1. The document summarizes research on CLN7 disease, which is caused by mutations in the CLN7 gene encoding a lysosomal membrane protein.
2. A mouse model of CLN7 disease was generated that recapitulates some neuropathological features seen in human patients, including accumulation of autofluorescent storage material in the brain.
3. The researchers aim to identify the pathomechanisms of CLN7 disease, develop biomarkers, analyze the function of the CLN7 protein, and understand how mutations impact its localization and function to inform potential therapies.
The DNA is the basis of our genetic code, we could almost say that we are all made of DNA; therefore all studies are trying to understand this important part of us. Over time, they have discovered that DNA contains all the instructions that control the development and function of every cell in our body. What we know is that the DNA is able to divide itself, replicating and giving two daughter strands which contain exactly the same information from DNA mother. Then these are transcribed into RNA and finally translated into proteins, this is what we know as the central dogma of genetic information.
Although nature seems to be so perfect there are some cases where this beautiful process fails, and this is where certain diseases are originated and can cause multiple problems. Scientists are increasingly closer to find answers and perhaps their studies can help in the future.
New treatments for Alzheimer's, autism and depression, could be developed.
It could be the starting point for future researches on genes involved in these diseases.
Knowing which genes are involved, people who are not sick yet, might prevent some disease.
These findings help us understand how diseases work and where they come from.
Encourages doctors and scientists to find more about this genes, to achieve excellent results that could benefit many people.
It gives us hope and determination to achieve incredible things in this medicine area; we know that humans are able to find and develop things that we have never imagine.
We know that DNA is the basis of everything, thus if we understand certain parts of it and what is involved on it, we would be able to control many diseases that affects society nowadays.
With these discovery we would be contributing to industry and researches.
new hypothesis could change the way we see things, and would make researchers focused in other cell structures such as ribosomes.
The cause of some diseases might not be in the DNA, but on the malfunctioning of ribosomes, in that way we must look for the real cause of them.
In my opinion this is a big step for medicine, although there is not yet a certain result, and they have to investigate more about the genes, they have a great part of the investigation that can guide them to find the solution to multiple diseases. I think that this kind of researches benefit a lot our society, because they are trying to improve people’s life, by finding the different places of de brain where illnesses are originated. With this project we can start thinking on possible cures and treatments for Alzheimer's, autism, depression and other disorders.
It's good to start investigating on other cellular structures that may be quite involved in the most complex processes of DNA. Scientists may have never wondered what real role of ribosome is. Thinking about new hypotheses and that maybe the ribosome is the central point is crazy but good, because they could be right.
Marc Dhenain Alzforum Webinar - Dec 7, 2016Alzforum
Presentation made at the Alzforum's live webinar of December 5, 2016, titled "Is Alzheimer’s Disease a Uniquely Human Disorder?" - review additional information and recording at www.alzforum.org/
Presentation made by Dr. Cliff Brangwynne on October 30, 2015 at the Alzforum-hosted live webinar titled "Fluid Business: Could “Liquid” Protein Herald Neurodegeneration?"
More information and the recording of the session available at http://www.alzforum.org/webinars/fluid-business-could-liquid-protein-herald-neurodegeneration
The DNA is the basis of our genetic code, we could almost say that we are all made of DNA; therefore all studies are trying to understand this important part of us. Over time, they have discovered that DNA contains all the instructions that control the development and function of every cell in our body. What we know is that the DNA is able to divide itself, replicating and giving two daughter strands which contain exactly the same information from DNA mother. Then these are transcribed into RNA and finally translated into proteins, this is what we know as the central dogma of genetic information.
Although nature seems to be so perfect there are some cases where this beautiful process fails, and this is where certain diseases are originated and can cause multiple problems. Scientists are increasingly closer to find answers and perhaps their studies can help in the future.
New treatments for Alzheimer's, autism and depression, could be developed.
It could be the starting point for future researches on genes involved in these diseases.
Knowing which genes are involved, people who are not sick yet, might prevent some disease.
These findings help us understand how diseases work and where they come from.
Encourages doctors and scientists to find more about this genes, to achieve excellent results that could benefit many people.
It gives us hope and determination to achieve incredible things in this medicine area; we know that humans are able to find and develop things that we have never imagine.
We know that DNA is the basis of everything, thus if we understand certain parts of it and what is involved on it, we would be able to control many diseases that affects society nowadays.
With these discovery we would be contributing to industry and researches.
new hypothesis could change the way we see things, and would make researchers focused in other cell structures such as ribosomes.
The cause of some diseases might not be in the DNA, but on the malfunctioning of ribosomes, in that way we must look for the real cause of them.
In my opinion this is a big step for medicine, although there is not yet a certain result, and they have to investigate more about the genes, they have a great part of the investigation that can guide them to find the solution to multiple diseases. I think that this kind of researches benefit a lot our society, because they are trying to improve people’s life, by finding the different places of de brain where illnesses are originated. With this project we can start thinking on possible cures and treatments for Alzheimer's, autism, depression and other disorders.
It's good to start investigating on other cellular structures that may be quite involved in the most complex processes of DNA. Scientists may have never wondered what real role of ribosome is. Thinking about new hypotheses and that maybe the ribosome is the central point is crazy but good, because they could be right.
Marc Dhenain Alzforum Webinar - Dec 7, 2016Alzforum
Presentation made at the Alzforum's live webinar of December 5, 2016, titled "Is Alzheimer’s Disease a Uniquely Human Disorder?" - review additional information and recording at www.alzforum.org/
Presentation made by Dr. Cliff Brangwynne on October 30, 2015 at the Alzforum-hosted live webinar titled "Fluid Business: Could “Liquid” Protein Herald Neurodegeneration?"
More information and the recording of the session available at http://www.alzforum.org/webinars/fluid-business-could-liquid-protein-herald-neurodegeneration
Female mammals achieve dosage compensation by inactivating one of their two X chromosomes
during development, a process entirely dependent on Xist, an X-linked long noncoding
RNA (lncRNA). At the onset of X chromosome inactivation (XCI), Xist is up-regulated
and spreads along the future inactive X chromosome. Contextually, it recruits repressive
histone and DNA modifiers that transcriptionally silence the X chromosome. Xist regulation is
tightly coupled to differentiation and its expression is under the control of both pluripotency
and epigenetic factors. Recent evidence has suggested that chromatin remodelers accumulate
at the X Inactivation Center (XIC) and here we demonstrate a new role for Chd8 in Xist
regulation in differentiating ES cells, linked to its control and prevention of spurious
transcription factor interactions occurring within Xist regulatory regions. Our findings have a
broader relevance, in the context of complex, developmentally-regulated gene expression.
CXCR7 is induced by hypoxia and mediates glioma cell migration towards SDF-1a...Enrique Moreno Gonzalez
Glioblastomas, the most common and malignant brain tumors of the central nervous system, exhibit high invasive capacity, which hinders effective therapy. Therefore, intense efforts aimed at improved therapeutics are ongoing to delineate the molecular mechanisms governing glioma cell migration and invasion.
1. Variant Infantile Batten Disease
Laura Brandenstein 1, Markus Damme 4, Susanne Fehr 2, M. Schweizer 2, U. Bartsch 3, Irm Hermans-Borgmeyer 2, and Stephan Storch 1
1 Children’s Hospital Biochemistry, 2 Center for Molecular Neurobiology Hamburg, 3 Department of Ophthalmology , University Medical Center Hamburg-Eppendorf,
Hamburg, Germany, 20246; 4 Department of Biochemistry, University of Kiel, 24118 Kiel, Germany. Contact: storch@uke.de
INTRODUCTION
CLN7 disease , variant late infantile phenotype, is
caused by mutations in the CLN7 gene which
encodes a lysosomal membrane protein of unknown
function. Based on its localization and sequence
homologies with the major facilitator superfamily
CLN7 is predicted to be a lysosomal transporter.
Mutations/sequence variations in the CLN7 gene (X)
lead to the biosynthesis of an altered CLN7 protein
with substitutions of single amino acids (;; ■; *) or
the loss of many amino acids. The altered CLN7
proteins are expressed in all cells and tissues of the
organism, also in the brain.
KEY PROJECTS
WHAT THIS MEANS
FOR THERAPY
Biochemistry
Cell Biology
Molecular Biology
Immunohisto
chemistry
Methods applied in the laboratory to analyze cell
and mouse models of CLN7 disease.
Aims
1. Identification of pathomechanisms
in a mouse model for CLN7 disease
2. Identification of specific bio-markers
for CLN7 disease
3. Analyzing the physiological function
of the CLN7 membrane protein
4. Impact of pathogenic mutations on
localization and function of CLN7
Our expertise
Mass Spectrometry
Live time
imaging
Confocal Laser
Scan Microscopy
I. Analysis of intracellular trafficking
of the CLN7 protein to lysosomes
Lysosomal membrane proteins carry a lysosomal
targeting code (LTC) code in their amino acid
sequence which directs them from their site of
synthesis to their final destination, the lysosome.
We could identify two key residues in the CLN7
protein sequence which constitute the LTC for
specific delivery to lysosomes (Steenhuis et al.,
2010). The correct intracellular transport of CLN7
to lysosomes is important for its function.
CLN7 with altered lysosomal targeting code (LTC) is
mislocalized at the cell surface (A; green, CS),
whereas wild-type CLN7 reaches lysosomes (B;
yellow, LYS).
II. Analysis of spatial and temporal
expression of CLN7 in the brain.
Since CLN7 is not highly expressed in the brain
and specific antibodies detecting endogenous
CLN7 protein are lacking we use a lacZ-reporter
gene mouse model for expression analyses.
III. Analysis of a mouse model for
CLN7 disease
Histochemical detection of b-galactosidase activity
reveals high CLN7 expression in two regions of the
brain of adult mice, the hippocampus (HC, A and B)
and the cortex (Ctx, A and C).
We have generated a mouse model for CLN7
disease which recapitulates partially the
neuropathological changes observed in human
CLN7 patients (Damme et al., 2014). Analyses
revealed (A) accumulation of autofluorescent
material in the brain of CLN7 mice which was not
observed in wild type mice , (B) accumulation of
storage material (db) in neurons shown by electron
microscopy, (C) increased amounts of subunit c of
mitochondrial ATP synthase (brown, SCMAS) shown
by immunhistochemistry and (D) localization of
SCMAS (green) in neuronal cells (red) of the
cerebellum.
In the CLN7 mouse model early degeneration of
photoreceptors in the eyes was observed.
Open questions:
Which pathomechanisms contribute to
progression of CLN7 disease (impaired
autophagy, lysosomal dysfunction, altered
Ca2+ homöostasis) ?
What is/are the substrate (s) of the putative
lysosomal transporter CLN7 ?
The function of CLN7 is unknown. One goal of our
research is to analyze its putative transporter function
and to identify its substrate (s). This knowledge is
required as a basis for designing and testing experimental
therapies.
Acknowledgements:
We thank Prof. T. Braulke, Prof. A. Kohlschütter and the
research group at the UKE for continuous scientific
support of the projects. Financial support from the
German Research Foundation (DFG), from the Research
Training Group 1459 (GRK1459) and BDSRA is
acknowledged.
*
*
A
B
*
*
A) Schematic representation of the CLN7 protein.
CLN7 is a membrane protein of unknown function
localized mainly inside cells in lysosomal
membranes.
B) GFP-CLN7 (green) co-localizes with LAMP-2
(red) in lysosomes (yellow). * denote GFP-CLN7
expressing cells.
Recent publications:
Steenhuis, P., Herder, S., Gelis, S., Braulke, T., Storch, S. (2010) Lysosomal targeting of the CLN7 membrane protein and transport via the plasma membrane require a dileucine motif. Traffic, 11:987-1000.
Steenhuis, P., Froemming, J., Reinheckel, T., Storch, S. (2012) Proteolytic cleavage of the disease-related lysosomal membrane protein CLN7. Biochim. Biophys. Acta, 822:1617-1628.
Damme, M., Brandenstein, L., Fehr, S., Jankowiak, A., Bartsch, U., Hermans-Borgmeyer, I., Storch, S. (2014) Gene disruption of Mfsd8 in mice provides the first animal model for CLN7 disease. Neurobio. Dis. 65:12-24.