transmission or seed ???
iatrogenic ???
what if ???
Prion 7:1, 92–97; January/February 2013; © 2013 Landes Bioscience 92 Prion
V olume 7 Issue 1
What’s to like about the prion-like hypothesis for the spreading of
aggregated α-synuclein in Parkinson disease?
Christopher J.R. Dunning,1,* Sonia George1 and Patrik Brundin1,2 1Neuronal
Survival Unit; Wallenberg Neuroscience Center; Lund University; Lund, Sweden;
2Van Andel Research Institute; Center for Neurodegenerative Science; Grand
Rapids, MI USA
Keywords: alpha-synuclein, prion-like, Parkinson disease, cell-to-cell
transfer, protein misfolding
*Correspondence to: Christopher J.R. Dunning; Email:
Christopher.Dunning@med.lu.se Submitted: 08/08/12; Revised: 01/17/13; Accepted:
01/28/13 http://dx.doi.org/10.4161/pri.23806
α-Synuclein is a key protein in Parkinson disease. Not only is it the major
protein component of Lewy bodies, but it is implicated in several cellular
processes that are disrupted in Parkinson disease. Misfolded α-synuclein has
also been shown to spread from cell-to-cell and, in a prion-like fashion,
trigger aggregation of α-synuclein in the recipient cell. In this minireview we
explore the evidence that misfolded α-synuclein underlies the spread of
pathology in Parkinson disease and discuss why it should be considered a
prion-like protein.
Introduction
Parkinson disease (PD) is the second most prevalent neurodegenerative
disease, and the most common synucleinopathy.
Synucleinopathies feature aggregated α-synuclein (α-syn) in intracellular
inclusion bodies, which are termed Lewy bodies (LB) or Lewy neurites (LN)
depending on their location. They are the classical neuropathological hallmark
of PD and were first described by Friedrich Lewy a century ago.1 It is not clear
why LB and LN form, or what impact these inclusions have on cell function.
Proteomic analysis reveals they are comprised of greater than 100 different
proteins,2 the major protein being α-syn. Since the discoveries that α-syn was
the major protein component of Lewy aggregates,3 and that point mutations and
genetic variation in the α-syn gene can cause rare forms of dominantly inherited
PD, it has been a major focus for PD researchers. More recently, research on
this little understood protein has taken an additional direction with the
discovery that not only is α-syn the major protein component of LB and LN, but
that intercellular exchange of the misfolded form might actually play a role in
spreading α-syn pathology from cell-to-cell.
α-Syn is a 140 amino acid protein of predominantly presynaptic localization
in neurons, although it is ubiquitously expressed.2,4 The protein is comprised
of 3 domains: (1) an N-terminal lipid binding α-helix, (2) a non-amyloidβ
component (NAC) domain and (3) an unstructured C-terminus. All three regions
α-Synuclein is a key protein in Parkinson disease. Not only is it the major
protein component of Lewy bodies, but it is implicated in several cellular
processes that are disrupted in Parkinson disease. Misfolded α-synuclein has
also been shown to spread from cell-to-cell and, in a prion-like fashion,
trigger aggregation of α-synuclein in the recipient cell. In this minireview we
explore the evidence that misfolded α-synuclein underlies the spread of
pathology in Parkinson disease and discuss why it should be considered a
prion-like protein.
SNIP...
Why a Prion-Like Hypothesis Makes Sense
Why is α-syn described as prion-like and not prion? Certainly, as has been
outlined here, misfolded α-syn could be responsible for the cellular
transmission of PD pathology, although the underlying mechanisms remain elusive.
On the other hand, the pathobiology of prion itself is relatively poorly
understood. It is not known how it causes damage to its host cell, what form of
prion oligomers are toxic, nor is its native function known. What we do know is
that it is capable of cell-to-cell transmission and that it is a change in
conformation from the normal cellular form (PrPC) to the toxic form (PrPSc) that
causes toxicity. It is assumed that PrPSc acts as a seed for PrPC aggregation, a
process that has been described as akin to that of crystal formation.80 While a
seeding or nucleation process has also been described for α-syn, it has yet to
be studied in the same level of detail as PrPSc and further work is needed to
clarify whether nucleation does indeed occur. Perhaps the most striking
difference between PrPSc and α-syn however is in its transmission. While
biologically it seems that α-syn in its toxic amyloid form is transmissible from
one cell to another,68,70 PrPSc is the only protein that has been shown to be
transmissible at the organism level, i.e., from one individual to another. There
is currently no evidence that misfolded α-syn can be transmitted from one
individual to another. This lack of transmissibility might be coupled to the
fact that α-syn has not been shown to be capable of self-replication. Thus with
current knowledge, it is clear that α-syn is not a prion protein.
What the experiments highlighted above suggest though is that α-syn can act
as a prion-like protein and the dynamic interplay that exists between misfolded
α-syn and cellular dysfunction. Of course this interplay on its own could
explain neurodegeneration in the PD brain.4 However, it does not fully explain
the slow degeneration associated with the disease. There is little debate that
PD is a disease that spreads. Pre-motor symptoms can appear decades before the
on-set of motor-symptoms,81 and while not every PD patient exactly fits the
staging scheme described by Braak,82 the degeneration observed in the majority
of cases suggests a slow, progressive spread of neuropathology. The question
remains, what causes this spread? And why are some neurons more vulnerable than
others?
We know that transferred α-syn can recruit host α-syn, potentially
depleting it from its site of normal function e.g., the synapse, which in turn
can lead to a reduction in synaptic function, the consequences of which were
discussed briefly above. If the transferred protein is misfolded, and
consequently causes more protein to misfold, then it is possible α-syn acquires
a “novel” function, that of a protein complex that binds and disrupts membranes,
again causing stress to the cell. We also know that α-syn levels increase with
age. As with all proteins, sometimes it misfolds. As our cells contain more and
more α-syn, the proportion of misfolded α-syn will increase, causing greater
burden to the cellular machinery tasked with dealing with misfolded protein.
While LBs or LNs can appear in most, if not all, cells of the brain, certain
cells appear more vulnerable to degeneration than others.83 The reason for this
is likely to lie in the cells ability to handle toxic protein i.e., misfolded
α-syn. A cell with a high energy requirement will be less able to cope with an
influx of toxic protein, likewise a cell which is rich in ROS is likely to
provide the right environment for further α-syn aggregation and subsequent
spread of pathology. The spread of pathology is also a very slow process,
suggesting that the cell can cope for a certain period of time and only when a
threshold is reached does sufficient degeneration occur.
Is α-Synuclein a Prion-Like Protein?
There are three factors that have been described for α-syn that are common
to other prion-like proteins. (1) α-Syn has different conformations. Under
physiological conditions it is predominantly unstructured or α-helical (possibly
organized in a tetramer) in structure. The pathological form of α-syn consists
of oligomers and fibrils rich in β-sheets. (2) α-Syn transfers from
cell-to-cell. Whether or not it transfers to a higher degree than other proteins
is unknown, but it is clear that aggregated α-syn can transfer between cells.
(3) Aggregated α-syn has been shown to propagate in vivo. Direct catalysis of
misfolding of endogenous α-syn has not been observed in these instances, but a
time dependent increase in aggregation is clear.
The trigger that leads to misfolding and aggregation of α-syn remains
unknown. In a number of rare cases, mutations in the α-syn gene alone may be
enough, but in the majority of cases a number of factors are likely to
contribute. What is becoming clear however, whatever the trigger, misfolded
α-syn is the likely bullet, spreading synuclein pathology throughout the brain.
What’s to like about the prion-like hypothesis for the spreading of
aggregated α-synuclein in Parkinson disease?
Christopher J.R. Dunning,1,* Sonia George1 and Patrik Brundin1,2 1Neuronal
Survival Unit; Wallenberg Neuroscience Center; Lund University; Lund, Sweden;
2Van Andel Research Institute; Center for Neurodegenerative Science; Grand
Rapids, MI USA
Keywords: alpha-synuclein, prion-like, Parkinson disease, cell-to-cell
transfer, protein misfolding
Sunday, February 10, 2013
Parkinson's Disease and Alpha Synuclein: Is Parkinson's Disease a
Prion-Like Disorder?
Friday, February 15, 2013
Scottish TSE Network November Symposium Announcement Event: 12 November
2012 Title: Is Alzheimer’s Disease a transmissible disease? SUMMARY
Thursday, February 14, 2013
The Many Faces of Mad Cow Disease Bovine Spongiform Encephalopathy BSE and
TSE prion disease
TSS
No comments:
Post a Comment