Information for the Lay Person


 The following articles were written by Dr. Pearce and/or colleagues on Batten Research for families.


Summary of 2005 International Conference

NCL2005 Conference Report. The 10th International Congress on Neuronal Ceroid Lipofuscinosis (Batten Disease). Helsinki, Finland, June 5- June 8 2005.

  • Dr. Jonathan Cooper, Institute of Psychiatry, King's College London, UK
  • Dr. Ruth Williams, Pediatric Neurologist, Guy's Hospital, London, UK
  • Dr. David Pearce, University of Rochester Medical School, USA

Every two years there is an international NCL (Batten disease, BD) conference which brings together scientists, medical doctors and some families from all over the world, with the US and Europe taking turns to host the conference. NCL2005 was hosted by scientists in Helsinki, Finland and took place early in June. This conference is the ideal venue for scientists and clinicians to establish new links, plan future work together and to present the latest research findings. This year's conference was spread over three days with sessions devoted to learning what happens inside cells in BD, how models are helping us to learn more about BD, progress that is being made towards therapies and the clinical management of BD.Molecules and DNA: We have known for some time which genes are mutated in most forms of BD. These genes would each normally make a different protein, but it's still not clear what these proteins usually do inside cells or what happens when these genes are mutated in BD. We don't fully know the answer to questions like: what do these proteins look like? where are they inside cells? and how does this go wrong in disease? Several advances have been made in answering these questions. There may be a role for infantile and juvenile BD proteins at the synapses that nerve cells use to communicate with one another. How each of the BD proteins move around inside cells also appears to be important, especially in the brain. We are also learning for the first time the identity of the partners that these BD proteins may interact with. Yeast, worms, flies and fish: The idea of trying to study something as complex as BD in something as simple as brewers yeast, nematode worms, fruit flies or zebrafish seems to make no sense.

However, these species are ideally suited to discovering what the BD proteins normally do. Breeding these models is relatively quick and easy, letting us perform basic genetic tricks to learn what happens in each form of BD. Because of their small size and relatively simple organization these models will also be very useful for the large scale testing of drugs that might be useful in BD.Mouse and large animal models: Moving up the scale of complexity there are several mouse models of different forms of BD. There are also larger animal models ranging from dogs and sheep to cows. With the discovery of which BD genes are mutated in these large animal models we can now begin using these species in much the same way as mouse models to understand the effect of BD upon the brain.

Studies are underway in mice to learn the effects of each form of BD upon a range of biological processes. These have pointed towards immune and inflammatory responses, the cytoskeleton (or scaffolding) inside each cell and nerve synapses as possible targets for the disease. Studying the brains of these models has also told us of early effects upon the brain's immune system an important event in both mice and sheep. We are now learning just how early the brain is affected and that the effects of disease move through the brain via interconnected groups of brain cells. What do we know now that we didn't know before? Our understanding of the genes and proteins involved in BD is rapidly increasing and mouse models are clearly proving useful for learning about the effects of disease upon the brain. Armed with this information we are now trying to compensate for the effects of disease in mice by using a variety of approaches. However, it's clear that we still need to learn much more if we are to optimize these strategies. A new approach to BD? The “storage material” or “autofluorescence” (or “stuff”) that builds up in BD is considered a hallmark of the disease. However, there is a growing consensus that this material may well be a secondary event, rather that being an important part of the disease process. Because of this we are now likely to focus on what causes the material to build up, rather than trying to eliminate it from cells. Moving towards therapy? Each of the models of BD gives us the chance to test whether any given therapy might be effective or not. A range of potential therapies are now being tested in mouse models of different forms of BD and a small number of very limited clinical trials are beginning in affected children.
Gene therapy is theoretically a way to deliver a corrected copy of the faulty gene and make the enzyme that is missing in infantile or late infantile BD. However, important questions of where and when these treatments must be given must be answered first. Also there are many sorts of viruses that can be used to deliver these genes and discovering which type works best is crucial. We heard that these studies to begin answering these questions are now underway in both infantile and late infantile BD mice and have showed promising effects upon disease related changes in their brains. But these effects are only partial at best and different strategies will be needed to make this approach more effective. A clinical trial of gene therapy for late infantile BD is also underway, but is only in its early stages.

Stem cell therapy may be another way to deliver the enzymes that are missing in infantile or late infantile BD. This could also possibly be a way to replace brain cells that have been lost in juvenile or other forms of BD. Although we heard that stem cell transplants are being tried in infantile BD mice, it is not yet clear what happens to the stem cells after grafting or whether this has any clinical benefit for these mice.
Immune approaches: The immune system appears to play a part in some forms of BD, especially in juvenile BD. Because of this a small trial is underway in Finland to see whether suppressing the immune system with steroids will be helpful in juvenile BD. However, steroids are not without side effects and it is too early to know what the effects will be.

Cystagon is a drug that might possible break down the storage material that builds up in the brain in infantile BD. This could only work in infantile BD and would not be useful in other forms of BD. Because cystagon appears to work in infantile BD cells in a dish, there is a small trial of this drug in the US. Some children with infantile BD have also been given cystagon in Finland. The children in the US have a later onset and slowly progressing form of infantile BD and it will take some years to know if cystagon has had an effect. However, cystagon has had no positive impact upon the more aggressive course of infantile BD in Finland.Medical update: In moving towards therapies for BD, one of the most important steps will be to have a good understanding of how the disease usually progresses. Collecting this sort of clinical information will give us landmarks to judge whether any test therapy has been successful. The Unified Batten Disease Rating Scale for juvenile BD has been developed in the US and is available for use generally. We also now have a more detailed picture of the behavioural and psychiatric symptoms in this form of BD.

Until new therapies become available, the support that is provided to families and effective clinical management of BD children become even more important. The Finnish foundations have particularly well established systems for educating and supporting parents. Efforts are now underway in the UK to bring medical doctors, occupational therapists, physiotherapists, and teachers together to provide much more effective care for affected children.

In conclusion, as scientists involved in BD research we recognize that progress is never fast enough. But with a growing number of scientists working on BD, we are now moving towards a much better understanding of these devastating disorders. 

Summary of 2003 International Conference

Since the 2002 BDSRA conference, much scientific research on the NCLs has been published, some of which received funding from the BDSRA.  In addition there was an international conference held in Chicago in April 2003 where researchers presented their most recent findings.

Discussed below is a selection of new data that was presented at this meeting.

Infantile NCL- A mouse that lacks the PPT1-protein defective in INCL, and a mouse lacking a similar but an apparently different protein, PPT2 were described by Dr. Sandy Hofmann's group. Further characterization of the PPT1-defective mouse was presented by Dr. Jon Cooper's group with regard to the neuroanatomical effect lacking PPT1 has on the brain. Dr. Sands is also researching this model with a focus on gene therapeutic strategies (see below). Dr. Hofmann's group introduced a yeast model for studying PPT1. Drs. Glaser and Korey described a Drosophilia (fruit fly) model for studying the function of CLN1. These studies will aid in understanding the biological pathways that are affected by PPT1 dysfunction

Late Infantile NCL- Dr. David Sleat reported that they are at the early stages of characterizing a mouse model for LINCL which has a mutated version of the TPP1 protease. Dr. Warburton presented a study on the role of TPP1 on degradation of certain peptides, which may be important in the brain. This may help us understand the natural substrates for the TPP1 protease. Dr. Golabek presented data indicating that TPP1 activity is highly regulated post-transcriptionally.

Juvenile NCL- Dr. MacDonald's group reported the initial characterization of a mouse that has the genetic mutation most common in JNCL; namely, a 1.02Kb deletion of the CLN3 gene. Dr. Mitchison presented evidence of necrotic cell death in the cln3-knockout mouse. Dr. Pearce's group presented data from a yeast model for Batten Disease, which suggested that CLn3 may be a transport protein. Drs. Cooper and Guerin presented data suggesting an inflammatory response and a possible blood brain barrier breach in the cln3-knockout mouse. Dr. Jalenko's group showed that the CLN3-protein is targeted to the synapse in neurons, suggesting a role for CLN3 in neurotransmission. Dr. Bennett has been working on identifying proteins that interact with CLN3 and presented findings suggesting that CLN3 interacts with proteins at the synapse. Dr. Mole's and Dr. Taschner's group have independently established nematode (worm) models for studying the function of CLN3. Dr. Mole's group introduced a yeast model for studying CLN3. Dr Pearce presented further evidence suggesting that there may be an autoimmune component to JNCL. Dr. Boustany's group presented a study that indicates a role for CLN3 in regulating cell growth and having anti-apoptotic activity.

CLN5- Dr. Peltonen's group reported preliminary characterization of a mouse that lacks the CLN5 gene. This will help identify whether there is a common theme amongst the NCLs.

CLN6- The gene defective in a variant late-infantile NCL, CLN6, was recently identified. Representatives from the groups of Dr. MacDonald and Dr. Mole presented different sub-cellular localizations for the CLN6-protein--to the mitochondria and ER, respectively. These studies are preliminary and further work will no doubt reveal the exact localization of the CLN6-protein. Dr. Palmer presented data characterizing the degeneration of sheep that have mutation of CLN6.

Research into Therapies- Dr. Boustany presented a study showing anti-apoptotic properties of Flupirtine on cultured neurons and NCL-cell lines. Dr Sands presented preliminary data showing that PPT1 protein can be introduced into the brain of the PPT1-lacking mice using a modified virus. Drs. Davidson and Crystal presented data showing that TPP1-protein can be expressed and introduced into the brain of animals using a similar viral vector gene delivery system as tha tused by Dr. Sands. Dr. Kida showed that manipulating the sequence of TPP1 can improve its delivery to cells. Dr. Katz's group showed preliminary data on delivering stem cells to the eye of a mouse model for NCL. Stem Cells Inc., presented an immunecompromised PPT1-knockout mouse in whose brain they had introduced stem cells that expressed PPT1

Update on research on Batten disease presented at BDSRA meeting 2002

Since last years BDSRA conference, much scientific research on the NCL's has been published, some of which received funding from the BDSRA. The following by disease type will be summarized in an overview and by some of the researchers themselves.

Infantile NCL- A mouse that lacks the CLN1 and bears a genetic defect that mimics this disease was generated by Dr. Sandy Hofmann, and has been further characterized by Dr. Hofmann and Dr. Jon Cooper. This is important for understanding exactly what happens the brain during the course of the disease. Dr. Sands is also researching this model with a eye on gene therapeutic strategies. Dr. Chu-LaGraff has established a drosophilia (fly) model for studying the function of CLN1.
Both Dr. Cooper, Dr. Sands and Dr. Chu-La Graff received BDSRA funding for their work.

Late Infantile NCL- Dr. Peter Lobel's group has been able to purify CLN2 (TPP1) protein from cultured cells. This is important for understanding the nature of the protein for potential protein replacement studies. Dr. Warburton has published a study on the role of TPP1 on degradation of certain peptides, which may be important in the brain. This may help us understand the natural substrates for the TPP1 protease.

Dr.Warburton was funded by the BDSRA.

Juvenile NCL- Dr. Jalenko has shown that the CLN3-protein is targeted to the synapse in neurons, suggesting a role for CLN3 in neurotransmission. Dr. Bennett has been working on identifying the specific type of cells that harbor the CLN3 protein. Dr. Mole has established a nematode (worm) model for studying the function of CLN3. Dr. Pearce published a study suggesting that there may be an autoimmune component to JNCL. Dr. Boustany published a study on the fact that CLN3 has increased expression in cancer, which may help us understand the function of CLN3.
Dr. Jalenko, Dr. Bennett, Dr. Mole and Dr. Boustany have received BDSRA funding.

CLN5- Dr. Peltonen published a study showing that CLN5 resides in the lysosome of cells. This will help identify whether there is a common theme amongst the NCL's.
Dr. Peltonen received BDSRA funding.

CLN6- The gene defective in a variant late-infantile NCL, CLN6, was identified by the groups of Dr. Wheeler and Dr. MacDonald.

CLN8- Dr. Messer has further characterized a mouse model for CLN8. Dr. Katz is exploring stem cell replacement in this same mouse model.
Dr. Katz received BDSRA funding.

General- Dr. Boustany published a study on the anti-apoptotic properties of Flupirtine. 

Yeast model for Batten's Disease

We have been using baker's yeast as a model to study JNCL. The yeast cell contains a gene designated BTN1 that is essentially the same as the human CLN3, which when defective causes Batten disease. Using yeast has many advantages, as it is simple to grow and easy to manipulate. We are studying BTN1 on the assumption that any information we gain as to what role BTN1 has in the yeast cell will be directly applicable to studying what the function of CLN3 will be.

It has been shown that CLN3 is found in the lysosome, and that Batten disease is a lysosomal storage disease due to accumulation of lipopigments in this compartment. The yeast BTN1 localizes to the yeast lysosome. We have been studying what effect an absence of BTN1 has on yeast, and in particular the yeast lysosome. We call these yeast the "Batten disease yeast". We have found that the pH, or degree of acidity, in the lysosome of "Batten disease yeast" is different. In fact, the lysosome is more acidic for a short period of time. The "Batten disease yeast" senses this abnormality and changes the expression of two other genes, HSP30 and BTN2, to correct this defect.

So what does this mean?
The fact that the lysosomal pH is decreased is very significant. If the same was the case in Batten disease, this might explain lysosomal accumulation of lipopigments as the physiology of the lysosome is altered. Also neuronal cells use acidified vesicles to transmit signals between them. A disturbance in acidity in the lysosome may affect this in some way, specifically affecting these cells. Whether or not this altered acidity occurs in Batten disease is now being followed up, and time will tell if this is part of the cause of Batten disease.

  • Summarized from an article published in a recent issue of Nature Genetics (Volume 22, pages 55-58) entitled "Action of BTN1, the yeast orthologue of the gene mutated in Batten disease" by David A Pearce, Tracy Ferea, Seth A Nosel, Biswadip Das and Fred Sherman. 

Microarray-Lay persons description

When the human genome is completed it is expected to reveal that humans are made up of 30,000-50,000 genes. What are genes ? A gene is a portion of DNA that translates into a protein. What is a protein ? A protein is one of the specific components that make us humans work…Yes, it takes 30,000-50,000 components !

Of these thousands of components not all are in use or made at the same time or in the same part of the body. Therefore it is of interest to scientists to know which of these components is made at certain times, for example in the particular organs of the body, or in response to certain stimuli like drugs. By examining which of these components is present in a certain part of the body, or which is made in response to these stimuli, scientists can put together a picture of how these components may interact with each other, and piece together how things may actually work ! It is important to understand how the body works, as without this information it is difficult to fix when something isn't working.

A new technology that is about to be exploited is Microarray technology. This technology essentially allows us to measure the abundance of each of the components or proteins in cells of the body. Most importantly it allows us to compare the abundance or "expression" of these components under different conditions. Therefore we can start to build a picture on which of these components are present in particular parts of the body and which may be produced under certain conditions. For the first time we can start to examine how all of the components, yes potentially 30,000-50,000, contribute to the workings of particular parts of the body. This will allow great strides to be made in the understanding of how we work.

How is it done?
The simplest way to think about it is to say that as each of the thousands of genes is sequenced or identified, this sequence can be stored as a tiny spot on a microscope slide. These are often called "chips". We can then use this chip to probe against, to see which gene is being expressed in our experimental paradigm. The process is very complex, but basically we take an extract from the tissue of interest and overlay it on the chip. Due to the incorporation of a colorful dye, if a particular gene is expressed the corresponding spot lights up in this color, if it is present. Also, the intensity of the color tells us how much is present. Currently there are slides available with up to 50,000 of these gene sequences on which we can probe for expression levels. Within the near future all 30,000-50,000 sequences will be available to test, once they are all identified.

Here at the Center for Aging and Developmental Biology, University of Rochester School of Medicine we are applying this technology into the understanding of the devastating childrens disorder, Batten disease. Batten disease results from lacking one particular component or protein called CLN3. We are therefore interested in seeing what happens to all the other components or proteins when one of these, CLN3, is lacking. This is very important as Batten disease is a progressive neurodegenerative disease. By revealing which other proteins have different "expression" in a normal situation as compared to lacking CLN3, we will gain valuable insight into how cells respond to the absence of one of these components. Furthermore, we will know a great deal more about the biology of the CLN3 component, that when missing results in this terrible disease. This will lead to a greater understanding of the disease. Once we know how the other 29,999-49,999 components of a cell respond to the lack of CLN3, we essentially have a foot-print for the response to lacking this component. Ultimately this foot-print may be used to assess the ability to compensate a lack of CLN3 with a therapeutic strategy.

Mouse Models for NCL's

We often hear of the importance of animal models for the study of devastating diseases such as the NCL's. It is of great importance to those studying the cause of such disorders, that they have an animal that in some way resembles the disorder that they are studying. The best characterized laboratory animal of choice for such studies is the mouse. Mice are well studied, easy to maintain and can be manipulated genetically.

What do I mean by easy to manipulate genetically?

Essentially because laboratory mice have been studied for many years we are capable modelling them to have a diseased state by altering their DNA.

What do I mean by altering their DNA?

When the human genome is completed it is expected to reveal that humans are made up of 80,000-100,000 genes. What are genes ? A gene is a portion of DNA that translates into a protein. What is a protein ? A protein is one of the specific components that make us humans work…Yes it takes 80,000-100,000 components !
In diseases such as Batten disease, individuals have an alteration in the DNA sequence that leads to either none of that particular protein being made, or that a defective version of that particular protein is made. It is the lack of this functional protein that leads to the disease. Therefore, when we know what the DNA defect is, we duplicate this DNA error in the DNA of a mouse, therefore creating the same or similar defect in the mouse. We then have an animal that we can study with the disease. Of course that sounds straight forward, but there is a lot do. Many molecular biological procedures are used to make a piece of DNA that is subsequently inserted or injected into embryonic cells of a normal mouse. You then essentially have to screen many cells and ultimately pup mice to see if you have created the desired DNA alteration. Of course once you have this alteration you need many mice to examine for evidence of a disease like state similar to what you are expecting. With luck you have a mouse that mimics the disease, and you can go on and try to elucidate what causes the disease. It can take as long as three years to get to this stage following identification of the DNA defect that causes the disease.

So what mice models exist for NCL?

Dr. Sandy Hofmann at UT Southwestern has recently generated a CLN1, or protein thiolesterase deficient mouse. This serves as a model for infantile NCL.

Dr's Peter Lobel and David Sleat at Robert Wood Johnson Medical Center and Dr. Marty Katz at the University of Missouri are in the process of making CLN2-deficient mice as a model for Late-Infantile NCL.

Dr Hannah Mitchison, University Collge London, Dr. Marty Katz, University of Missouri and Dr. Terry Lerner, Massachusetts General Hospital have independently made CLN3 deficient mice that serve as a model for Juvenile NCL. These mouse models are in fact being utilized by several other researchers thank's to the generosity in sharing by these researchers.

In addition there is a mouse model called the mnd mouse that manifests symptoms similar to Juvenile NCL. It was recently discovered by Dr. Susanna Ranta, University of Helsinki, that the DNA defect in this mouse is in the same gene as for CLN8, or Progressive Epilepsy with Mental Retardation (EPMR), which has been characterized as an NCL. This provides researchers with an additional model for the study of NCL's.

Dr. Sandy Hoffman's PPT1 knock-out mouse

Dr Sandy Hofmann's group recently reported the construction and initial characterization of mice that lack PPT1 (CLN1) which is defective in Infantile-NCL, and also PPT2 an enzyme similar to PPT1, in the Proceedings of the National Academy of Sciences (PNAS, 98, 13566-71, 2001). This publication is significant as there is now an animal model that lacks the same protein activity associated to Infantile-NCL that can be utilized to gain a better understanding of the effects of lacking PPT1, and therefore further our understanding of Infantile-NCL. Dr. Hofmann also presented some of her finding to the BDSRA conference in Chicago, 2001.

The Infantile-NCL mouse, or cln1-knockout mouse, was shown to have accumulation of fluorescent storage material in the brain at a very young age. This storage is similar to storage seen in the NCL's, and therefore demonstrates that this cln1-knockout mouse behaves in a similar manner to the Infantile-NCL disease process. This is extremely important as further characterization of this animal will help to pin-point specific effects, and perhaps the earliest effects of lacking the PPT1 enzyme. It is also important as it can be assumed that at the biochemical level the cln1-knockout mouse may have the same defect as seen in Infantile-NCL. This is important as future studies will no doubt utilize this mouse model for screening potential therapeutic agents, and the fact that this mouse has a disease similar to Infantile-NCL will provide valuable markers to assess the efficacy of any treatment. Interestingly the study also reported that cln1-knockout mice exhibited prominent myoclonic jerking and seizures. Again this is significant, as this represents a clear effect that is associated to NCL-diseases as a whole, and further study of this phenomenon in the mice will aid a better understanding of the seizures associated to these disorders. 

Lysosomal ceroid depletion by drugs: Therapeutic implications for a hereditary neurodegenerative disease of childhood. by Z Zhang, J Butler, S Levin, K Wisnieski, S Brooks and A Muhkerjee. April 2000, Nature Medicine.

The above article will appear in Nature Medicine in April 2000. This is a truly exciting publication which may have profound implications on the potential to treat Infantile NCL, and will help us understand all types of NCL.

In summary these researchers have recognized a particular function of the PPT1 protein, which we know is defective in Infantile NCL, and attempted to by-pass this function. This is a powerful approach considering we know that Infantile NCL lacks this PPT1 function, as these researchers are trying to replace the defect with a drug. The PPT1 protein hydrolyzes thioester bonds in certain proteins, which it is believed are then degraded. It is therefore thought that by not being able to hydrolyze these bonds that these proteins are not degraded, leading to their accumulation in the lysosome, resulting in the lysosomal storage disease, Infantile NCL. The authors recognized that the thioester bonds are susceptible to "nucleophilic attack" which may break these bonds, which would be the same as hydrolyzing them. This basically means that certain compounds may be able to attack or break the bond similar to the hydrolysis brought about by normal PPT1. Therefore, if you don't have PPT1, perhaps this type of drug may be able to do this.

Cutting a long story short the authors have identified drugs, one called phosphocysteamine in particular, with the ability to hydrolyze or break thioester bonds in compounds made to mimic those that accumulate in Infantile NCL in the test tube.

Will this help break the thioester bonds of proteins accumulating in Infantile NCL?
The authors cultured a type of blood cell from individuals with Infantile NCL, and have shown that the accumulation of deposits in the lysosome, become depleted. Therefore if the accumulating material in the lysosome is a primary cause of the disease, then this has been somewhat decreased. Furthermore the drug in question crosses the blood brain barrier which is extremely important, as Infantile NCL is neurodegenerative, and any potential therapy must be able to access the brain where so much harm is occurring.

Will these alleviate Infantile NCL?
There is certainly a potential as the results are extremely promising, so much so that a small clinical trial is to go ahead to test the efficacy of this approach for treatment of Infantile NCL. We must remember though, there is still so much to be learned about how the brain works, and also how the NCL's cause such devastation to the brain. While this study provides a potential breakthrough, taking results from the test tube and cultured cells to a human being is a big step. However, it's a step in the right direction, a possible therapy.

Lysosomal Storage Diseases

Lysosomal Storage diseases are inherited genetic defects which result in protein deficiency. The absence of the protein prevents the lysosome in the cells of the body from performing its natural recycling function, and various materials are inappropriately stored in the cell. This leads to a variety of progressive physical and/or mental deterioration over time. Some patients survive into adulthood, but others with more severe symptoms die in their teens or earlier.

There are currently close to 50 conditions which come within the category of Lysosomal Storage diseases. Examples of these types of disorders are Krabbe disease, Tay-Sach's disease, Sandhoff disease and Batten disease.

There are many types of protein defects that might result in a lysosomal storage disease, some examples being: First, an absence of a protein that is required for a specific function will create a lesion in a biochemical pathway such that this pathway is no longer completed. This would result in an inability to complete a biochemical process that is presumably necessary. Second, an incomplete biochemical pathway could lead to the accumulation of the protein's substrate, which could subsequently interfere with the lysosomal environment so as to disturb the activity of other lysosomal proteins. Third, a loss of a protein may not directly lead to an accumulation of this enzymes substrate but could lead to the accumulation of other proteins through an alteration in the lysosomal environment precipitated by the loss of this protein. Fourth, if the protein in question is involved in a pathway where it has multiple substrates, such as processing or protein modification for example, then the activity or function of several other proteins may not be controlled due to their not being activated, or deactivated.

The neuronal ceroid lipofuscinoses, or Batten disease, are a group of pediatric diseases that result in degeneration of the brain. These devastating disorders are characterized clinically by vision loss, seizures, mental retardation and premature death. Pathologically these disorders are characterized by accumulation of storage material in the lysosome of cells. These disorders result from inheritance of defects in the code of life, DNA, that make proteins called CLN-proteins. Different types of Batten disease are associated to defects in different CLN-proteins. Several researchers worldwide are working on trying to understand the function of these CLN-proteins. This will enable researchers to better understand what goes wrong when there is a defect in one of these CLN-proteins, with the ultimate aim of trying to correct this defect.