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8/6/2019 Artigo 19- The Propagation of Prion-like Protein Inclusions in Neurodegenerative Diseases
http://slidepdf.com/reader/full/artigo-19-the-propagation-of-prion-like-protein-inclusions-in-neurodegenerative 1/9
The propagation of prion-like proteininclusions in neurodegenerative
diseasesMichel Goedert1, Florence Clavaguera2 and Markus Tolnay2
1 MRC Laboratory of Molecular Biology, Hills Road, Cambridge, CB2 0QH, UK2 University of Basel, Institute of Pathology, Scho ¨ nbeinstrasse 40, 4031 Basel, Switzerland
The most common neurodegenerative diseases, in-
cluding Alzheimer’s disease and Parkinson’s disease,
are characterized by the misfolding of a small number
of proteins that assemble into ordered aggregates in
affected brain cells. For many years, the events leading
to aggregate formation were believed to be entirely cell-
autonomous, with protein misfolding occurring inde-
pendently in many cells.Recent research has now shown
that cell non-autonomous mechanisms are also import-
ant for the pathogenesis of neurodegenerative diseases
with intracellular filamentous inclusions. The intercellu-
lar transfer of inclusions made of tau, a-synuclein, hun-
tingtin and superoxide dismutase 1 has been
demonstrated, revealing the existence of mechanisms
reminiscent of those by which prions spread through the
nervous system.
Prions
The prion concept [1] continues to influence the under-
standing of neurodegeneration. Prions are infectiousproteins whose ability to propagate results from their
b-sheet-rich conformation converting the prion protein to
the aberrant form through a process of nucleated polymer-
ization. They cause the invariably fatal transmissible
spongiform encephalopathies (TSEs), also known as prion
diseases (Table 1). These diseases include Kuru, Creutz-
feldt–Jakob disease, Gerstmann–Straussler–Scheinker
disease (GSS) and fatal familial insomnia in man, bovine
spongiform encephalopathy (BSE) in cattle and scrapie in
sheep.
Prion diseases are sporadic, inherited or infectious and
rely on the conversion of the normal cellular form of the
prion protein, PrPC, to a misfolded form, PrPSc. Cases of
familial prion disease cosegregate with germline
mutations in the prion protein gene [2]. PrPSc can assemble
into several structurally distinct conformers or strains,
giving rise to distinct disease traits, incubation periods,
rates of progression and pathologies [3].
Prion-like aggregates have also been identified in fungi,
where proteins unrelated to the prion protein, such as
Ure2, Sup35, Rnq1 and HET-s, replicate through a mech-
anism of self-propagating conformation [4]. Each protein
assembles into filaments that are infectious through their
ability to grow by recruiting the soluble form of the protein.
Filament fragmentation is important for replication
because a reduction in filament length, also known as
secondary nucleation, enhances filament load through seed
extension. This could also be true of mammalian prions, for
which an inverse correlation between aggregate stability
and incubation times of disease has been demonstrated [5].
Neurodegenerative diseases that involve protein
misfolding
Prion diseases belong to the group of protein misfolding
neurodegenerative diseases that are characterized by the
abnormal aggregation of defined host proteins. The mis-
folded proteins form highly ordered filamentous
inclusions with a core region of cross-b-conformation.
Tau, b-amyloid and a-synuclein are the most commonly
misfolded proteins [6]. Whereas prion diseases are rare,
Alzheimer’s disease (AD), Parkinson’s disease (PD) and
frontotemporal dementia (FTD) are common. Like most
cases of prion disease, they are largely sporadic, with a
small percentage being inherited (Table 1). Mutations inthe genes encoding amyloid precursor protein (APP), tau
and a-synuclein cause dominantly inherited forms of AD,
FTD and PD [7–12]. Mutations in superoxide dismutase 1
(SOD1), TAR DNA-binding protein 43 (TDP-43) and fused
in sarcoma (FUS) cause familial forms of amyotrophic
lateral sclerosis (ALS) [13–16]. Some cases of inherited
FTD are also caused by mutations in TDP-43 (Table 1).
Huntington’s disease (HD), which is caused by mutations
in huntingtin [17], and other polyglutamine diseases, are
always inherited.
An important difference between TSEs and other mis-
folding diseases is that prions behave like infectious
agents. They can be transmitted between individualsand across species, giving rise to epidemics, such as Kuru
and BSE. In addition, prions can spread from the point of
infection, often a peripheral tissue, to the central nervous
system (CNS), where they cause devastating neurodegen-
eration [3]. The ability to transfer between cells is a central
property of prions.
Current evidence suggests that common misfolding dis-
eases are not transmitted between individuals. However,
investigation of the formation of tau and a-synuclein
inclusions as a function of age has shown that they develop
in a stereotypical manner in particular brain regions from
where they appear to spread [18,19] (Figure 1). This is
consistent with an intercellular transfer of inclusions,
Review
Corresponding author: Goedert, M. ([email protected] ).
0166-2236/$ – see front matter ß 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.tins.2010.04.003 Trends in Neurosciences 33 (2010) 317–325 317
8/6/2019 Artigo 19- The Propagation of Prion-like Protein Inclusions in Neurodegenerative Diseases
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provided one accepts that studies of their temporal appear-ance describe a single pathophysiological process.
The relationship between TSEs and other neurodegen-
erative diseases has been studied for many years [20–23].
However, it is the flurry of recent research describing the
induction of protein misfolding and spreading between
cells [24–38] that has shown most convincingly that com-
mon neurodegenerative diseases can be driven by cell non-
autonomous mechanisms. Research has indicated that
characteristics of misfolded prion protein can be shared
by other proteins central to neurodegenerative diseases.
Proteins exhibiting prion-like properties have also been
named ‘prionoids’ [35,36].
Tau protein
The microtubule-associated protein tau is the most com-
monly misfolded protein in human neurodegenerative dis-
eases. These diseases include AD, some cases of GSS,
familial British and Danish dementias, Pick’s disease, pro-
gressive supranuclear palsy (PSP), corticobasal degener-ation (CBD), argyrophilic grain disease (AGD), Guam
Parkinsonism-dementia complex, tangle-only dementia,
white matter tauopathy with globular glial inclusions and
frontotemporal dementia and Parkinsonism linked to
chromosome 17 (FTDP-17T) [6] (Table 1). In these diseases,
the normally soluble tau protein is hyperphosphorylated
and filamentous. Whereas the hyperphosphorylated sites in
tau are similar between diseases, filament morphologies
vary widely [39].
Intraneuronal tau inclusions coexist with extracellular
deposits of b-amyloid in AD, prion protein in some forms of
GSS and BRI2 in British and Danish dementias. However,
Table 1. Protein misfolding neurodegenerative diseases
Misfolded protein Human disease Familial
cases
Prion protein Kuru À
Creutzfeldt-Jakob disease +/ À
Gerstmann–Stra ¨ ussler– +
Scheinker disease
Fa tal famili al i nsomnia +/ À
b-Amyloid Alzheimer’s disease +/ À
BRI2 British dementia +Danish dementia +
Tau Alzheimer’s disease À
Gerstmann–Stra ¨ ussler– À
Scheinker disease
British dementia À
Danish dementia À
Pick’s disease +/ À
Progressive supranuclear
palsy
+/ À
Corticobasal degeneration +/ À
Argyrophilic grain disease +/ À
Guam Parkinsonism-
dementia complex
À
Tangle-only dementia À
White matter tauopathy
with globular glialinclusions
À
Frontotemporal dementia
and Parkinsonism linked
to chromosome 17
+
a-Synuclein Parkinson’s disease +/ À
Dementia with Lewy
bodies
+/ À
Multiple system atrophy À
Pure autonomic failure À
Lewy body dysphagia À
Superoxide dismutase 1 Amyotrophic lateral
sclerosis
+/ À
TAR DNA-binding
protein 43
Amyotrophic lateral
sclerosis
+/ À
Frontotemporaldementia
+/ À
Fused in sarcoma Amyotrophic lateral
sclerosis
+/ À
Frontotemporal
dementia
À
Huntingtin Huntington’s disease +
Symbols: ‘‘+’’ indicates that the disease is inherited and caused by dominant
mutations in the gene encoding the misfolded protein or multiplications of the
gene, ‘‘+/ –’’indicates that thediseaseis inherited insomecasesandcaused bysuch
mutations or multiplications and ‘‘À’’ indicates that known cases of the disease are
not caused by dominant mutations in the gene encoding the misfolded protein or
multiplications of the gene.
Figure 1. Temporospatial spreading of tau-positive neurofibrillary lesions in the
process of Alzheimer’s disease (left, green) and a-synuclein-positive lesions (Lewy
bodies and neurites) in the process of Parkinson’s disease and dementia with Lewy
bodies (right, red). (Left) According to Braak and Braak [18], six stages (I–VI) of tau
pathology can be distinguished. Stages I–II show alterations that are largely
confined to the upper layers of the transentorhinal cortex (transentorhinal stages).
Stages III–IV are characterized by a severe involvement of the transentorhinal and
entorhinal regions, with a less severe involvement of the hippocampus and several
subcortical nuclei (limbic stages). Stages V–VI show the massive development of
neurofibrillary pathology in neocortical association areas (isocortical stages) and a
further increase in pathology in the brain regions affected during stages I–IV. The
shading intensities of the areas colored in green are proportional to the severity of
tau pathology. Adapted, with permission, from Ref. [18]. (Right) According to
Braak et al. [19,83], six stages (I–VI) of a-synuclein pathology can be distinguished.
The first lesions appear in the olfactory bulb, the anterior olfactory nucleus and the
dorsal motor nucleus of the vagus and glossopharyngeal nerves in the medulla
oblongata (stages I and II). From the brainstem, the inclusions take an ascending
path to the lower raphe nuclei, the gigantocellular reticular nucleus and the locus
coeruleus (indicated by white arrows). In stages III and IV, they reach the
amygdala, the cholinergic nuclei of the basal forebrain and the substantia nigra.
The cerebral cortex also becomes affected starting with the anteromedial temporal
mesocortex. In stages V and VI, the inclusions spread to the higher order sensory
association and prefrontal areas, the first order sensory association areas, the
premotor area and the primary sensory and motor fields. The shading intensities
of the areas colored in red are proportional to the severity of a-synuclein
pathology. Adapted, with permission, from Ref. [83].
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there are diseases, such as PSP, CBD, AGD, Pick’s disease,
Guam Parkinsonism-dementia complex, tangle-only
dementia, white matter tauopathy with globular glial
inclusions and FTDP-17T, which are characterized by
the presence of tau inclusions in the absence of extracellu-
lar deposits. Whereas most of these diseases are sporadic,
FTDP-17T is caused by mutations in Tau, establishing
that dysfunction of tau is sufficient to cause neurodegen-
eration and dementia [6,10–
12].Genetic variation in Tau also plays a role in sporadic
diseases. Thus, inheritance of the Tau H1 haplotype is a
risk factor for PSP and CBD [40–42]. Haplotypes H1 and
H2 result from a 900-kb inversion polymorphism that
encompasses the tau gene [43]. Heterozygous microdele-
tions of this region give rise to a clinical syndrome of
mental retardation, hypotonia and facial dysmorphism
[44–46], consistent with the notion that tauopathies are
caused by a gain of toxic function of tau.
The formation of tau inclusions thus appears to be
essential for causing neurodegeneration. From the above,
it is clear that multiple factors can trigger their formation.
What is less clear is whether, as it develops, tau pathology becomes self-sustaining and why it is characteristic of so
many diseases.
In adult human brain, six tau isoforms are expressed
from a single gene through alternative mRNA splicing [47]
(Figure 2). The microtubule-binding repeats form the core of
the tau filamentswhose isoform composition varies between
diseases [6]. The assembly of four-repeat tau into filaments
is characteristicof PSP, CBD, AGD,white matter tauopathy
with globular glial inclusions and many cases of FTDP-17T.
A combination of neuronal and glial tau pathology is pre-
sent, with the glial pathology predominating in white mat-
ter tauopathy with globular glial inclusions [48]. By
contrast, in Pick’s disease and some cases of FTDP-17T,
three-repeat tau predominates in the neuronal inclusions,
whereas in AD, other diseases with extracellular deposits,
Guam Parkinsonism-dementia complex, tangle-only
dementia and some cases of FTDP-17T, both three- and
four-repeat tau make up the neurofibrillary lesions.
Filamentous inclusions made of all six tau isoforms form
in a stereotypical manner during aging. This underlies the
‘‘Braak stages’’ of tau pathology, which range from stages I
toVI [18] (Figure 1). Stages I and II are thought to correlatewith preclinical AD, stages III and IV with mild cognitive
impairment and stages V – VI with AD. It suggests that the
process leading to full-blown AD begins in the transen-
torhinal cortex, where the first cells in the brain to develop
neurofibrillary lesions are located, from where it spreads to
the hippocampal formation and the neocortex. Many tau
inclusions survive the death of the affected nerve cells as
extracellular or ghost tangles.
Stereotypical spatial and temporal spreading of tau
inclusions has also been noted in AGD, a four-repeat
tauopathy [49,50]. The earliest changes are restricted to
the ambient gyrus (stage I), from where the pathological
process extends to the anterior and posterior medialtemporal lobe (stage II), followed by the septum, insular
cortex and anterior cingulate gyrus (stage III). Stage III is
characteristic of patients with a clinical diagnosis of
dementia.
These findings are consistent with an intercellular
transfer of tau aggregates. The presence of inclusions made
of distinct sets of tau isoforms in different diseases is
consistent with the existence of tau strains, akin to the
prion strains made of distinct conformers of PrPSc.
Although suggestive, these findings are merely correla-
tional and lack direct experimental support. This has
changed over the past year, with the description of the
intercellular transfer of tau aggregates, both in vivo and in
vitro [29,30]. Thus, the injection of sonicated brain extract
from mice transgenic for human mutant P301S tau
(Figure 3a) into the cerebral cortex and hippocampus of
mice transgenic for human wild-type tau (Figure 3b)
induced the assembly of wild-type human tau into fila-
ments (Figure 3c) and led to the spreading of pathology
from the sites of injection to neighboring brain regions [29].
The induction of filamentous tau was time- and brain
region-dependent and included the formation of neurofi-
brillary tangles, neuropil threads and oligodendroglial
coiled bodies. When brain extract from human P301S
tau mice was injected into control mice, neuropil threads
and coiled bodies formed at the injection sites.
Injection of brain extract immunodepleted of tau(Figure 3d) or divided into soluble and insoluble fractions
showed that insoluble tau induced aggregation. The
absence of obvious signs of neurodegeneration following
the injection of brain extract came as a surprise and stands
in marked contrast to the extensive nerve cell loss that
characterizes the P301S tau parent line [51]. At a mini-
mum, this suggests that the tau species responsible for
transmission and toxicity are not identical. It remains to be
seen how this relates to the relevance of current transgenic
mouse models of tauopathy, which often exhibit massive
neurodegeneration in the absence of abundant inclusions
[52], for an understanding of human tauopathies.
Figure 2. Schematic representation of the human tau gene and the six tau
isoforms expressed in adult brain. The human tau gene consists of 16 exons (E).
Alternative splicing of E2 (red), E3 (green) and E10 (yellow) gives rise to the six tau
isoforms (352–441 amino acids). The constitutively spliced exons (E1, E4, E5, E7,
E9, E11, E12, E13) are indicated in blue. E0, which is part of the promoter, and E14
are non-coding (white). E6 and E8 (violet) are not transcribed in human brain. E4a
(orange) is only expressed in the peripheral nervous system. Black bars indicate
the microtubule-binding repeats of tau, with three isoforms having four repeats
each (4R hTau) and three isoforms having three repeats each (3R hTau). Each
repeat is 31 or 32 amino acids in length. Similar levels of 4R and 3R tau isoforms
are expressed in normal human brain. The exons and introns are not drawn to
scale.
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Parallel work has demonstrated the transfer of tau
inclusions between transfected non-neuronal cells [30]
and the templated transmission of the conformational
properties of assembled recombinant tau [53]. Filaments
made in vitro from the microtubule-binding domain of four-
repeat human tau were taken up into cells by fluid-phase
endocytosis, where they induced filament formation of full-
length tau, probably following direct contact through a
prion-like mechanism. The likely relevance of these find-
ings is underscored by the fact that in human tauopathies,
especially AD, tau inclusions outlast the death of affectednerve cells and accumulate in the extracellular space.
This research has demonstrated that tau aggregates can
propagate a misfolded state to the inside of cells and has
provided an experimental system by which to identify the
molecular mechanisms underlying the intercellular trans-
fer of inclusions. The behavior of misfolded tau is reminis-
cent of that of protease-resistant prion protein and the
yeast prion Sup35NM [54,55].
b-Amyloid
Unlike inclusions made of tau, a-synuclein, huntingtin and
SOD1, b-amyloid deposits form in the extracellular space.
Several years ago, it was shown that the injection of brain
extract from AD patients into the brain of mice transgenic
for human mutant APP promotes the aggregation and
deposition of b-amyloid [24]. The mice developed amyloid
deposits earlier and in larger amounts than vehicle-injected
littermates. Similar findings were subsequently reported
following the intracerebralinjection of b-amyloid-containing
brain extract from transgenic mouse lines APP23 and
APPPS1 [27]. APP23 mice mainly overproducethe 40-amino
acid peptide of b-amyloid, which results in the deposition of
diffuse and filamentous deposits with age. APPPS1 miceoverproduce the 42-amino acid peptide of b-amyloid and
developcompact,punctatedeposits.Injectionofbrainextract
fromaged APPPS1mice intoyoung APP23 hosts inducedthe
formation of punctateb-amyloid deposits, whereas injection
of brain extract from APP23 mice into APP23 hosts gave
rise to diffuse and filamentous deposits. Injection of brain
extract from APP23 mice into young APPPS1 hosts resulted
in a mixture of filamentous and punctate b-amyloid
deposits, whereas injection of APPPS1 brain extract into
APPPS1-expressing mice resulted in punctate staining.
These findings areconsistent withearlier studiessuggesting
the existence of polymorphic strains of b-amyloid [56,57].
Figure 3. Induction of filamentous tau pathology in the brain of transgenic ALZ17 mice expressing human wild-type tau following the injection of brain extract from mice
transgenic for human mutant P301S tau. (a) Mice expressing the 383 amino acid four-repeat isoform of human tau (4R hTau) with the P301S mutation under the control of
the murine Thy1 promoter develop abundant Gallyas–Braak silver-positive filamentous tau inclusions and widespread nerve cell loss, including in the brainstem, the brain
region used for preparation of the extract injected in parts (c) and (d). The silver-positive tau inclusions are immunoreactive with antibody AT8, a marker for
hyperphosphorylated tau. In humans, the P301S mutation causes an aggressive form of FTDP-17T [109]. (b) In contrast, mice expressing the 441 amino acid 4R hTau
isoform under the control of the murine Thy1 promoter (line ALZ17) do not develop Gallyas –Braak silver-positive inclusions (right inset) or nerve cell loss, even though
human tau is hyperphosphorylated at the AT8 epitope (left inset), as shown for the hippocampus. Hyperphosphorylation (detected by AT8) precedes the assembly of tau
into filaments (detected by Gallyas–Braak silver). The mechanistic connections between hyperphosphorylation and aggregation of tau, two invariant features of human
tauopathies, remain to be fully elucidated. (c) The injection of brain extract from P301S tau transgenic mice into the hippocampus and the cerebral cortex of ALZ17 mice
induces the formation of Gallyas–Braak silver-positive inclusions made of filamentous, hyperphosphorylated wild-type human tau [29]. Hippocampal dentate gyrus from an
ALZ17 mouse is shown 15 months after the injection of brainstem extract from a 6-month-old P301S mouse. Silver-positive neurofibrillary tangles, neuropil threads andoligodendroglial coiled bodies are in evidence. (d) Injection of the same extract as in part (c), but immunodepleted of tau, shows no Gallyas–Braak silver-positive inclusions
15 months later. Scale bar, 50 mm.
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b-Amyloid deposits appeared to spread from the sites of
injection to more distant brain regions. Immunodepletion or
formic acid treatment abolished the amyloid-promoting
activity of the extract, indicating that the active agent
consisted of aggregated species of b-amyloid. However,
synthetic filaments of b-amyloid failed to promote amyloid
deposition. Administration of brain extract through an oral,
intravenous, intraocular or intranasal route did not lead to
cerebral b-amyloidosis, in contrast to the experimentaltransmission of prion diseases [31]. In cultured nerve
cells, b-amyloid is taken up and concentrated in endo-
somes/lysosomes [34]. Vesicular b-amyloid can aggregate
and is capable of seeding the growth of amyloid filaments
inside cells. It remains to be seen whether filaments can be
released and seed the formation of extracellular plaques.
The injection of brain extract from aged b-amyloid-
depositing APP23 mice into the brains of mice transgenic
for human mutant P301L tau markedly potentiated the
formation of silver-positive tau inclusions [58], in line with
previous research on double transgenic mouse lines [59]. A
similar effect was observed following the injection of syn-
thetic b-amyloid filaments into the brains of mice trans-genic for human mutant P301L tau [60], indicating that
the molecular species which promote the formation of tau
inclusions and b-amyloid aggregates are not identical.
These findings have demonstrated the existence of mech-
anisms by which aggregated b-amyloid can cause the
hyperphosphorylation and aggregation of human mutant
tau. However, the relevance of studies using mutant APP
and mutant tau for AD remains to be clarified, because b-
amyloid fails to induce tau aggregation in mouse lines
transgenic for human wild-type tau [61].
a-Synuclein
a-Synuclein is the major component of the largely neuronal
filamentous inclusions that make up Lewy bodies and
Lewy neurites, the defining neuropathological character-
istics of PD, dementia with Lewy bodies (DLB) and several
rarer conditions including pure autonomic failure and
Lewy body dysphagia [62,63] (Table 1). a-Synuclein is also
the major component of Papp–Lantos inclusions, the
mainly oligodendroglial filamentous inclusions that are
diagnostic of multiple system atrophy (MSA) [64,65]. Fila-
ment morphologies differ between Lewy body diseases and
MSA, indicating that distinct conformers of assembled a-
synuclein can give rise to different neurodegenerative
diseases. They also differ between wild-type and mutant
a-synuclein, further suggesting the existence of different
strains [66].Whereas most cases of Lewy body disease and MSA are
sporadic, rare familial forms of PD and DLB are caused by
missense mutations in the a-synuclein gene or multipli-
cations of the gene [9,67]. Furthermore, sequence variation
in the a-synuclein gene is a risk factor for sporadic PD and
MSA [68–71]. More unexpected was the finding that the H1
haplotype of Tau is also a risk factor for PD [70–72].
Missense mutations in the a-synuclein gene and overpro-
duction of wild-type a-synuclein are believed to cause
disease through a gain of toxic function, implying that
the formation of a-synuclein inclusions is essential for
causing neurodegeneration.
a-Synuclein is an abundant brain protein of 140 amino
acids that binds lipids through its amino-terminal repeat
region [73–75]. It also assembles through this region,
which forms the core of the disease filaments [76].
Although its physiological function is unknown, a-synu-
clein is believed to play a role in the assembly of the protein
complexes required for chemical neurotransmission [77].
Incidental Lewy body disease describes the presence of
small numbers of Lewy bodies and neurites in the absenceof clinical symptoms [78]. It is observed in 5–10% of the
general population over the age of 60 years and may
represent a preclinical form of Lewy body disease. Anec-
dotal evidence has suggested that a prodromal form of
MSA could also exist [79]. In cases with incidental Lewy
body disease, the first a-synuclein-positive structures in
the brain form in the dorsal motor nucleus of the glosso-
pharyngeal and vagus nerves, the olfactory bulb and the
anterior olfactory nucleus [19]. The inclusions then ascend
rostrally from the brainstem to the midbrain and cerebral
cortex (Figure 1), contradicting the long-held view that PD
begins in the nigrostriatal system and is limited to the
degeneration of dopaminergic nerve cells of the substantianigra. Recent research is consistent with the presence of
non-motor signs in PD, including hyposmia, sleep depri-
vation and sensory symptoms [80].
a-Synuclein deposits appear to form even earlier in the
enteric and peripheral nervous systems, suggesting that
Lewy body diseases could originate outside the CNS
[81,82]. This view underlies a staging scheme, which pro-
poses that pathological inclusions progress from enteric
and autonomic nervous systems to the brainstem and
higher parts of the neuraxis [83]. It suggests that environ-
mental factors could gain access to the enteric nervous
system, where they induce the aggregation of a-synuclein.
This would be analogous to the transmission and spread-
ing of prion disease following the ingestion of BSE-infected
meat [84]. A recent study has shown that intragastric
administration of the pesticide rotenone resulted in the
formation of pathological forms of a-synuclein in the
enteric nervous system, the dorsal motor nucleus of the
vagus nerve and the substantia nigra of wild-type mice
[85].
This raises the possibility that a-synuclein pathology
could spread between synaptically connected neurons. In
support, studies of the brains of PD patients who had
received fetal mesencephalic nerve cell transplants 11–
16 years earlier revealed the presence of Lewy bodies in
the grafts [86–88] (Figure 4). These findings are consistent
with a spread of seeds from the diseased host tissues to thegrafts, followed by the nucleated polymerization of a-synu-
clein. In the grafts, up to 5% of dopaminergic neurons
contained Lewy bodies [89], similar to the proportion of
Lewy body-bearing neurons (3.6%) in the substantia nigra
of patients with PD [90]. It has been suggested that nerve
cells with Lewy bodies die within 6 months of inclusion
formation and that the generation of Lewy bodies and
nerve cell death reaches a steady state [90]. According to
this model, a-synuclein inclusions cause nerve cell death.
Experimental support for the existence of cell-to-cell
transfer of a-synuclein inclusions has come from research
showing that misfolded intraneuronal a-synuclein can
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transfer to neighboring cells both in culture and in trans-
genic mice [32]. This was associated with pathological
changes and signs of neurodegeneration in acceptor cells.
It had previously been reported that a small amount of a-
synuclein is intravesicular and secreted [91]. A separate
study has provided evidence for the nucleated polymeriz-ation of a-synuclein in transfected cells but failed to
observe efficient cell-to-cell transfer of the misfolded
protein [33]. This discrepancy between the two studies
could reflect the fact that the intercellular transfer of
misfolded seeds of a-synuclein is a relatively rare event.
Other proteins forming intracellular inclusions
Assessing the temporospatial spreading of inclusions
requires hundreds of brains with different amounts of
pathology. This has only been achieved for inclusions made
of tau protein and a-synuclein [18,19]. For a-synuclein, it
has been shown that the accumulation of internalized
misfolded protein increases when lysosomal function is
reduced, with little effect of proteasomal inhibition [32].
Reduced lysosomal activity of acceptor cells could therefore
be partially responsible for the accumulation of misfolded
a-synuclein. Proteins endocytosed and trafficked in this
manner will be inside vesicles, with soluble tau and a-
synuclein being cytoplasmic. Nucleated polymerization
therefore requires the penetration of the cytoplasmic com-
partment by filamentous aggregates. The presence in the
cytoplasm of aggregates following their uptake into cells
has been demonstrated most clearly for filaments made
from peptides of polyglutamine in the pathological range
[28].
Several years ago, it was shown that polyglutamine
aggregates are readily taken up by cells, where they exhi-bit marked cytotoxicity upon nuclear translocation [25].
Recent research has shown that polyglutamine aggregates
can gain access to the cytoplasmic compartment, where
they nucleate the assembly of a soluble, amino-terminal
fragment of huntingtin [28].
Dominantly inherited mutations in SOD1 cause ALS,
which is characterized by the formation of filamentous
inclusions made of the mutant protein [13] (Table 1).
Multiple lines of evidence indicate that the mechanisms
underlying nerve cell death in the human disease and
animal models thereof are cell non-autonomous [92]. Inter-
estingly, mutant, but not wild-type SOD1, interacts with
chromogranins A and B, leading to its secretion [26].
Extracellular mutant SOD1 has been reported to activate
microglia, resulting in the degeneration of motor neurons
[36]. These findings have suggested that toxicity of mutant
SOD1 requires activation of the innate immune system.
The relevance of this work could be more general, as it hasbeen reported that a variant in chromogranin B (P413L) is
a risk factor for sporadic ALS [93].
It remains to be seen whether mammalian cells can
mount a defense response to eliminate cytosolic protein
aggregates, similar to what happens when bacterial patho-
gens escape into the nutrient-rich cytosol. Bacteria are
eliminated by mechanisms involving ubiquitination and
clearance by autophagy [94], reminiscent of studies which
have shown that the pharmacological or genetic induction
of autophagy delays the onset of model AD, PD, HD, ALS
and prion disease [95,96].
Mechanistic implications
It seems likely that prion-like aggregates are released
from cells and taken up by neighboring cells, where
they penetrate the cytoplasm and nucleate further
aggregation (Figure 5). The full significance of recent
findings will only become clear when the underlying
mechanisms are better understood. It has been reported
that prions transfer between cultured cells through
exosomes and tunneling nanotubes (TNTs) [97,98].
Alternatively, the spread of prions could be mediated
by the conversion of PrPC on the surface of one cell to
PrpSc by contact with another cell bearing PrpSc on its
surface [99]. However, the latter mechanism is unlikely
to be relevant for cytoplasmic proteins, such as tau,
a-synuclein, huntingtin and SOD1.Exosomes are small vesicles of endocytic origin that are
released by most cells [100] (Figure 5a). They participate in
the transport of proteins, lipids and RNA. Exosomes form
intracellularly by the inward budding of early endosomes,
resulting in the formation of multivesicular bodies (MVBs).
The latter fuse with the plasma membrane, releasing the
exosomes into the extracellular space. Following their
release, exosomes can be endocytosed by neighboring cells.
The endocytic pathway can be coupled to autophagy. It has
been reported that autophagy promotes the fusion of MVBs
with autophagic vacuoles and blocks exosome secretion,
suggesting a possible link between the cellular reaction to
Figure 4. Host-to-graft spreading of Lewy body pathology in a patient with Parkinson’s disease. This patient received a transplant of fetal human mesencephalic
dopaminergic neurons into the putamen 16 years previously. Immunohistochemistry for a-synuclein visualizes Lewy bodies and Lewy neurites in (a) the host substantia
nigra and (b, c) the transplant. Scale bars, 40 mm. Adapted, with permission, from Ref. [86].
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cytoplasmic aggregates and intercellular aggregate trans-
fer [101]. b-Amyloid has been shown to be secreted via
exosomes [102]. The amyloidogenic processing of APP by b-
and g-secretases generates b-amyloid in early endosomes,
which are then trafficked to MVBs. It remains to be seen
whether aggregates of tau, a-synuclein, huntingtin and
SOD1 can shuttle between cells via exosomes.In addition to exosomes, TNTs have been reported to
play a role in the intercellular spread of prions [98]. They
are believed to provide the predominant route for the
transfer of prions between immune cells and neurons.
TNTs are F-actin-containing membranous channels that
connect cells over long distances and traffic proteins and
organelles [103] (Figure 5b). Their relevance, if any, for the
intercellular spread of prion-like aggregates remains to be
established.
The internalization of aggregates and the subsequent
nucleated polymerization of cytosolic proteins in target
cells is perhaps the most mysterious aspect of the inter-
cellular transfer of prion-like aggregates. If the aggregates
are internalized through endosomes, the vesicular con-
tents of endosomes could be released into the cytoplasm
of target cells through fusion with the plasma membrane or
the endosomal membrane (Figure 5a). Mechanisms could
also exist that allow aggregates to diffuse across the endo-
somal membrane into the cytoplasm (Figure 5b). The latter
is reminiscent of how some toxins and viruses gain access
to the cytoplasm [104,105].
Concluding remarks
Until recently, the most common neurodegenerative dis-
eases were believed to develop in a cell-autonomous man-
ner, which implies that abnormal protein aggregates form
independently in affected brain cells. It is easy to see how
this can happen in inherited cases of disease, where the
aggregating protein is either mutant or overproduced. It is
more difficult to envisage a similar process occurring in
sporadic cases of disease, where the aggregating protein is
wild-type and its expression is unchanged. Recent studies
have suggested that cell non-autonomous mechanisms
could play a more important role than hitherto suspected,emphasizing the relevance of ongoing immunotherapeutic
approaches [106–108]. The processes underlying sporadic
cases of disease could originate in a highly localized man-
ner (i.e. a single cell), from where they spread to remote
brain areas through intercellular transfer. These findings
are likely to influence thinking about the most common
neurodegenerative diseases and open the way to the
development of novel therapeutic strategies.
AcknowledgementsM.G. is supported in part by the UK Medical Research Council and the
Alzheimer’s Research Trust. F.C. and M.T. are supported by the Swiss
National Science Foundation.
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