Etiology and Pathophysiology of Parkinson's Disease

1. Immature myogenous cells are infected by improved GDNF-carrier genes.

4. GDNF is transferred into the body of neurons and maintains the survival of the cells.

by nerve fibers.

(Figure source: www.epfl.ch)

2. The infected myogenous cells are injected into muscle in amyotrophic lateral sclerosis (ALS) mice 3. The infected cells mix with myogenous cells, and produce and secrete GDNF, which is absorbed

Fig. 5. Injection of GDNF into the CNS to transfer neurotrophic factors via virus-vehicle.

Results from animal models provide invaluable information for clinical research. In 2002, Steven Gill and colleagues injected GDNF directly into the brain of PD patients, which significantly attenuated the PD symptoms (Gill *et al.*, 2003). The purpose of this Phase I clinic trial was to evaluate the safety of GDNF injections. Previous data, based on animal models, showed that GDNF can prolong the survival time of DA-ergic neurons and enhance their functions. In this study, researchers pumped GDNF into the striatum corpora of five PD patients at dose of 40 mg/d, for 18 months. These researchers believed that the cells closest to tip of the catheter absorbed the GDNF first. After permeating the brain tissues, GDNF reached the DA-ergic cells. The results demonstrated that the symptoms were attenuated, After the identification of GDNF, three other family members (NTN, PSP and ART) were identified, and as further studies are undertaken, more family members may be uncovered. The receptors of these factors are composed of two parts: the GDNF family receptor and the transmembrane tyrosine kinase RET. The GPI-coupled GFR determines their specific signal transduction.

Initially, researchers assumed that only one signal pathway for GDNF existed: via GFRα1/2, anchored by receptor tyrosine kinase RET and glycosyl-phosphatidyl inositol. In 2003, *in vitro* studies demonstrated that the adhesion molecule NCAM was a receptor for GFLs that was independent of RET signaling. Recently, studies have indicated that integrin αV/β1 and N-cadherin may also be selective receptors for GDNF. As more evidence comes to light, it is evident that the signal pathway for GDNF protection of DA-ergic neurons is a complex one.

In DA-ergic neurons, GDNF activated Ras-MAPK and PI3K/Akt signaling pathways play vital roles in neuronal survival and axon growth. Present studies indicate that NCAM, a new GFI receptor, is also involved in the signaling pathways of GDNF-GFRα1-MET and NGF-TrkA-RET, which also makes the biological characteristics of GDNF complex.

Some progress has been made in therapeutic trials for neuronal degenerative diseases based on the neurotrophic actions of GDNF. Repeated, direct injection of GDNF is especially valuable for treating myeleterosis such as amyotrophic lateral sclerosis (ALS). Because of the features of the blood-brain barrier and brain tissues, direct injections of GDNF to treat PD and other neurodegenerative diseases have limited use. Thus, direct GDNF gene injection mediated by vehicle or transgenic cellular transplant is a promising alternative. Currently, the challenge lies in the development of a safe, novel vehicle for the delivery of genes that can be specially expressed in tissues, can induce gene expression and can replace the virus vehicle.

In the management of PD, the application of drugs with low molecular weights is another choice for recombining neurotrophic factors. Other GFLs may be of potential value for treatment. Present studies demonstrate that, in murine PD models, PSPN, which is transferred into brains via neuronal stem cells, exerts effects as well as GDNF, on the survival of DA-ergic neurons in the midbrain (Akerud *et al.*, 2002). As we know, the expression of GFRα4, which is the receptor of PSPN, is more limited than that of GFRα1, the receptor of GDNF. Thus, we can propose that, even if high concentrations of PSPN are used, the adverse effects may be fewer than using GDNF (Lindahl *et al.*, 2000). The next challenge is to identify novel drugs, with low molecular weights and natural neurotrophic properties, to influence intracellular signal transduction. These explorations should be based on the comprehensive recognition of GFLs and the 3D structure of its receptor, as well as molecules, cells and disease.

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**10** 

*Spain* 

**The Hsp70 Chaperone System in** 

*CSIC-University of Seville-UPO-Junta de Andalucía, Seville, 2Laboratory of Molecular Biophysics, Institute for Research in* 

Adahir Labrador-Garrido1, Carlos W. Bertoncini2 and Cintia Roodveldt1 *1CABIMER-Andalusian Center for Molecular Biology & Regenerative Medicine* 

Several neurodegenerative diseases are associated with a build up of misfolded or abnormal proteins and the formation of distinct aggregates, resulting in a putative pathological protein load on the nervous system (Chiti & Dobson, 2006). This aberrant accumulation of amyloid or amyloid-like aggregates occurs in Parkinson's (PD), Alzheimer's (AD), and Huntington's (HD) diseases, amyotrophic lateral sclerosis, and frontotemporal dementia, among others. A broad array of cellular defence mechanisms operate to counteract this effect, including antioxidant proteins, the stress-inducible response and, in particular, molecular chaperones (Morimoto, 2008; Voisine et al., 2010). Molecular chaperones are responsible for maintaining normal protein homeostasis within the cell by assisting protein folding, inhibiting protein aggregation, and modulating protein degradation pathways (Hartl & Hayer-Hartl, 2009). Currently, there is substantial evidence supporting the involvement of these protein aggregational processes and a role of molecular chaperones, and especially of Hsp70, in PD pathogenesis (Bandopadhyay & de Belleroche, 2010; Broadley & Hartl, 2009; Witt, 2009). Firstly, extensive colocalization of Hsp70 with αsynuclein (αSyn), the major component of Lewy bodies (LBs) (Spillantini et al., 1998), within the intraneuronal inclusions in PD brains has been demonstrated (Auluck et al., 2002; McLean et al., 2002). Secondly, patients with PD show highly perturbed expression of different members of the Hsp70 family in the *substantia nigra pars compacta* (SN) of the brain, which is precisely the target of neurodegeneration (Grunblatt et al., 2001; Hauser et al., 2005). Finally, there is a considerable amount of data derived from studies performed *in vitro*, in cell culture and with animal models of PD (Arawaka et al., 2010; Witt, 2009), that support the protective effects of Hsp70 against αSyn aggregation and toxicity, considered to

The discovery within the last few years of three different missense mutations (A30P, E46K and A53T) in the αSyn gene as causative of early onset PD unambiguously linked this protein to disease onset and progression (Kruger et al., 1998; Polymeropoulos et al., 1997; Zarranz et al., 2004). Additionally, a locus triplication causing an increased dosage of the wild-type (Wt) αSyn gene has been found to potentiate neurodegeneration (Singleton et al.,

**1. Introduction** 

be central in the aetiology of the disease.

**Parkinson's Disease** 

*Biomedicine (IRB), Barcelona,* 

