Basic Research on the Neuropathology of CLN8; Variant Late-Infantile Batten Disease

1. BASIC RESEARCH ON THE NEUROPATHOLOGY OF
cln8; Variant Infantile Batten Disease
MSc Mervi Kuronen, Prof. Anna-Elina Lehesjoki and Dr. Outi Kopra, Folkhälsan Institute of Genetics, University of Helsinki, Finland, outi.koprai@helsinki.fi
INTRODUCTION
Human and mouse CLN8 genes and
proteins are highly homologous.
Cln8 mutant mouse is a naturally
occurring mouse model for CLN8
deficiency mimicking the human
disease well. We utilize this mouse
model in order to understand the
mechanisms of neuronal dysfunction
in CLN8-related diseases and to shed
light on the molecular networks to
which CLN8 is connected. We utilize
a wide range of molecular and cell
biological methods, e.g. genome-
wide expression profiling, lipid
profiling, neuronal stem cells,
primary neuron and glial cell cultures
as well as mouse brain MRI and
stereological analysis methods.
In the cell, the CLN8 protein
works in the endoplasmic
reticulum, the site for the
buildup of cellular components
including proteins and lipids
(Lonka et al. 2000, 2004).
2
KEY FINDINGS
7
8
WHAT THIS COULD
MEAN FOR
THERAPY
Neuron loss is apparent in the
brains of Cln8 mutant mice.
Oligodendrocytes are one of the
cell types in the brain, and we
carried on analysis on the rest of
the cell types in Cln8 mutant
mouse brain.
According to previous work with
Cln8 mutant mice, their light-
responsive neurons in the eye
are lost at an early age (Chang
et al. 1994).
The brain areas involved in the
processing of visual information
are intact until very late in the
Cln8 mutant mouse (Kuronen et
al. in press).
Astrocytes and microglia,
cells that are responsible
for brain’s response to
injury, are activated in
CLN8 mutant mouse brain
(Kuronen et al. in press).
In microscopic analysis of the
mouse brains, slight reduction in
brain myelin was observed
before the mouse shows clear
NCL symptoms. Cultured
oligodendrocytes that generate
the myelin membrane, showed
slightly delayed maturation
(Kuronen et al. in press).
In the Cln8 mutant mouse, we
found differences in the amount
and production of brain lipids
(Kuronen et al. in press)
Main collaborators:
Prof. Jonathan D. Cooper, King’s
College London, UK
Dr. Anu Jalanko, National Institute
for Health and Welfare (THL) ,
Finland
Prof. Pentti Somerharju, University
of Helsinki, Finland
Dr. Matthias Eckhardt, University of
Bonn, Germany
Acknowledgements:
Minnamari Talvitie, Otto Manninen,
Martin Hermansson, Isabell Zech,
Ulla Lahtinen,
Funding:
EMBO Short-Term Fellowship
Orion-Farmos Research Foundation
Paulo Foundation
Finnish Concordia Fund
Finnish Cultural Foundation
Folkhälsan
Modified from
PhD thesis of
Liina Lonka, 2004
CTSD
1
3
4
5
astrocytes
microglia
6
neurons
9 Conclusions
Changes in oligodendrocytes, astrocytes and microglia are seen
before the neuron loss is observed in Cln8 mutant mice. Neuron
loss is progressive in the retina and brain of Cln8 mutant mice.
However, visual brain regions are fairly intact.
Not only neurons but also other
cell types of the brains need to
be considered when developing
therapies for CLN8-related
Batten disease. However,
developing such therapies will
most likely require a far better
understanding on the normal
function of the CLN8 protein.
Retinal cell loss occurs very
early compared to the loss of
visual pathway neurons in the
brain. Gene therapy targeting
retina could be a potential
therapeutic strategy. However,
preventing the retinal cell loss
would need to be started early.