Objective/Rationale:
Observations made in brains from patients with Parkinson’s disease indicate that the disease may start at the level of the axons and that loss of the affected neurons occur later in the process. In early stages of the disease, therefore, the symptoms may be caused by impaired function in neurons that still remain alive. This opens an interesting new approach to therapy, based on strategies aimed at restoring function in the damaged neurons, or protecting them against ongoing axonal damage.
Project Description:
The study will be performed in pre-clinical models, using a gene vector to express human alpha-synuclein in the midbrain dopamine neurons, causing a progressive neuronal degeneration which starts at the axon terminal level, similar to that seen in the human disease. The analysis will focus on two stages of disease development: early changes in axons, seen within the first 3 weeks after alpha-synuclein delivery, and the long-term changes in the dysfunctional dopamine neurons, when the alpha-sunuclein-induced cell loss has taken place. In a second aim of the study we will analyze the extent to which so-called retrograde axonal transport is impaired in the treated pre-clinical models. Normally, this transport allows neuronal survival factors, like GDNF, to reach the cell bodies. Here, we will study whether retrograde transport of GDNF is affected by alpha-synuclein-induced axonal damage.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
The experiment is designed to replicate the situation seen in both early and late stage Parkinson’s disease: First, the pre-Symptoms & Side Effects or early-stage when the dopamine neurons survive in large numbers, but in a damaged, dysfunctional state. And secondly, a late stage seen in more advanced patients when the residual dopamine neurons survive long-term in a dysfunctional state characterized by alpha-synuclein inclusions, neuritic pathology and impaired dopamine release. The goal of the study is to provide a validated pre-clinical model, which will allow the development of new therapeutic approaches aimed at reversing the axonopathy associated with these early and late dysfunctional states.
Anticipated Outcome:
We expect to learn more about the way alpha-synuclein affects the structure and function of axons, and obtain new insights into how alpha-synuclein-induced damage is spreading, from the initial insult at the axonal and terminal level to involve the cell body. Recent clinical trials have raised the concern that defects in axonal transport may affect the ability of survival factors to reach the cell body from the innervated territories, and thus impair the clinical efficacy of neurotrophic factor therapy, such as used in the ongoing Neurturine and GDNF delivery trials. The results of the GDNF experiments will be of particular interest in this context.
Final Outcome
It is known that the survival of neurons, at least in part, depends on the transport of so-called trophic factors from the innervated targets to the parent cell bodies. This insight has led to the development of therapeutic strategies where survival promoting proteins are delivered to the striatum in patients with advanced Parkinson´s disease in order to block further degeneration of the dopamine neurons in the substantia nigra (i.e. the neurons most affected by the disease). Observations made in an ongoing clinical trial, using intrastriatal delivery of the neurotrophic factor Neurturin, have raised the concern that defects in transport may affect the ability of neurotrophic factors to reach the cell body from the innervated territories, and thus impair the clinical efficacy of neurotrophic factor therapy. This project was designed to addresses this issue in pre-clinical models where a PD like condition is induced by an increased production of the disease causing protein alpha-synuclein. The results show that transport of the trophic factor GDNF indeed is impaired. These findings have interesting implications for the application of neurotrophic factor therapy. Impaired protein transport may not only play a role in the progression of the disease, i.e. in the progressive development of degenerative changes that start in the axons and progress to the cell bodies, but may also constitute a barrier for the access of GDNF or Neurturin, delivered in the striatum, to the disease-affected cell bodies in the substantia nigra.
Publications
Part of these findings were included an article published in Decressac M, Kadkhodaei B, Mattsson B, Laguna A, Perlmann T, Björklund A: α-Synuclein-Induced Down-Regulation of Nurr1 Disrupts GDNF Signaling in Nigral Dopamine Neurons. Sci. Transl. Med. 163ra156, 2012, and in Decressac M, Mattsson B, Lundblad M, Weikop P, Björklund A: Progressive neurodegenerative and behavioural changes induced by AAV-mediated overexpression of α-synuclein in midbrain dopamine neurons. Neurobiol Dis. 45(3):939-53, 2012.