Summary: A new study reports disrupted transportation routes in nerve cells are a significant cause of Parkinson’s disease.
Source: University of Erlangen-Nuremberg.
‘Traffic jams’ can also occur in the brain and they can be damaging. Researchers at Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU) have been able to confirm that this is the case. They have been able to prove that disrupted transportation routes in nerve cells are a significant cause of Parkinson’s disease.
Nerve fibres give nerve cells their characteristic long shape. Measuring up to one metre in length, they form the contact points to other nerve cells. In order to carry out the important task of communicating with other nerve cells, the fine branches of these nerve fibres and their ends, called synapses, must be regularly supplied with energy from the cell body. If this energy supply is interrupted, the synapses are destroyed. Connections between nerve cells are then disrupted, which can lead to the cells dying off. This process is typical for the development of brain disorders such as Parkinson’s disease.
It is unclear which mechanisms are responsible for the loss of nerve cells in Parkinson’s. Researchers at FAU led by Dr. Iryna Prots and Prof. Dr. Beate Winner from the Department of Stem Cell Biology in conjunction with researchers from the Department of Molecular Neurology (Janina Grosch, head: Prof. Dr. Jürgen Winkler) have now succeeded in demonstrating that a type of ‘traffic jam’ in the nerve cells could be the cause.
The researchers discovered that the traffic jam is triggered by a protein called alpha-synuclein, which is also found in healthy nerve cells. In abnormal nerve cells, the protein forms deposits, or even lumps, leading to a delay, disrupting the energy supply of the nerve fibres and, ultimately, damaging the synapses.
The researchers were also able to demonstrate this mechanism in cell cultures taken from patients with Parkinson’s. A small skin sample was taken from affected patients. These skin cells were then converted into stem cells, which can be developed into any type of cell, and in this case, into nerve cells.
In initial trials, the researchers succeeded in suppressing the formation of lumps of alpha-synuclein, thus improving the transportation of information in the nerve fibres. However, the substance they used has not yet passed clinical trials. Nevertheless, the lead author of the study, Dr. Iryna Prots, says ‘Our findings mean we can improve our understanding of the mechanisms that cause Parkinson’s and push forward new strategies for treatment during the progression of the disease.’
Source: University of Erlangen-Nuremberg
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Original Research: Open access research for “α-Synuclein oligomers induce early axonal dysfunction in human iPSC-based models of synucleinopathies” by Iryna Prots, Janina Grosch, Razvan-Marius Brazdis, Katrin Simmnacher, Vanesa Veber, Steven Havlicek, Christian Hannappel, Florian Krach, Mandy Krumbiegel, Oliver Schütz, André Reis, Wolfgang Wrasidlo, Douglas R. Galasko, Teja W. Groemer, Eliezer Masliah, Ursula Schlötzer-Schrehardt, Wei Xiang, Jürgen Winkler, and Beate Winner in PNAS. Published July 10 2018.
α-Synuclein oligomers induce early axonal dysfunction in human iPSC-based models of synucleinopathies
α-Synuclein (α-Syn) aggregation underlies neurodegeneration in synucleinopathies. However, the nature of α-Syn aggregates and their toxic mechanisms in human pathology remains elusive. Here, we delineate a role of α-Syn oligomeric aggregates for axonal integrity in human neuronal models of synucleinopathies. α-Syn oligomers disrupt anterograde axonal transport of mitochondria by causing subcellular changes in transport-regulating proteins and energy deficits. An increase of α-Syn oligomers in human neurons finally results in synaptic degeneration. Together, our data provide mechanistic insights of α-Syn oligomeric toxicity in human neurons. Taking into account that α-Syn oligomers and axonal dysfunction are characteristic for early neurodegeneration in synucleinopathies, our data might deliver targets for therapeutic interference with early disease pathology.
α-Synuclein (α-Syn) aggregation, proceeding from oligomers to fibrils, is one central hallmark of neurodegeneration in synucleinopathies. α-Syn oligomers are toxic by triggering neurodegenerative processes in in vitro and in vivo models. However, the precise contribution of α-Syn oligomers to neurite pathology in human neurons and the underlying mechanisms remain unclear. Here, we demonstrate the formation of oligomeric α-Syn intermediates and reduced axonal mitochondrial transport in human neurons derived from induced pluripotent stem cells (iPSC) from a Parkinson’s disease patient carrying an α-Syn gene duplication. We further show that increased levels of α-Syn oligomers disrupt axonal integrity in human neurons. We apply an α-Syn oligomerization model by expressing α-Syn oligomer-forming mutants (E46K and E57K) and wild-type α-Syn in human iPSC-derived neurons. Pronounced α-Syn oligomerization led to impaired anterograde axonal transport of mitochondria, which can be restored by the inhibition of α-Syn oligomer formation. Furthermore, α-Syn oligomers were associated with a subcellular relocation of transport-regulating proteins Miro1, KLC1, and Tau as well as reduced ATP levels, underlying axonal transport deficits. Consequently, reduced axonal density and structural synaptic degeneration were observed in human neurons in the presence of high levels of α-Syn oligomers. Together, increased dosage of α-Syn resulting in α-Syn oligomerization causes axonal transport disruption and energy deficits, leading to synapse loss in human neurons. This study identifies α-Syn oligomers as the critical species triggering early axonal dysfunction in synucleinopathies.