Biochimica et Biophysica Acta 1832 (2013) 1882–1893 Contents lists available at SciVerse ScienceDirect Biochimica et Biophysica Acta journal homepage: www.elsevier.com/locate/bbadis Review NCL disease mechanisms☆ David N. Palmer a,⁎, Lucy A. Barry a, Jaana Tyynelä b, Jonathan D. Cooper c,⁎⁎ a Department of Wine, Food and Molecular Biosciences, Faculty of Agricultural and Life Sciences, Lincoln University, PO Box 85084, Lincoln 7647, Christchurch, New Zealand b Institute of Biomedicine, Biochemistry and Developmental Biology, University of Helsinki, Helsinki, Finland c Pediatric Storage Disorders Lab, Department of Neuroscience, Centre for the Cellular Basis of Behaviour and King's Health Partners Centre for Neurodegeneration Research, James Black Centre, Institute of Psychiatry, King's College London, 125 Coldharbour Lane, London SE5 9NU, UK article info abstract Article history: Despite the identification of a large number of disease-causing genes in recent years, it is still unclear what Received 17 October 2012 disease mechanisms operate in the neuronal ceroid lipofuscinoses (NCLs, Batten disease). As a group they Received in revised form 8 May 2013 are defined by the specific accumulation of protein, either subunit c of mitochondrial ATP synthase or SAPs Accepted 9 May 2013 A and D in lysosome-derived organelles, and regionally specific neurodegeneration. Evidence from biochemical Available online 23 May 2013 and cell biology studies indicates related lesions in intracellular vesicle trafficking and lysosomal function. There is also extensive immunohistological evidence of a causative role of disease associated neuroinflammation. How- Keywords: fi Pathogenesis ever the nature of these lesions is not clear nor is it clear why they lead to the de ning pathology. Several differ- Selective neuron loss ent theories have proposed a range of potential mechanisms, but it remains to be determined which are central Glial activation to pathogenesis, and whether there is a mechanism consistent across the group, or if it differs between disease Synaptic pathology forms. This review summarises the evidence that is currently available and the progress that has been made in Storage material accumulation understanding these profoundly disabling disorders. This article is part of a Special Issue entitled: The Neuronal Biochemical abnormalities Ceroid Lipofuscinoses or Batten Disease. © 2013 Elsevier B.V. All rights reserved. 1. Introduction level of investigation will resolve all the issues of NCL pathogenesis, but when the evidence from multiple disciplines is viewed collectively, it The neuronal ceroid lipofuscinoses (NCLs, Batten disease) are devas- becomes apparent that considerable progress has been made towards tating neurodegenerative diseases of children, leading to severe mental understanding disease mechanisms. and physical decline, and finally death. These diseases were initially grouped together because of their clinical similarities and broadly uni- 2. Genetic considerations form neuropathological features, which include a similar progression of clinical symptoms, lysosomal accumulation of fluorescent storage Although it had been known for a long time that the diseases material, with defining histochemical properties and ultrastructures, which became known as the NCLs were genetically inherited, it was as well as profound neurodegeneration and widespread gliosis within not until the 1990s that any disease-causing genes were identified, and the CNS. it was unequivocally established that these were actually a group of ge- Despite the identification of several disease causing genes and many netically distinct diseases. Since then there has been a comprehensive in- studies of the respective NCL proteins, the underlying pathological crease in our knowledge of NCL genetics, starting with the discovery of mechanisms remain obscure. Even the fundamental question as to mutations underling classic forms, causing what are now regarded as whether there is a common pathway that unites all or some of the CLN1 and CLN3 diseases, closely followed by CLN2 disease [1–3] and sub- NCLs remains unanswered. sequently followed by many others. It is now apparent that these dis- A number of hypotheses have arisen over the years to explain NCL eases occur far more widely than was originally thought and many disease progression. Until recently its downstream pathology was con- previous estimates of incidence are far too low. Aside from the addition sidered to be a consequence of storage body accumulation, but this idea of CLN5, CLN6, CLN7, CLN8 and CLN10 to the NCL family, a number of is no longer tenable. Furthermore, it has become apparent that no single other genetic forms have been proposed recently, some with more se- cure foundations than others. At the time of writing these include three adult onset forms, CLN4/DNAJC5, CLN11/GRN, CLN13/CTSF [4–6],another ☆ This article is part of a Special Issue entitled: The Neuronal Ceroid Lipofuscinoses or infantile form CLN14/KCTD7 [7], and another juvenile form, CLN12/ Batten Disease. ATP13A2 [8]. ⁎ Corresponding author. While diagnoses of adult onset NCL have a strong historical basis ⁎⁎ Corresponding author. Tel.: +44 2078480286; fax: +44 2078480986. E-mail addresses: [email protected] (D.N. Palmer), [email protected] on clinical and neuropathological grounds and there are at least ultra- (J.D. Cooper). structural similarities in the nature of the stored material, information 0925-4439/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.bbadis.2013.05.014 D.N. Palmer et al. / Biochimica et Biophysica Acta 1832 (2013) 1882–1893 1883 about other common differential classification markers is not complete Subunit c storage is generalised in these diseases, this protein being the with these later additions, and none meet the full suite of classification major component of storage bodies in all tissues that contain them, in- criteria. Furthermore mutations in some of the genes implicated are as- cluding liver, kidney and pancreas. It has also been confirmed that the sociated with other diseases, including a frontotemporal lobar degener- structure of the stored subunit c is identical to that mature protein func- ation in people heterozygous for mutations in CLN11/GRN [5] while tional in intact mitochondria, including the trimethylation of lysine 43 mutations in ATP13A2 also cause a rare parkinsonism, Kufor–Rakeb syn- [26], so this is not the storage of a partial degradation product of some drome [8]. A stated above little is known of the underlying pathogenic proteolytic pathway. The N-terminal mitochondrial import signalling se- mechanisms that may unite the NCLs, so it follows that a definitive dec- quences have been removed, indicating a history of importation into the laration of which diseases should, and which should not, be grouped to- 16 oligomer multimeric ATPase complex in the inner mitochondrial gether in the NCLs is also not possible. Nevertheless abundant evidence membrane. Subunit c is packed into a ring of eight c subunits that drives of defining similarities at the biochemical, cell biology, and neuropatho- the rotation of the γ subunit forcing conformational changes in the F1 logical levels indicates where it should be productive to look for common portion of the molecule and synthesis of ATP [27]. None of the other steps in the disease mechanisms, as reviewed below. Meanwhile the ad- ATP synthase subunits are stored [28], highlighting the specificity of dition of more recent forms in the catalogue of NCLs should be treated subunit c storage and its turnover pathway. somewhat tentatively, relative to the collective identity of the classic Different proteins are stored in CLN1 disease, CLN4 disease (Parry forms. At some point there will be a need for a reconsideration of the re- disease) and CLN10 disease, as well as in miniature Schnauzer dogs quirements for a disease to be delineated as an NCL, for the general clas- affected by NCL, where the storage of the sphingolipid activator pro- sification to be useful. Meanwhile it is interesting how little commonality teins (SAPs) A and D has been reported [26,29–31]. Some subunit c can be inferred from the diverse nature of the causative genes, shown in storage has also been reported in cathepsin D (CTSD, CLN10) deficien- comprehensive reviews of the genetic bases of these disorders [9,10]. cy [32]. Knowledge of the storage material and sites of storage in the more recently classified forms of NCL is variable, although the ultra- 3. Biochemical investigations structures and fluorescent properties of the neuronal storage bodies are consistent with being NCLs. In a sense the classic forms of NCL 3.1. Storage body analyses are misnamed, the phrase ceroid lipofuscinosis being misleading be- cause the storage bodies do not have the molecular composition usu- The last century saw the common assumption of a connection be- ally attributed to ceroid or lipofuscin, as explained above. Whether or tween the material stored in lysosomal storage diseases and the disease not they should be called neuronal is also a moot point. On one hand pathogenesis. Until the 1960s the disorders that are now termed the the neurological symptoms and neurodegeneration indicate a neuro- NCLs were usually grouped together with some other lysosomal storage nal disease, but on the other hand storage body accumulation is not diseases under a catch-all description of “amaurotic family (familial) exclusively neuronal but generalised, with storage bodies