Summary: New research identifies disrupted intracellular transport in neurons as a key contributor to Parkinson’s disease.
Source: University of Erlangen-Nuremberg.
Traffic jams in nerve cells linked to Parkinson’s disease
Researchers at Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU) report that interruptions in the cellular transport system of nerve cells — comparable to traffic jams — can trigger the degeneration seen in Parkinson’s disease.
Neurons are uniquely shaped cells with long extensions called axons that can reach up to a metre in length in humans. These axonal branches and their terminals, the synapses, rely on a continuous supply of energy and molecular cargo delivered from the cell body. When this supply is disrupted, synapses deteriorate. Loss of synaptic connections weakens neuronal communication and can ultimately lead to cell death — a hallmark of neurodegenerative disorders such as Parkinson’s disease.
Until now, the precise mechanisms that initiate neuronal loss in Parkinson’s disease have remained unclear. A research team at FAU led by Dr. Iryna Prots and Prof. Beate Winner, together with collaborators from the Department of Molecular Neurology headed by Prof. Jürgen Winkler, has demonstrated that impaired axonal transport caused by protein aggregates is a major factor in early neuronal dysfunction.
The investigators found that a normally occurring neuronal protein, alpha-synuclein, is central to this process. In healthy neurons alpha-synuclein performs normal functions, but under pathological conditions it can aggregate into oligomers and larger deposits. These oligomeric forms of alpha-synuclein create a “traffic jam” along axons, slowing or blocking the anterograde transport of mitochondria and other essential cargo. The resulting energy deficit and mislocalization of transport-regulating proteins compromise axonal integrity and lead to synapse loss.
Crucially, the team reproduced these transport defects in human neurons derived from patients with Parkinson’s disease. They obtained a small skin sample from affected individuals and reprogrammed those skin cells into induced pluripotent stem cells (iPSCs). The iPSCs were then differentiated into neurons, providing a human cell model that carries the patient’s genetic background. In neurons derived from a patient with a duplication of the alpha-synuclein gene, increased levels of alpha-synuclein oligomers were associated with impaired mitochondrial movement along axons and with early synaptic degeneration.
To probe causality, the researchers used genetic and molecular approaches to increase alpha-synuclein oligomerization in healthy human iPSC-derived neurons and, conversely, to inhibit oligomer formation. Enhancing oligomerization with particular alpha-synuclein variants recapitulated the transport deficits, energy shortages, misplacement of transport regulators such as Miro1, KLC1 and Tau, and subsequent synaptic loss. Importantly, reducing oligomer formation restored anterograde mitochondrial transport and improved axonal function in their experimental models. Although the compound used to suppress oligomer formation has not yet completed clinical testing, these results point to oligomer inhibition as a promising therapeutic strategy for early-stage intervention.
Implications for treatment and future research
These findings advance our mechanistic understanding of Parkinson’s disease by identifying alpha-synuclein oligomers as a critical species that disrupts axonal transport and energy balance, thereby initiating synapse degeneration. Targeting oligomer formation or rescuing axonal transport and mitochondrial energetics could slow or prevent early neurodegenerative processes. The work emphasizes the importance of studying early, pre-symptomatic neuronal dysfunction to develop therapies that intervene before extensive cell loss occurs.
Source: University of Erlangen-Nuremberg
Publisher: NeuroscienceNews summary of the original study
Image source: Public domain image provided with the original article
Original research: Prots I., Grosch J., Brazdis R.-M., et al. “α-Synuclein oligomers induce early axonal dysfunction in human iPSC-based models of synucleinopathies.” Proceedings of the National Academy of Sciences (PNAS), July 2018.
DOI: 10.1073/pnas.1713129115
Abstract (concise)
Alpha-synuclein aggregation, progressing from oligomers to fibrils, is a central hallmark of synucleinopathies like Parkinson’s disease. This study demonstrates that alpha-synuclein oligomers disrupt anterograde axonal transport of mitochondria in human iPSC-derived neurons, cause subcellular alterations in transport-regulating proteins (including Miro1, KLC1 and Tau), and induce ATP depletion. These deficits lead to reduced axonal density and synaptic degeneration. Inhibition of alpha-synuclein oligomer formation restored mitochondrial transport, indicating that alpha-synuclein oligomers trigger early axonal dysfunction and represent a target for therapeutic intervention aimed at the earliest stages of disease.