Another Protein Plays a Role in Spreading Harmful Alpha-synuclein in Parkinson’s, Mouse Study Shows

Another Protein Plays a Role in Spreading Harmful Alpha-synuclein in Parkinson’s, Mouse Study Shows

Scientists have linked the clumping of alpha-synuclein protein to Parkinson’s disease, and a study in mice indicates that the clumps accumulate and spread by interacting with the protein responsible for mad cow disease.

What scientists call the cellular prion protein, or PrPc, is associated with the development of a number of rare neurodegenerative disorders known as prion diseases. One is bovine spongiform encephalopathy, or mad cow disease.

The connection between alpha-synuclein and the cellular prion protein gives scientists more insight into the underlying mechanisms of neurodegenerative diseases — understanding that could him them develop new targets for therapies.

Italian researchers published their study in Scientific Reports. Its title is “α-Synuclein Amyloids Hijack Prion Protein to Gain Cell Entry, Facilitate Cell-to-Cell Spreading and Block Prion Replication.

Alpha-synuclein accumulation is a hallmark of a group of neurodegenerative diseases collectively known as synucleinopathies, which include Parkinson’s, dementia with Lewy bodies, and multiple system atrophy.

But how the clumps form and spread remained a mystery until the Italian study.

“Several mechanisms of cell-to-cell spread have been proposed (endocytosis, receptor-mediated endocytosis, exosomes, tunneling nanotube formation, etc.) and most probably all of them contribute to some extent to α-Syn aggregate propagation,” the researchers wrote.

The team from the International School for Advanced Studies, or SISSA, discovered that cellular prion protein increases the clumping and spread of alpha-synuclein.

Prions are small particles composed of an abnormally folded protein that cause progressive neurodegenerative conditions. A structural anomaly in one prion can be transmitted to normally folded prion proteins, spreading the disease like a viral infection.

The Italian team, led by Professor Giuseppe Legname, found that PrPC binds to alpha-synuclein, facilitating the accumulation and spread of alpha-synuclein clumps.

Researchers first made the discovery in lab cultures of mice neurons. When they compared cells with and without PrPc expression, they noticed that the lack of the prion protein prevented alpha-synuclein accumulation.

The team then confirmed their observation in mice. They found that mice expressing PrPc had more alpha-synuclein clumps than mice without PrPc.

They also discovered that while the prion protein helps trigger the development of synucleinopathies, alpha-synuclein deposits interfered with prion multiplication by binding to PrPc.

“The inhibitory effect we observed is most readily explained by alpha-synuclein amyloid binding to PrPC on the cell surface, which blocks the docking of PrPSc template for further replication,” they explained.

Overall, “the potential function of PrPC in binding and mediating cell-to-cell spread of alpha-synuclein amyloids offers an intriguing new role for PrPC and opens new venues of research,” their study concluded.

3 comments

  1. sylvia purdon says:

    There! I told you that it is catching and here we are with those cells catching this from each other. Just keep out of my head, you guys.

  2. Lou says:

    An earlier study (see below) indicates that alpha-synuclein strands aggregate during times that they are in transition from one stable folding to another. Researchers found that Curcumin decreases the time that it takes to transition from one stable state to the other, and thus reduced opportunities for aggregation to occur, reducing the amount of aggregation.

    https://www.ncbi.nlm.nih.gov/m/pubmed/18189141/

  3. Lou says:

    It looks like there was a new article on the effects of curcumin on alpha-synuclein aggregation just last month, which references studies performed since that in vitro study I posted above, which have confirmed the efficacy of curcumin in vivo, as well.

    ” Curcumin, which plays a neuroprotective role in various animal models of PD, was found to directly modulate the aggregation of α-synuclein in in vitro as well as in in vivo studies. While curcumin has been shown to exhibit strong anti-oxidant and anti-inflammatory properties, there are a number of other possible mechanisms by which curcumin may alter α-synuclein aggregation which still remains (sic) obscure. Therefore, the present study was designed to understand such concealed mechanisms behind neuroprotective effects of curcumin. An animal model of PD was established by injecting lipopolysaccharide (LPS, 5 µg/5 µl PBS) into the substantia nigra (SN) of rats which was followed by curcumin administration (40 mg/kg b.wt (i.p.)) daily for a period of 21 days. Modulatory functions of curcumin were evident from the inhibition of astrocytic activation (GFAP) by immunofluorescence and NADPH oxidase complex activation by RT-PCR. Curcumin supplementation prevented the LPS-induced upregulation in the protein activity of transcription factor NFκB, proinflammatory cytokines (TNF-α, IL-1β, and IL-1α), inducible nitric oxide synthase (iNOS) as well as the regulating molecules of the intrinsic apoptotic pathway (Bax, Bcl-2, Caspase 3 and Caspase 9) by ELISA. Curcumin also resulted in significant improvement in the glutathione system (GSH, GSSG and redox ratio) and prevented iron deposition in the dopaminergic neurons as depicted from atomic absorption spectroscopy (AAS) and Prussian blue staining, respectively. Curcumin also prevented α-synuclein aggregates in the dopaminergic neurons as observed from gene as well as protein activity of α-synuclein using RT-PCR and IHC. Collectively, our results suggest that curcumin can be further pursued as a candidate drug in the molecules targeted therapy for PD and other related synucleopathies.”

    https://link.springer.com/article/10.1007/s10787-017-0402-8

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