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Propagation of host disease to grafted neurons: Accumulating evidence
Jeffrey H. Kordowera,⁎, Patrik Brundinb
aDepartment of Neurological Sciences, Rush University Medical Center, 1735 West Harrison Street, Chicago, IL 60612, USA
bNeuronal Survival Unit, Wallenberg Neuroscience Center, Lund University, BMC A10, 221 84 Lund, Sweden
a r t i c l ei n f o
Received 27 August 2009
Revised 9 September 2009
Accepted 15 September 2009
Available online 26 September 2009
In a recent issue of Experimental Neurology, Stefanova et al. (2009)
present an intriguing finding in which human α-synuclein-positive
oligodendroglia invade fetal striatal transplants in transgenic mice
and alter their composition and integration with the host brain. They
used a transgenic mouse model of multisystem atrophy in which
human α-synuclein is overexpressed in oligodendrocytes. Multisys-
tem atrophy (MSA) is a fatal disorder in humans involving both
striatal and nigral neurodegeneration as well as α-synuclein aggre-
gation in oligodendrocytes. The mice were given systemic injections
of the mitochondrial toxin 3-nitropropionic acid, in order to model
striatal degeneration, prior to receiving intrastriatal implants of
embryonic striatal tissue. The authors report that the overall survival
of the grafts did not differ between the transgenic MSA mice and wild
type control mice. However, the proportion of the grafted cells that
expressed striatal neuronal markers (so-called P-zones) was lower
and innervation of the graft by host dopaminergic fibers was reduced
compared to when the surgery was performed in wild type mice. In
addition, they found oligodendrocytes expressing human α-synuclein
in the transplants and which presumably had migrated from the host
into the implants. Thus, these data indicate that the modeling of MSA
(i.e. expression of α-synuclein in oligodendrocytes) in the graft
recipients negatively affects grafts of healthy neurons. The resulting
pathology bears similarities to the one that occurs in the human
disease, adding fuel to the growing concept that α-synucleinopathy in
a graft recipient can negatively affect otherwise normal transplanted
neurons in a disease-specific manner.
Our groups (Kordower et al., 2008a,b; Li et al., 2008) recently
reported the intriguing discovery that Lewy bodies–intracytoplas-
mic inclusions that are pathognomonic of Parkinson's disease (PD)–
develop in a subset of nigral neurons transplanted to patients with
PD, more than a decade after surgery. These Lewy bodies express
α-synuclein (including the form phosphorylated at serine residue
129), ubiquitin, and most importantly, thioflavin S (Kordower et al.,
2008a,b; Li et al., 2008; Chu and Kordower, in press; Li et al
submitted), the critical light microscopic characteristic of β-pleated
sheet protein structures. In addition, both our groups recently
independently obtained electron microscopic evidence further
strengthening the view that these inclusions are Lewy bodies (Li et
al., submitted; Kordower unpublished observations). In short, these
are true Lewy bodies observed in neurons that are equivalent to an
age of only 9–15 years post-natal years. In some of these cases, the
formation of Lewy bodies was associated with other PD-like changes
such as loss of dopamine transporter and reductions in tyrosine
hydroxylase (Kordower et al., 2008a,b). Recent evidence from
experimental animals indicates that host α-synuclein can be
transferred to grafted neurons from a synuclein-laden host, support-
ing the hypothesis that the clinical observations of Lewy bodies in
long-term (N10 years) fetal nigral transplant recipients can be
explained by the transfer of a α-synuclein from the host to the graft
(Brundin et al 2008). In this regard, Desplats and coworkers (2009)
demonstrated that grafted mouse cortical precursor cells take up α-
synuclein from the host brain when grafted into the hippocampus of a
transgenic mouse overexpressing human α-synuclein driven by the
Thy-1 promoter. It is intriguing that, despite using a mouse model of
α-synucleinopathy as graft recipient, the pathological changes
reported by Stefanova et al. (2009) are dissimilar to both our clinical
findings and the observations of Desplats and collaborators. Thus
there seems to be a degree of disease-specificity, such that the type of
pathology that develops in the grafts mirrors the changes seen in the
host brain. In this regard, Stefanova demonstrated that reduced graft
size and disturbed connectivity with the host brain were associated
with the invasion of α-synuclein-positive oligodendroglia, a charac-
teristic specific for MSA, but not PD.
While the presence of these Lewy bodies in grafted neurons is
unequivocal, the mechanism by which they form is not clear
(Brundin et al 2008). Possibly, the inflammatory response following
Experimental Neurology 220 (2009) 224–225
⁎ Corresponding author. Fax: +1 312 563 3571.
E-mail address: firstname.lastname@example.org (J.H. Kordower).
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the grafting and persisting around the implantation site could pro-
mote α-synuclein aggregation, which would be in line with cell
culture and animal experiments demonstrating that pro-inflamma-
tory mediators can trigger formation of α-synuclein aggregates in
neurons (cf Brundin et al 2008). However, multiple lines of evidence
refute this hypothesis. First, striatal grafts that survived in patients
with Huntington's disease for N10 years performed in the same
manner, by the same neurosurgeon, and displaying the same robust
inflammatory response as seen in some PD graft cases, do not display
Lewy bodies (Cicchetti et al., 2009). The origin of the tissue (fetal
discrepancy in pathology seen in grafts in the PD and Huntington's
brains because striatal neurons do form Lewy bodies and Lewy
neurites in PD as well (Duda et al., 2002; Mori et al., 2008). Thus, an
inflammatoryresponse alone is not sufficient to trigger the generation
of Lewy bodies in grafted neurons, even if they are of a cell type that is
capable of developing such protein aggregates. Therefore, we contend
that the generation of Lewy bodies in grafts in PD patients is process
that is specific to the host. Second, one might expect that different
transplant procedures resulting in differing degrees of inflammatory
responses would affect the likelihood of Lewy bodies forming. How-
ever, if the grafts survive longer than 10 years, Lewy bodies have now
been seenin several centerswherepatients have beengrafted usingat
least five different techniques and with varying approaches to the
4 cases from our two groups (2–4), one case from Curt Freed's team
that we were able to examine (Kordower unpublished observations),
one case operated by Deane Jacques and studied by JW Langston and
Dennis Dickson (Langston, personal communication) and even one of
the cases initially reported by Mendez et al. to be lacking Lewy bodies
(cited in ref Kordower et al., 2008b). Thus, all groups that have
systematically studied the morphology of long term transplants so far,
have cases that display Lewy bodies in grafts regardless of the tissue
preparation used (solid tissue blocks versus cell suspension), immu-
nosuppression protocol (ranging from none to long-term, multi-drug
approach) or the level of microglial response (varying from none to
moderate in different cases).
Finally, even if inflammatory processes were to contribute to the
formation of Lewy bodies in grafted neurons, this would not explain
the differences seen between grafts in the MSA model and exper-
imental/clinical PD studies because neuroinflammation is a character-
istic feature of both diseases (Mrak, 2009; Long-Smith et al., 2009).
Thus it is interesting that Stefanova and colleagues (Stefanova et al.,
2009) also reported that while there was no increase in microglial
response in the grafted MSA transgenic mice compared to control mice
receiving transplants, the transgenic MSA mice displayed an increased
astroglial response that may reflect an enhanced inflammation and
could have played a role in the compromised graft survival.
In summary, Stefanova et al. (2009) provide intriguing data
illustrating that host pathology influences grafted neurons, and that
this pathology exhibits features that are analogous to what occurs in
MSA. The specificity of effects, and the conceptual similarity to what
we (Kordower et al., 2008a,b; Li et al., 2008) and others (Desplats
et al., 2009) have observed in PD patients and animal models are
striking. These findings suggest that future studies will likely reveal
important insights concerning the molecular mechanisms that
underlie host-to-graft transfer of pathology and shed new light
on the pathogenesis of a variety of synucleinopathies.
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Parker, J.R., Chu, Y., Mufson, E.J., Kordower, J.H., Freeman, T.B., 2009. Long-term
graft survival and clinical benefits are attenuated in Huntington's disease. Proc.
Natl. Acad. Sci. 106 (30), 12483–12488.
Chu, Y., Kordower, J.H., Lewy body pathology in fetal grafts, Ann. NY Acad Sci, Major
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E., Lee, S.J., 2009. Inclusion formation and neuronal cell death through neuron-to-
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J.H. Kordower, P. Brundin / Experimental Neurology 220 (2009) 224–225