Download The neuronal ceroid lipofuscinoses: the same, but different?

1448
Biochemical Society Transactions (2010) Volume 38, part 6
The neuronal ceroid lipofuscinoses: the same, but
different?
Jonathan D. Cooper1
Pediatric Storage Disorders Laboratory, Department of Neuroscience and Centre for the Cellular Basis of Behaviour, James Black Centre, Institute of
Psychiatry, King’s College London, 125 Coldharbour Lane, London SE5 9NU, U.K.
Biochemical Society Transactions
www.biochemsoctrans.org
Abstract
The NCLs (neuronal ceroid lipofuscinoses) (also known as Batten disease) are a group of at least ten fatal
inherited storage disorders. Despite the identification of many of the disease-causing genes, very little
is known about the underlying disease mechanisms. However, now that we have mouse or large-animal
models for most forms of NCL, we can investigate pathogenesis and compare what happens in the brain in
different types of the disease. Broadly similar neuropathological themes have emerged, including the highly
selective nature of neuron loss, early effects upon the presynaptic compartment, together with an early and
localized glial activation. These events are especially pronounced within the thalamocortical system, but it is
clear that where and when they occur varies markedly between different forms of NCL. It is now becoming
apparent that, despite having pathological endpoints that resemble one another, these are reached by a
sequence of events that is specific to each subtype of NCL.
Introduction
LSDs (lysosomal storage disorders) broadly share several
common features. Each is caused by a single gene defect
that results in lysosomal dysfunction, resulting in the
intralysosomal accumulation of material that would normally
be degraded [1,2]. The end result is a devastating impact
upon the affected individual, their families and those that
care for them. However, this superficially similar picture
masks a great deal of heterogeneity, both in terms of the
underlying gene defect and material stored, and also in
the clinical presentation of affected individuals [1,2]. This
heterogeneity represents a considerable challenge in terms of
understanding the pathogenesis of these disorders and trying
to devise effective therapies, and highlights the importance of
carefully investigating each disorder individually. It also raises
a more general concern about how to classify disorders that
are broadly similar, but display marked differences between
individual subtypes.
What’s in a name?
There are several different ways to classify LSDs, according
to the type of material stored, age of onset and whether the
disease-causing gene codes for a soluble lysosomal enzyme
or a transmembrane protein [1]. Uncomfortably straddling all
of these classification schemes sit the NCLs (neuronal ceroid
lipofuscinoses), a group of at least ten storage disorders that
are more commonly known as Batten disease [3,4]. Although
Key words: Batten disease, lysosomal dysfunction, lysosomal storage disorder (LSD)
neuroimmune response, neuronal ceroid lipofuscinosis (NCL), selective neuron vulnerability.
Abbreviations used: LSD, lysosomal storage disorder; NCL, neuronal ceroid lipofuscinosis.
1
email [email protected]
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Authors Journal compilation individually rare, these disorders are collectively the single
largest cause of childhood neurological impairment in the
U.K. [5,6]. Once considered a form of ‘amaurotic familial
idiocy’, the term NCL was coined in the 1960s [7], initially
to distinguish these profoundly neurodegenerative disorders
from Tay–Sachs disease. This was largely on the basis that
all forms of NCL display the distinctive intralysosomal
accumulation of autofluorescent lipopigments [3,8], not only
in the brain, but also throughout the body. Characteristically,
the NCLs also share a number of other features, including
visual failure leading to blindness, seizures of increasing
severity and a relentless decline in cognitive and motor ability,
invariably ending in a premature death [3,8]. However, this
may present at widely different ages ranging from shortly
after birth to early middle age.
It’s all in the genes
Originally, it was thought that there were just four different
types of NCL, each caused by a mutation in a single gene,
with infantile-, late-infantile- and juvenile-onset forms and
a rarer adult-onset subtype proposed. However, the advent
of molecular genetics has revealed that at least ten genetically
distinct forms of NCL exist, with several new disease-causing
‘CLN’ genes identified in recent years [9,10]. (This ‘CLN’
nomenclature is another potential source of confusion, rather
than the more logical choice ‘NCL’, but this was already
assigned to another group of completely unrelated genes.)
Many of these mutations result in additional variant forms of
late-infantile NCL, but a congenital form has also recently
been found [11]. There is a certain degree of phenotype–
genotype correlation in some forms of NCL, but this does
Biochem. Soc. Trans. (2010) 38, 1448–1452; doi:10.1042/BST0381448
Lysosomes in Health and Disease
not hold true for all of these disorders, with many different
mutations in an individual gene producing apparently similar
clinical presentations [8,9].
Identifying the genetic basis of eight of the postulated
forms of NCL has revealed multiple levels of complexity.
Not only do these genes code for distinctly different
types of protein [3,10,12], soluble (CLN1, CLN2, CLN10
and probably CLN5) compared with transmembrane protein
(CLN3, CLN6, CLN7 and CLN8), but also not all of
them are expressed within the lysosome, with the remainder
expressed elsewhere within the endosomal–lysosomal system
(e.g. CLN6 and CLN8 in the endoplasmic reticulum). Even
this issue of intracellular location has been difficult to resolve,
with a lack of sufficiently specific antisera available against
highly hydrophobic transmembrane proteins such as CLN3.
Similarly, very little is known about how mutations in these
different genes lead to such devastating effects upon the
brain [13,14], with apparently relatively few consequences
in the rest of the body. Nor is it clear how genes that
code for proteins of such radically different nature and that
are expressed at different intracellular sites might produce
neurological disorders that resemble one another.
The model answer
Examining post-mortem material from individuals with
different forms of NCL provides the first hints that these
disorders do not resemble one another as closely as might be
thought [14,15]. Even at the disease end stage, it is apparent
that not all brain regions or cell types are affected equally in
any given type of NCL and, perhaps unsurprisingly, that these
phenotypes vary between different forms of the disease. For
example, there are pronounced differences between the extent
of neuron loss between different hippocampal subfields [15]
and cortical regions [16], with accompanying differences in
the extent of glial activation. Although informative, the main
drawback of these post-mortem studies is that they provide
a static snapshot of the disease endpoint and cannot reveal
anything of the events leading to this conclusion.
Fortunately, revealing the genes defective in most forms
of NCL has also made it possible to generate a series of
genetically modified mouse models and to identify spontaneously occurring mutants which bear mutations in these genes
[17]. In addition to mice, these models include a diverse series
of large-animal species [18], with dog and sheep models the
best characterized and most widely used. The larger and more
complex brain of these species has particular advantages for
modelling human disease and for addressing the translation
of experimental therapies into a clinical setting. Nevertheless,
as for many other diseases, the mainstay of our research
remains mouse models of NCL [17], with at least one available
for each genetically identified form of NCL, the exception
being the most recently identified CLN7 [19]. These include
both knockout mice, in which the function of the diseasecausing gene has been disrupted, and knockin mice, in which
a particular disease-causing mutation has been introduced
into this gene [17].
What do we know about NCL pathogenesis
so far?
Over the last decade, we have been characterizing each
of the available mouse models of NCL, documenting the
onset and progression of pathological changes [20–34] and
testing the efficacy of a range of therapeutic interventions
[35–38]. Our studies have revealed a number of new and
surprising pathological features that are broadly shared by the
different forms of NCL, but with subtype-specific differences
in the staging of these events and some more pronounced
differences between certain forms of NCL.
Selective neuron loss in the NCLs
At the outset of our studies, it was assumed that neuron loss
occurred to very similar extents throughout the NCL brain.
Although the loss of neurons is indeed widespread at the
end stages of disease, there is remarkable selectivity in its
earlier stages with populations of GABAergic interneurons,
thalamocortical projection neurons and cerebellar Purkinje
neurons proving especially vulnerable [4,17]. The vulnerability of interneuron populations might be predicted, given
that seizures are a prominent feature of these disorders, but
it remains to be seen whether these events are related to one
another. More unexpected, given the profound degeneration
of the cortical mantle, was the discovery that neuron loss
within the thalamocortical system consistently starts in the
thalamus in the vast majority of NCL mouse models [25–
27,30]. Even more surprising has been the observation that
this sequence of neuron loss is completely reversed in at least
one form of NCL [33], starting instead within the cortex.
Clearly, even within one defined set of pathways, the impact
of mutations in these disease-causing genes may have radically
different consequences.
A key consideration is whether these phenotypes observed
in mice are also present in a more complex CNS (central
nervous system), most importantly in the human disease. In
this respect, large animal models of NCL are particularly
informative [18], as we can examine the onset and progression
of the same neuropathological features we have seen in
mice. Making such comparisons between mice and sheep
that model the same form of NCL [17,39,40] reveals that,
although similar phenotypes are evident, they are much
more severe in sheep and in the corresponding human
disease. This may just reflect the inherent complexity of
these larger brains compared with mice. However, another
plausible explanation for such species-specific effects is that
gene defects in the endosomal–lysosomal system impair
intracellular trafficking and/or anterograde transport within
neurons. This has already been reported in murine NCL [29]
and would be expected to have greater effects in a larger and
more complex brain, in which the distances for transport
are much greater, and the precise requirements for accurate
trafficking are more demanding.
The challenge lies in determining why such specific effects
upon neuron survival should exist, and certainly this is at
odds with the ubiquitous accumulation of storage material
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Biochemical Society Transactions (2010) Volume 38, part 6
within the NCL brain. As new data become available for
the regional and cellular expression of genes within these
pathways [34], a clearer picture of the underlying mechanisms
will undoubtedly emerge. Until this happens, another fruitful
approach has been to determine the other pathological events
that precede neuron loss.
Trouble in store?
The ubiquitous and characteristic build up of storage material
that occurs in the NCLs has traditionally been thought to
be central to its pathogenesis and may even be toxic to
neurons. Easily detected via UV illumination and with a
subtype-specific ultrastructural appearance, it is not difficult
to see why much attention has been focused upon this
phenotype. However, more recent evidence suggests that
there is no direct relationship between neuron loss and
storage material accumulation [4,17]. Certainly, there is
no correlation between the regional and temporal patterns
of these events in any form of NCL. It is also possible
to pharmacologically induce this type of storage material
accumulation with no effects on neuron survival [41] and to
significantly decrease the storage burden with no appreciable
effect on neuron survival or lifespan [36].
If the accumulation of storage material is not the decisive
event that leads to neuron loss, then what might be? Without
a clear understanding of the normal function of any of the
‘CLN’ gene products, it has been difficult to determine the
underlying disease mechanisms. As with other disorders, a
whole variety of different possibilities have been suggested
across the different forms of NCL, including, among others,
an autoimmune response, oxidative stress or mitochondrial
dysfunction [3,4,17]. Many of these are likely to be secondary
events and determining which are central to pathogenesis is a
significant challenge.
Pathways to neuron loss?
We have started investigating these issues and identified glial
activation and synaptic pathology as two key events that
happen early in the pathogenesis of all forms of NCL and
accurately predict the distribution of subsequent neuron
loss. The same regions and pathways that exhibit neuron
vulnerability display anterograde transport defects [29], an
early rearrangement of the presynaptic compartment, altered
SNAP (soluble N-ethylmaleimide-sensitive fusion proteinattachment protein)/SNARE (soluble N-ethylmaleimidesensitive fusion protein-attachment protein receptor) formation and synapse elimination before the onset of neuron loss
[30,34,42].
As in other LSDs, several lines of evidence point to
important roles for both astrocytes and microglia in the early
stages of disease progression, although the precise nature and
timing of these events vary markedly between different forms
of NCL [4,17]. Neuron loss in all forms of NCL is invariably
preceded by localized glial activation of one type or another
[24,25,27,30,31,33,39], and this process starts much earlier
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Authors Journal compilation than previously suspected, already being evident prenatally in
sheep models of NCL [43]. There is also evidence for a direct
relationship between the extent of astrocytosis, microglial
activation and neuron loss in human NCL post-mortem
material [15,32,37]. We have begun exploring this relationship
in more detail and have obtained preliminary evidence that
the biology of astrocytes and microglia may be compromised
in certain forms of NCL. The activation of astrocytes and
microglia appear to be attenuated in human [15] and murine
[24,25] juvenile NCL, phenotypes that we are exploring in
primary microglial or astrocyte cultures.
Concluding comments
Until recently, it was assumed that neurons were the main
pathological target in the NCLs, with widespread and global
neurodegeneration at the later stages of disease. However,
evidence that glial cells may themselves be affected in
these disorders raises the likelihood of non-cell-autonomous
effects in these disorders. Indeed, astrocytes and microglia
have the potential to be key players in the pathogenesis of
multiple forms of NCL, with the synapse as the prime site
where these cell types all converge and interact with one
another. The immediate challenge is now to identify the
precise contribution of these different cell types to disease
progression and how their interactions ultimately lead to
neuron loss.
Whatever the underlying mechanisms, it is becoming
apparent that there are significant differences between the
pathological profiles of different forms of NCL. This is not
especially surprising given the different types of proteins
that are deficient in these disorders and raises the distinct
possibility that these subtypes of NCL are far less similar
than was once assumed. Perhaps more remarkable is that
defects in such widely differing gene products converge to
produce pathological endpoints so similar that they have been
considered a closely related group of disorders.
Funding
The studies from the Pediatric Storage Disorders Laboratory cited in
this review are the result of a wide series of collaborations and were
funded by grants to J.D.C. and collaborators from the U.S. National
Institutes of Health [grant numbers NS40297, NS41930, NS043105
and NS044310]; The Wellcome Trust [grant numbers GR079491MA
and WT084151AIA and Biomedical Research Collaboration Grant
023360); European Commission 6th Framework Programme [grant
number LSHM-CT-2003-503051]; Royal College of Paediatrics and
Child Health (WellChild) Fellowship; The Batten Disease Support
and Research Association; The Batten Disease Family Association;
NCL Stiftung; The Natalie Fund and Ph.D. studentships from the U.K.
Medical Research Council.
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Received 30 August 2010
doi:10.1042/BST0381448