New Insights Into Parkinson’s Traveling Protein

A laboratory study indicates that one of the main proteins involved in Parkinson’s disease pathology does not behave as a ‘prion’.

In Parkinson’s disease, the protein “alpha-synuclein” aggregates within neurons of patients and appears to propagate across interconnected areas of the brain. How this happens remains largely unknown. It has been proposed that alpha-synuclein may behave like a “prion”: pathological forms of the protein may be capable of changing the conformation of normal alpha-synuclein and thus triggering its aggregation and neuron-to-neuron propagation (a phenomenon referred to as “seeding”). Recent findings by scientists at the German Center for Neurodegenerative Diseases (DZNE) reveal that aggregation, spreading and pathology caused by alpha-synuclein do not necessarily involve prion-like seeding. Instead, they could be triggered by enhanced alpha-synuclein expression and trans-neuronal passage of monomeric and oligomeric forms of the protein. Researchers led by Prof. Donato Di Monte report on this in the journal BRAIN.

Abundant evidence underscores a critical role of the protein alpha-synuclein in the pathogenesis of Parkinson’s disease. In particular, alpha-synuclein is a major component of the intraneuronal inclusions, named Lewy bodies, that are progressively accumulated in the brains of patients with Parkinson’s disease. Alpha-synuclein pathology often starts in a region of the lower brain called medulla oblongata from where it spreads upwardly toward midbrain and cortical areas. In the current study, sponsored in part by the Paul Foundation, DZNE researchers mimicked this phenomenon in mice. With the aid of a tailor-made viral vector, they transferred the blueprint of the human alpha-synuclein gene specifically into neurons in the mouse medulla oblongata. These cells then began producing and accumulating relatively large amounts of the exogenous (human) alpha-synuclein.

Long-distance protein transmission

Using specific antibodies that recognize human alpha-synuclein, Di Monte and his colleagues tracked the spreading of this protein throughout the mouse brain over a period of 6 to 12 weeks. They also compared spreading and pathology in normal mice, which expressed both exogenous (human) and endogenous alpha-synuclein, versus mutant mice lacking their endogenous protein.

In both groups of animals, increased expression of human alpha-synuclein resulted in its progressive diffusion from the medulla oblongata toward more rostral brain regions. This protein spreading involved at least one trans-synaptic jump and followed a stereotypical pattern consistent with diffusion via anatomically interconnected pathways. Furthermore, accumulation of the spreading protein within recipient neurons was accompanied by evidence of neuronal damage.

Unlike prions

A prion-like seeding mechanism would predict that spreading of alpha-synuclein should be facilitated by interactions between abnormal forms of the protein generated within donor neurons and “uncorrupted” alpha-synuclein expressed within recipient cells. “In other words,” says Di Monte “we were expecting less efficient protein transmission and less pronounced pathology in mutant mice lacking endogenous alpha-synuclein. We were also expecting spreading and pathology to be associated with the accumulation of amyloidogenic alpha-synuclein; these are forms of the protein capable of producing insoluble fibrous aggregates.”

Image shows alpha-synuclein.
For the current study, DZNE researchera transferred the genetic blueprint of human alpha-synuclein into mice neurons (indicated by a dotted line). Credit: DZNE/M. Helwig.

Contrary to these predictions, spreading of alpha-synuclein was enhanced rather than being counteracted by ablation of the endogenous protein in mutant mice. Furthermore, trans-neuronal passage of non-fibrillar alpha-synuclein species was responsible for protein diffusion and triggered neuronal pathology. The researcher explains, “We believe that these findings bear a number of important implications for disease pathogenesis. Not only can we conclude that long-distance diffusion of alpha-synuclein does not necessarily require the generation of prion-like species. Our data also reveal that spreading and pathology can be triggered by simple overexpression of the protein and are mediated, at least initially, by monomeric and/or oligomeric alpha-synuclein.”

Moving forward with studies on a “moving” protein

The possibility that alpha-synuclein may behave like a prion has raised the speculation that, similar to some prion diseases (for example, Creutzfeldt-Jakob disease), cases of Parkinson’s disease may arise from exposure to contagious protein species. Di Monte stresses: “There is absolutely no indication that Parkinson’s could be a contagious disease. In fact, an important contribution of our new study is that it emphasizes how critical aspects of Parkinson’s disease pathogenesis, such as neuron-to-neuron alpha-synuclein transmission and protein aggregation, can be explained by mechanisms that are not prion-like.”

Di Monte and his colleagues at the DZNE intend to continue working on alpha-synuclein and are particularly interested in elucidating how alpha-synuclein could be targeted to slow down or halt the pathologic and clinical progression of the disease.

About this Parkinson’s disease research

The German Center for Neurodegenerative Diseases (DZNE) investigates the causes of diseases of the nervous system and develops strategies for prevention, treatment and care. It is an institution within the Helmholtz Association of German Research Centres with nine sites across Germany (Berlin, Bonn, Dresden, Göttingen, Magdeburg, Munich, Rostock/Greifswald, Tübingen and Witten). The DZNE cooperates closely with universities, their clinics and other research facilities.

Source: DZNE
Image Credit: The image is credited to DZNE/M. Helwig
Original Research: Abstract for “Brain propagation of transduced α-synuclein involves non-fibrillar protein species and is enhanced in α-synuclein null mice” by Michael Helwig, Michael Klinkenberg, Raffaella Rusconi, Ruth E. Musgrove, Nour K. Majbour, Omar M. A. El-Agnaf, Ayse Ulusoy, and Donato A. Di Monte in Brain. Published online December 30 2015 doi:10.1093/brain/awv376


Brain propagation of transduced α-synuclein involves non-fibrillar protein species and is enhanced in α-synuclein null mice

Aggregation and neuron-to-neuron transmission are attributes of α-synuclein relevant to its pathogenetic role in human synucleinopathies such as Parkinson’s disease. Intraparenchymal injections of fibrillar α-synuclein trigger widespread propagation of amyloidogenic protein species via mechanisms that require expression of endogenous α-synuclein and, possibly, its structural corruption by misfolded conformers acting as pathological seeds. Here we describe another paradigm of long-distance brain diffusion of α-synuclein that involves inter-neuronal transfer of monomeric and/or oligomeric species and is independent of recruitment of the endogenous protein. Targeted expression of human α-synuclein was induced in the mouse medulla oblongata through an injection of viral vectors into the vagus nerve. Enhanced levels of intra-neuronal α-synuclein were sufficient to initiate its caudo-rostral diffusion that likely involved at least one synaptic transfer and progressively reached specific brain regions such as the locus coeruleus, dorsal raphae and amygdala in the pons, midbrain and forebrain. Transfer of human α-synuclein was compared in two separate lines of α-synuclein-deficient mice versus their respective wild-type controls and, interestingly, lack of endogenous α-synuclein expression did not counteract diffusion but actually resulted in a more pronounced and advanced propagation of exogenous α-synuclein. Self-interaction of adjacent molecules of human α-synuclein was detected in both wild-type and mutant mice. In the former, interaction of human α-synuclein with mouse α-synuclein was also observed and might have contributed to differences in protein transmission. In wild-type and α-synuclein-deficient mice, accumulation of human α-synuclein within recipient axons in the pons, midbrain and forebrain caused morphological evidence of neuritic pathology. Tissue sections from the medulla oblongata and pons were stained with different antibodies recognizing oligomeric, fibrillar and/or total (monomeric and aggregated) α-synuclein. Following viral vector transduction, monomeric, oligomeric and fibrillar protein was detected within donor neurons in the medulla oblongata. In contrast, recipient axons in the pons were devoid of immunoreactivity for fibrillar α-synuclein, indicating that non-fibrillar forms of α-synuclein were primarily transferred from one neuron to the other, diffused within the brain and led to initial neuronal injury. This study elucidates a paradigm of α-synuclein propagation that may play a particularly important role under pathophysiological conditions associated with enhanced α-synuclein expression. Rapid long-distance diffusion and accumulation of monomeric and oligomeric α-synuclein does not necessarily involve pathological seeding but could still result in a significant neuronal burden during the pathogenesis of neurodegenerative diseases.

“Brain propagation of transduced α-synuclein involves non-fibrillar protein species and is enhanced in α-synuclein null mice” by Michael Helwig, Michael Klinkenberg, Raffaella Rusconi, Ruth E. Musgrove, Nour K. Majbour, Omar M. A. El-Agnaf, Ayse Ulusoy, and Donato A. Di Monte in Brain. Published online December 30 2015 doi:10.1093/brain/awv376

Feel free to share this neuroscience news.
Join our Newsletter
I agree to have my personal information transferred to AWeber for Neuroscience Newsletter ( more information )
Sign up to receive our recent neuroscience headlines and summaries sent to your email once a day, totally free.
We hate spam and only use your email to contact you about newsletters. You can cancel your subscription any time.