G Mudò

Current disease modifying approaches to treat Parkinson’s disease

Parkinson’s disease (PD is a progressive neurological disorder characterized by the degeneration and death of midbrain dopamine and non-dopamine neurons in the brain leading to motor dysfunctions and other symptoms, which seriously influence the quality of life of PD patients. The drug L-dopa can alleviate the motor symptoms in PD, but so far there are no rational therapies targeting the underlying neurodegenerative processes. Despite intensive research, the molecular mechanisms causing neuronal loss are not fully understood which has hampered the development of new drugs and disease-modifying therapies. Neurotrophic factors are by virtue of their survival promoting activities attract candidates to counteract and possibly halt cell degeneration in PD. In particular, studies employing glial cell line-derived neurotrophic factor (GDNF) and its family member neurturin (NRTN), as well as the recently described cerebral dopamine neurotrophic factor (CDNF) and the mesencephalic astrocyte-derived neurotrophic factor (MANF) have shown positive results in protecting and repairing dopaminergic neurons in various models of PD. Other substances with trophic actions in dopaminergic neurons include neuropeptides and small compounds that target different pathways impaired in PD, such as increased cell stress, protein handling defects, dysfunctional mitochondria and neuroinflammation. In this review, we will highlight the recent developments in this field with a focus on trophic factors and substances having the potential to beneficially influence the viability and functions of dopaminergic neurons as shown in preclinical or in animal models of PD.

Involvement of cyclin-dependent kinase-5 in the kainic acid-mediated degeneration of glutamatergic synapses in the rat hippocampus.

Increased levels of glutamate causing excitotoxic damage accompany neurological disorders such as ischemia/stroke, epilepsy and some neurodegenerative diseases. Cyclin‐dependent kinase‐5 (Cdk5) is important for synaptic plasticity and is deregulated in neurodegenerative diseases. However, the mechanisms by which kainic acid (KA)‐induced excitotoxic damage involves Cdk5 in neuronal injury are not fully understood. In this work, we have thus studied involvement of Cdk5 in the KA‐mediated degeneration of glutamatergic synapses in the rat hippocampus. KA induced degeneration of mossy fiber synapses and decreased glutamate receptor (GluR)6/7 and post‐synaptic density protein 95 (PSD95) levels in rat hippocampus in vivo after intraventricular injection of KA. KA also increased the cleavage of Cdk5 regulatory protein p35, and Cdk5 phosphorylation in the hippocampus at 12 h after treatment. Studies with hippocampal neurons in vitro showed a rapid decline in GluR6/7 and PSD95 levels after KA treatment with the breakdown of p35 protein and phosphorylation of Cdk5. These changes depended on an increase in calcium as shown by the chelators 1,2‐bis(o‐aminophenoxy)ethane‐N,N,N ′,N′‐tetraacetic acid acetoxymethyl ester (BAPTA‐AM) and glycol‐bis (2‐aminoethylether)‐N,N,N ′,N ′‐tetra‐acetic acid. Inhibition of Cdk5 using roscovitine or employing dominant‐negative Cdk5 and Cdk5 silencing RNA constructs counteracted the decreases in GluR6/7 and PSD95 levels induced by KA in hippocampal neurons. The dominant‐negative Cdk5 was also able to decrease neuronal degeneration induced by KA in cultured neurons. The results show that Cdk5 is essentially involved in the KA‐mediated alterations in synaptic proteins and in cell degeneration in hippocampal neurons after an excitotoxic injury. Inhibition of pathways activated by Cdk5 may be beneficial for treatment of synaptic degeneration and excitotoxicity observed in various brain diseases.

Peroxisome proliferator-activated receptor-γ coactivator-1α mediates neuroprotection against excitotoxic brain injury in transgenic mice: role of mitochondria and X-linked inhibitor of apoptosis protein

Peroxisome proliferator‐activated receptor gamma coactivator‐1α (PGC‐1α) is a transcriptional coactivator involved in the regulation of mitochondrial biogenesis and cell defense. The functions of PGC‐1α in physiology of brain mitochondria are, however, not fully understood. To address this we have studied wild‐type and transgenic mice with a two‐fold overexpression of PGC‐1α in brain neurons. Data showed that the relative number and basal respiration of brain mitochondria were increased in PGC‐1α transgenic mice compared with wild‐type mitochondria. These changes occurred concomitantly with altered levels of proteins involved in oxidative phosphorylation (OXPHOS) as studied by proteomic analyses and immunoblottings. Cultured hippocampal neurons from PGC‐1α transgenic mice were more resistant to cell degeneration induced by the glutamate receptor agonist kainic acid. In vivo kainic acid induced excitotoxic cell death in the hippocampus at 48 h in wild‐type mice but significantly less so in PGC‐1α transgenic mice. However, at later time points cell degeneration was also evident in the transgenic mouse hippocampus, indicating that PGC‐1α overexpression can induce a delay in cell death. Immunoblotting showed that X‐linked inhibitor of apoptosis protein (XIAP) was increased in PGC‐1α transgenic hippocampus with no significant changes in Bcl‐2 or Bcl‐X. Collectively, these results show that PGC‐1α overexpression contributes to enhanced neuronal viability by stimulating mitochondria number and respiration and increasing levels of OXPHOS proteins and the anti‐apoptotic protein XIAP.

Parkinson’s disease: towards better preclinical models and personalized treatments

We thank Dr. Segura-Aguilar, Paris and Muñoz for their interesting letter ‘‘The need of a new and more physiological preclinical model for Parkinson’s disease’’ [1] that as such nicely complement issues raised in our recent review on Parkinson’s disease (PD) [2]. The letter by Segura et al. brings forward some very important problems in the field particularly related to the use of toxin models in preclinical PD research and their value for our understanding the human disease and for the development of better treatment strategies for PD patients. To clarify these issues we would like to highlight the following points further. Despite great efforts made during the last 50 years by many skilled and devoted scientists we still lack rational disease-modifying treatments of (PD) [2–4]. As discussed by Segura-Aguilar et al. [1] at least two major problems and obstacles do exist that have hampered progress in this field. One is the lack of understanding of the pathogenic mechanisms underlying PD and its progression, and the second concerns with the limitations of the current animal models used to study PD. Recent progress made in the field of molecular genetics has led to the discovery of more than dozen genes regulating different signaling pathways and cellular processes responsible for the familial forms of PD [2–4]. These insights have stimulated research and raised high expectations that similar mechanisms would prevail in sporadic PD representing the majority of PD patients. Unfortunately the progress has so far been rather modest. Even in the case of a-synuclein that was identified as the first PD causing gene almost 20 years ago, we do not still know the precise function of this protein in brain neurons. The funding for PD research has no doubt increased in recent years, but we think that one reason for the slow progress to unravel the pathogenesis of PD are the still insufficient research resources. There is a genuine concern about funding for other brain diseases as well and research devoted to PD makes no exception. The situation becomes more clear when one considers how much resources have been assigned to the study for example of AIDS and for the development of drugs to prevent HIV replication. Even with these significant resources we still lack effective vaccines to HIV. Segura-Aguilar et al. [1] correctly mention that the current neurotoxin models have serious limitations. However, we should still remind that many drugs that efficiently work in the symptomatic treatment of PD, such as catechol-o-methyltransferase inhibitors, MAO-B inhibitors, rasagiline, etc. have been developed using the MPTP and 6-OHDA animal models of PD [3]. We suggest that there is another very important point that has not considered with sufficient attention, as PD is a disease of aging people. However, the vast majority of studies on rodent models of & Dan Lindholm dan.lindholm@helsinki.fi