Pathomechanisms in the neuronal ceroid lipofuscinoses

Journal Pre-proof Pathomechanisms in the neuronal ceroid lipofuscinoses

Hemanth R. Nelvagal, Jenny Lange, Keigo Takahashi, Marta A. Tarczyluk-Wells, Jonathan D. Cooper PII:

S0925-4439(19)30293-5

DOI:

https://doi.org/10.1016/j.bbadis.2019.165570

Reference:

BBADIS 165570

To appear in:

BBA - Molecular Basis of Disease

Received date:

5 August 2019

Revised date:

30 September 2019

Accepted date:

3 October 2019

Please cite this article as: H.R. Nelvagal, J. Lange, K. Takahashi, et al., Pathomechanisms in the neuronal ceroid lipofuscinoses, BBA - Molecular Basis of Disease(2019), https://doi.org/10.1016/j.bbadis.2019.165570

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© 2019 Published by Elsevier.

Journal Pre-proof

Pathomechanisms in the Neuronal Ceroid Lipofuscinoses

Hemanth R Nelvagal1, Jenny Lange2,3, Keigo Takahashi1, Marta A TarczylukWells2,4, Jonathan D Cooper1

1

Pediatric Storage Disorders Laboratory, Department of Pediatrics, Division of

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Genetics and Genomics, Washington University in St. Louis, School of Medicine,

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St Louis, MO, 63110, USA.

2

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Department of Basic and Clinical Neuroscience, Institute of Psychiatry,

Department of Neurodegenerative Disease, Institute of Neurology, University

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3

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Psychology & Neuroscience, King's College London, London SE5 9NU, UK.

Centre for Brain Research, Faculty of Medical and Health Sciences, University

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4

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College London, London WC1N 3BG.

of Auckland, New Zealand.

Authors for correspondence: [email protected] or [email protected]

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Journal Pre-proof ABSTRACT The neuronal ceroid lipofuscinoses (NCLs) are a group of inherited neurodegenerative lysosomal storage disorders (LSDs), traditionally grouped together based on shared clinical symptoms. The recent emergence of new forms of NCL along with an improved understanding of endo-lysosomal system function have necessitated the reassessment of their classification and pathogenesis. Novel clinical findings, as well as observations

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in various animal models of NCL, have revealed significant pathological changes in

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regions outside the brain, as well as progression of disease along connected anatomical

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pathways. The characterization of animal models of NCLs has not only highlighted the

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vulnerability of certain neuron populations but has also revealed glial cells to be adversely affected and actively contribute to disease progression. While the lysosome

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has been thought of as being the ‘waste-disposal’ unit of the cell, recent evidence of the

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endo-lysosomal system playing a crucial role in nutrient sensing and cellular homeostasis have shown that NCL mutations have far-ranging effects on cellular

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functions including autophagy and synaptic dysfunction. The discovery of the machinery

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controlling endo-lysosomal function via transcription factor EB (TFEB) and mTORC1, have also shed light on potential mechanisms by which NCL mutations may exert their effect. While the NCLs share many common down-stream pathologies, there is a growing body of evidence for unique pathogenic pathways in each form. In light of the rapid advances in therapeutic strategies for the NCLs and LSDs, these new lessons learnt about unique NCL pathomechanisms will be key for informing the targeting, timing and strategies for future treatments.

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Journal Pre-proof KEYWORDS:

Neuronal

ceroid

lipofuscinoses,

Lysosomal

storage

disorders,

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Pathogenesis, Neurodegeneration, Glial dysfunction, Synaptopathy.

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Journal Pre-proof INTRODUCTION The neuronal ceroid lipofuscinoses (NCLs) are a group of inherited neurodegenerative lysosomal storage disorders (LSDs) that mainly affect children and young adolescents and are the most common cause of childhood dementia [1,2]. The NCLs continue to be classified together based on common and broadly similar clinical features that present in the first two decades of life - including loss of vision leading to blindness, epileptic

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seizures and a progressive decline of motor and cognitive abilities. However, the order

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and age at which symptoms present varies greatly depending on the form of NCL [3].

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To date, there are up to 13 different forms of NCLs, each having distinct monogenetic defects in genes encoding proteins in the endo-lysosomal system [4]. Largely, these

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can be classified into – a) soluble lysosomal enzyme or cytosolic protein deficiencies or

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b) insoluble transmembrane protein defects. These transmembrane proteins may either be present in the lysosomal membrane or the endoplasmic reticulum (ER) which are

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involved in the endo-lysosomal system [Reviewed in 5]. Crucially however, the exact

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mechanisms by which these mutations lead to the common downstream phenotypes remains largely unresolved. These include the pathognomic accumulation of autofluorescent storage material (AFSM), dysregulated autophagy as well as significant and progressive glial activation and neuronal death within the nervous system [6–8]. It is important to note that since the NCLs arise from distinct monogenetic mutations, each form may have unique pathomechanisms that affect the endo-lysosomal system that can result in these phenotypes [5,6,9]. Nevertheless, these diseases ultimately end in broadly similar pathological appearances. The characteristic AFSM accumulation, which

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Journal Pre-proof actually contains a complex mixture of different lipids and proteins in each form [10–12], has hampered any consideration and classification of the NCLs as being distinct disorders, albeit ones that share certain features. Indeed, many of the pathological phenotypes seen in the NCLs are common to other LSDs as well as other neurodegenerative disorders [13–15].

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Understanding the underlying pathological mechanisms that operate in individual NCLs

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is important on at least three fronts - A) Timing and targeting of therapy to the

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appropriate affected tissues and in the correct therapeutic windows, B) Elucidating the

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up- and down-stream interactions of these affected proteins that could lead to novel therapeutic strategies and C) Insights into lysosomal physiology that can greatly

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improve our knowledge of pathogenesis in LSDs and other diseases as well as help

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design novel therapeutic strategies. This review summarizes what is currently known about pathological changes in different NCLs and how this information may shape

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future studies and therapies.

Modelling NCL pathology

The generation of a variety of animal models of the NCLs has provided researchers with tools to investigate the effects of these gene deficiencies in vivo (reviewed separately in this issue). In many neurodegenerative diseases including other LSDs, there are commonly a subset of tissues or cell populations that are selectively vulnerable to pathogenic insult [14,16,17]. The characterization of animal models, particularly the widely used mouse models of NCLs has allowed us to investigate disease phenotypes

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Journal Pre-proof at an organismal level, as they largely recreate certain disease-relevant phenotypes, within obvious species constraints [16-26]. Comparative studies in the NCLs have also been greatly aided by crossing these murine models on a common genetic background [29,30]. Recently, with the advent of better technologies to generate mouse models with specific mutations, efforts have been made to re-create the most common human disease-causing mutations in mice in order to better replicate the pathological changes

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seen in human NCL [31–34]. In addition to mouse models, naturally-occurring larger

have

proved

very

useful

in

understanding

the

anatomical

and

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models

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animal models of NCLs have been identified in dogs [35–40] and sheep [41]. These

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pathophysiological spread of disease as they more closely mimic the human disease and provide a means to test the delivery and dosing of therapeutic agents in a way that

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is not possible in mice. The advent of CRISPR-Cas9 technology has also allowed for

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the generation of a genetically accurate sheep model of CLN1 [42], and a pig model of CLN3 disease [43], and it is likely that similar models will be generated for other forms

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of NCLs. Together, the analysis of both mouse and larger animal models of NCLs have

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given us significant new perspectives on disease progression including novel sites of pathology, cell type specific pathology and novel disease mechanisms.

Anatomical perspectives in NCL pathogenesis Cerebral and cerebellar atrophy along with an enlargement of lateral ventricles in the brain is a consistent finding in the NCLs. However, such atrophy does not occur in a uniform fashion with some regions affected before others [7,8,44–46]. Previous studies in mouse models revealed the thalamus and cerebellum to be particularly vulnerable

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Journal Pre-proof regions, across different forms of NCL and that somatosensory regions of the cortex are affected earlier and more severely than motor regions [24,47–50]. This is evidenced by marked glial activation, AFSM accumulation and neuron loss, in addition to pronounced interneuron loss within the cortex and hippocampus. The staging of and progression of pathology has also been defined in larger animal models of NCLs, confirming that these

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regions are indeed likely to be clinically relevant [39,40,42,51–55].

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The identification of patterns of pathology occurring along thalamocortical and

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cerebellar pathways has also opened the possibility of similar pathology occurring within

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interconnected nuclei that lie up- or down-stream of affected structures. Recent evidence suggests this concept extends outside the brain, or even outside the CNS

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[56,57]. As most NCL proteins are widely expressed in various tissues and cell types

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[58–60], it is highly probable that other organ systems in the body are affected by deficiency in these proteins. While this may not be to the same extent as the brain, but it

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is probable that these effects will nonetheless require therapeutic intervention. In this

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context, treating the brain alone is likely to prove insufficient to alleviate disease burden, and as such identifying these unexpected sites of pathology has considerable translational importance. Treating these previously overlooked pathologies may provide additional clinical benefit improving life quality. Given the significant sensory and motor deficits seen in the NCLs [3,61], it was perhaps not surprising that exploration of the spinal cord revealed significant pathology in this region in CLN1 disease [62]. Various observations in other animal models, as well as human autopsy studies suggest that this spinal pathology is very likely present in multiple NCLs [7,42,43,63–65].

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Similarly, NCL patients, with only few exceptions, present with loss of vision [2,3] and as such the visual pathway has been explored in great detail. Pronounced retinal degeneration is observed in NCL patients [3,66,67], and this is recapitulated in animal models of multiple forms of NCLs, together with degeneration of the optic nerve [57,68– 81]. However, the limitations of mouse models should also be kept in mind, as mouse

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models of Cln3 disease do not display significant retinal degeneration [73], other than

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that as a complication of strain background [82]. Nevertheless, mouse models do

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display significant pathology in central visual pathways within dorsal-lateral geniculate

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nucleus of the thalamus and visual cortex across multiple forms of NCL [24,47–49], and it is likely that other retinorecipient nuclei are also affected. Another consideration of

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mouse models is that rodent species depend far more on sensory information from their

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whiskers than visual input [83], which may explain why the somatosensory pathways through the ventral posterior nucleus of the thalamus to the somatosensory barrel-field

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cortex are so severely affected in mouse models of NCL [48–50,84–88], even more

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than the central visual pathways [24,47–49].

There is also a growing body of evidence for significant cardiac pathology from both clinical and experimental observations [89–93]. These are best established in CLN3 disease, and also include evidence for disturbances in autonomic nervous system function [94]. Furthermore, the range of bowel problems NCL children display clinically are suggestive of enteric disturbances across multiple NCLs [3,95]. Work is ongoing to explore these phenotypes in mouse models of NCL, and it will be important to

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Journal Pre-proof determine their relationship to events in the CNS. Better understanding of the sites and progression of pathology in each form of NCL will also greatly aid the timing and targeting of therapies.

Cell-type specific vulnerability in NCLs

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Apart from learning about which anatomical regions are vulnerable in disease, using

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animal models of the NCLs has provided insights into how different cell types within

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these regions might be affected by disease [29,30,96,97]. Neuronal dysfunction and

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loss are critical pathological features of the NCLs with certain neuronal populations clearly being more vulnerable in these diseases [30]. Interneuron populations identified

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by various calcium-binding proteins or neuropeptides are lost in the thalamus, cortex

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and hippocampus early in disease progression, as compared to other neurons [47,48,53,73,84,86]. Recently, these cell populations have been implicated in playing a

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major role in neurodegenerative pathways across various diseases such as epilepsy

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[98], Alzheimer disease [99], amyotrophic lateral sclerosis (ALS) [100] and Parkinson disease [101]. The unique electrophysiological properties and bioenergetics of interneurons suggest that they are more vulnerable to disease [102]. Also, Purkinje cells of the cerebellum have also been shown to be especially vulnerable [103,104], and it appears that lysosomal function is critical in their normal physiology [33,105]. It is not clear whether this apparent vulnerability of Purkinje neurons is related to their need to maintain such a complex dendritic structure, or their greater dependence on overall lysosomal function, or some other as yet unidentified disease-specific mechanism.

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Another major change in our understanding of NCL pathogenesis has been in reassessing the role that glial cells play in disease progression. Given the widespread neuronal dysfunction and loss, the NCLs have always been largely considered as predominantly ‘neuronal’ diseases, and this notion even extends to the naming of these diseases as the ‘neuronal ceroid lipofuscinoses’[1], despite AFSM accumulating in

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many cell types [56,57,93]. However, a growing body of evidence has shown there to be

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a significant and early impact of disease upon other cells of the central nervous system,

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which also normally express the genes that are deficient in these disorders. These

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include astrocytes and microglia which are observed to be in activated states, both biochemically and histologically [34,47,48,52,106]. Such glial activation typically occurs

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before neuron loss, and its initial localized distribution more accurately predicts where

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loss of neurons occurs, than the appearance of storage material [2,6,10]. This apparent correlation raised the question of whether there is contributory role of glial activation in

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causing neuron loss in the NCLs, as has been suggested in various other lysosomal

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[107] and neurodegenerative disorders [108–110]. Recently, primary cell culture experiments exploring the properties of glial cells derived from mouse models of CLN1 and CLN3 have shown that astrocytes and microglia themselves have significant functional, morphological and survival defects, although these differ markedly between these forms of NCL [111,112]. In co-culture systems, Cln3 deficient astrocytes and microglia appeared to harm or negatively impact the survival of both healthy and mutant neurons [111]. Furthermore, Cln1 astrocytes and microglia each adversely affected neuron morphology, and appeared to cross-prime one-another to cause neuron loss

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Journal Pre-proof [112]. The mechanisms underlying these events remain unclear, and it will be important to validate these data in vivo by generating cell-type specific mutant mice. Nevertheless, these experiments further implicate the contributory role that glial cells appear to play in NCL pathogenesis. Apart from the innate immune changes evidenced by glial activation in the CNS, there is also evidence for an overall humoral immune response in the NCLs [113,114] with a possible autoimmune component, especially in CLN3 [115,116].

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Building on these, some anti-inflammatory paradigms have been tested experimentally

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in different models of NCLs [41,116–119] with mixed results.

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While there is currently no mechanistic explanation for such cell-type specific vulnerability, it is becoming apparent that these will probably differ between types of

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NCL, as the primary consequences of gene deficiency will likely be different in each

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disease subtype. It is probable that further investigation into the dysregulated signalling

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pathways in each form of NCL would yield specific therapeutic targets.

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Intracellular defects in NCLs

Since the lysosome was first described by de Duve and colleagues [120], its function has largely been considered to be the breakdown and recycling of endogenous and internalized molecules [121]. However, research over the last few decades has shown that the lysosome plays a crucial role in overall cellular homeostasis, particularly in response to environmental changes as part of the greater endo-lysosomal compartment [122–124]. Apart from its traditional degradative roles, the lysosome is also involved in a

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Journal Pre-proof variety of cellular processes such as nutrient sensing, calcium and bio-metal homeostasis, cell growth axonal transport and synaptic homeostasis [5,122,125].

As NCL mutations affect the endo-lysosomal system, it would follow that there would be defects in autophagic function in these diseases, as these systems are intrinsically linked. Autophagy is required for normal cellular homeostasis and altered autophagic

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flux has been linked to a variety of lysosomal and neurodegenerative disorders [126–

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128]. While abnormal autophagy has been reported in various forms of NCL

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[33,88,129–133], the exact mechanisms by which individual NCL protein deficiencies

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lead these alterations and in turn cause cell death remain uncertain .

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Synaptic dysfunction has been observed in various models of NCLs, evidenced by

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changes in synaptic vesicle density, exocytosis as well as electrophysiological changes [49,54,85,87,132,134–138]. While lysosomes were shown to be trafficked to the

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synapse to facilitate synaptic remodelling, pre-synaptic autophagy, synaptic vesicle

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sorting and overall synaptic homeostasis [139–142], the exact mechanisms by which NCL protein defects lead to synaptic dysfunction are still poorly understood. However, since these synaptic changes precede neuron loss, they may prove important in the steps that lead to it. This may plausibly be due to altered neural conductance as well as other intracellular signalling defects [143,144]. The involvement of astrocytes and microglia upon synaptic function must also be taken into account [145–148], and may represent another means by which these cell types may influence neuronal function in the NCLs. Other neuronal defects observed in NCLs include disturbances in calcium

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Journal Pre-proof homeostasis in CLN3 [149,150], bio-metal homeostasis [151] and lipid metabolism defects [152–155].

Another major development in the field of lysosomal biology has been the discovery of cellular machinery that controls the expression of many endo-lysosomal proteins. The discovery of the CLEAR (coordinated lysosomal expression and regulation) transcription

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initiation site, the transcription factor EB (TFEB) and its phosphorylation by mTORC1

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have provided a pathway by which lysosomal defects can exert a larger influence on

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cellular function [125,156–158]. This pathway has been shown to be dysregulated in a

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number of NCLs, [158–162]. It is therefore foreseeable that this would make a viable therapeutic target downstream of the primary lysosomal defect in NCLs, as upregulating

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TFEB increases overall cellular clearance, which could circumvent existing lysosomal

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dysfunction. Pre-clinical studies in CLN3 and CLN11 mice have provided promising

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Conclusion

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evidence for this approach [163,164].

Research into the NCLs is primarily focused on devising the optimal therapeutic strategies for these devastating diseases. As in any field of biomedical research, a fundamental understanding of underlying pathology and disease mechanisms is critical to facilitating such treatments. While the common presentations and pathomechanisms that might be amenable to therapy across this group of disorders have taken precedence [2,5], it is becoming increasingly important to consider the distinct effects of deficiency in each of these genes as these phenotypes emerge. Nonetheless, the

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Journal Pre-proof discoveries of certain pathomechanisms in the NCLs have directly informed the testing of a variety of pre-clinical strategies such as immunomodulatory agents [115– 117,119,165], modulators of endo-lysosomal function [164,166–169], enzyme mimetics [170–172] and glutamate receptor antagonists [173,174] with varying degrees of success. However, while some drugs such as the immunosuppressive agent mycophenolate mofetil [175, NCT01399047] and the PPT1 mimetic, cystagon [176,

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NCT00028262] have been tested clinically, the benefits of these have only been modest

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in patients. This has further highlighted the importance of targeting pathomechanisms

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that are specific to each form of the disease. Nonetheless, targeting the known common

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downstream phenotypes such as neuroinflammation and autophagy defects may help with the creation of important adjunct therapies that could greatly improve the

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therapeutic efficacy as compared to single-therapy strategies.

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As reviewed elsewhere in this issue, there have been significant recent improvements in the efficacy of CNS-directed therapies for the NCLs. The discovery of pathology in

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unexpected sites within or outside the CNS will necessitate the development of

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therapies that can be targeted to these tissues successfully. This may either be as combinatorial therapeutic approaches delivered via multiple routes, or the development of more holistic treatments [177]. Such knowledge of the anatomical and temporal spread of pathology in distinct forms of the NCLs is currently informing the design of various clinical trials including the intrathecal delivery of gene therapy for CLN6 disease (NCT02725580) and CLN3 (NCT03770572). Therefore, defining the timing of disease in these different tissues in relation to events in the CNS, will provide important information about effective therapeutic windows.

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From a pathological perspective, the evidence of similar regions and cell types being affected across different forms of NCL has traditionally been taken as being indicative of common downstream mechanisms effected by the dysregulation of the endo-lysosomal system. Yet, understanding the emerging differences that exist between forms of NCLs is equally important. While there is undoubtedly a similar pathological endpoint in these

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disorders, as we finally learn more about the consequences of deficiencies in each

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disease-causing gene, it is becoming more apparent that unique mechanisms will

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operate in different forms of NCL [59,164,178–181].

It is clear that there is still much work to be done in the field of NCL research. However,

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the advances made in the past few years has provided enough evidence to suggest the

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path that lies ahead. Although major advances have been made in CNS-directed therapies, it is now important to consider the NCLs as diseases that can affect multiple

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organ systems, and not just the brain as has been the traditional view. Importantly, the

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progression and anatomical spread of pathology may be unique to each form and will have to be mapped out appropriately to refine therapeutic delivery and timing. Furthermore, the generation of animal models in large animal species will dictate a comparative study of such biology across these different species so as to facilitate the accurate modelling of these diseases for the subsequent testing of various therapies.

The elucidation of cell-type specific contributions to disease such as vulnerable neuronal populations, glial contributions to pathogenesis and even pathology in non-

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Journal Pre-proof CNS cell types like myocardiocytes may help us understand the mechanisms by which lysosomal biology differs between such cell populations. Lastly, understanding the role of lysosomes in different cell types and how their dysfunction leads to pathological and behavioural phenotypes in animal models and patients will provide important opportunities for mechanistic interventions that may still target the primary defects that

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occur in each form of NCL.

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While the NCLs have much in common with each other in terms of pathology, the same

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is just as true for lysosomal diseases in general [30]. Thus, their classification as a common group of diseases should be re-considered, especially in light of the potential

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‘novel’ forms of NCL and emerging evidence of the cell biology of individual NCL

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proteins. Elucidating the different pathomechanisms in each form of the NCLs also

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allows researchers to probe the functions of the endo-lysosomal system. This not only improves our understanding of cellular function, but given the emergence of the

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lysosome as a therapeutic target in a host of pathologies [122,158,182], it will also help

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to identify novel means of modulating its function for a broader range of diseases.

ACKNOWLEDGEMENTS The many studies from the Pediatric Storage Disorders Laboratory (PSDL) cited in this review were funded from a variety of sources: US National Institutes of Health, the Wellcome Trust, UK Medical Research Council, European Union FP6, FP7 and Horizon 2020 research and innovation programme under grant agreement No. 666918 (BATCure), Sparks Foundation, Batten Disease Support and Research Association

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Journal Pre-proof (BDSRA), Batten Disease Family Association (BDFA), Beyond Batten Disease Foundation, NCL Stiftung, The Saoirse Foundation and Health Research Board of Ireland, The Natalie Fund, and The Bletsoe Family. The support of these organisations is greatly appreciated, as is the outstanding efforts of members of the laboratory past and present. We would also like to thank Dr. Alison Barnwell for constructive comments

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on the manuscript.

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Journal Pre-proof Declarations of interest

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JDC has been in receipt of research support from BioMarin Pharmaceutical Inc., Abeona Therapeutics Inc., Regenexbio Inc. and CereSpir Inc, but none of these projects relate directly to the subject of this review. The other authors have no declarations of interest.

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Journal Pre-proof Highlights There is evidence that multiple novel organ systems are affected by NCL pathology.



Specific sub-populations of neurons are more vulnerable to NCL pathology.



Regional gliosis accurately predicts neuron loss, rather than AFSM accumulation.



Dysfunction in synaptic, autophagic and CLEAR pathways may cause phenotypes.



Novel pathological sites and mechanisms are targets for future therapies.

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