Modulation of the ROCK pathway in models of Parkinson´s disease
by Kim Ann Saal
Date of Examination:2015-01-16
Date of issue:2015-12-09
Advisor:Prof. Dr. Paul Lingor
Referee:Prof. Dr. Mathias Bähr
Referee:Prof. Dr. Martin Göpfert
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Abstract
English
The cure of neurodegenerative diseases is one of the main goals in today’s neuroscience research. One of the main obstacles is the delayed diagnostics in relation to molecular pathology. In Parkinson’s disease (PD), several pathophysiological mechanisms participating in neurodegeneration have been elucidated, e.g. protein aggregation, increased oxidative stress, mitochondrial malfunction etc., but the precise etiological cascade still remains elusive. In order to prevent the progression of neuronal degeneration and to facilitate regeneration the potential of modulating the Rho kinase (ROCK) pathway is gaining recognition. Here we could show that ROCK protein expression is altered at least in astrocytes in post mortem PD brains, indicating a role of the ROCK signaling cascade in PD neurodegeneration. Furthermore, there seems to be an age-dependent decrease in the expression of the growth associated protein GAP-43, accompanied by astroglia infiltration and declined synaptophysin abundance in certain brain areas, which are affected in PD. These age-related changes are exacerbated in PD patients, but it is still unknown whether this is the cause or the consequence of neurodegeneration. In the 6-OHDA mouse model of PD we found attenuated dopaminergic cell loss after specific shRNA mediated ROCK2 downregulation in neurons of the substantia nigra (SN), which confirms the potential of intrinsic ROCK2 inhibition to promote neuronal survival. Moreover, we here evaluated the role of ROCK inhibition in the context of transmitter regulation. We could show that pharmacological long-term ROCK inhibition is attenuating transmitter release by reducing the readily releasable pool (RRP) of synaptic vesicles in vitro. Thus, additive detrimental effects generated by excitotoxicity from overactive glutamatergic synapses in the progression of PD, could potentially be antagonized by ROCK inhibition in the respective cells. Taken together, by affecting cell survival, neuronal growth, glial responses and transmitter release, the modulation of the ROCK pathway is a highly promising target for the future treatment of PD and other neurodegenerative disorders and warrants more in-depth pre-clinical and clinical evaluation.
Keywords: Parkinson´s disease; Rho associated kinase; astrogliosis; protein expression; ROCK inhibition; synaptic vesicles; actin cytoskeleton; striatum; substantia nigra; neurodegeneration; 6-OHDA mouse model