This document discusses lysosomal biomarkers for neuronal ceroid lipofuscinosis (NCL), a group of rare genetic disorders. The author identifies two key points: 1) Lysosomal changes can provide a rapid method to determine if treatments for NCLs are effective, as these diseases progress slowly and standard clinical methods make efficacy difficult to evaluate. 2) Studying lysosomal changes may provide insights into the functions of deficient NCL proteins and why their deficiency causes disease. The author has identified secondary alterations in lysosomal proteins in mouse models of three NCL types (CLN1, CLN2, CLN3) using mass spectrometry and aims to validate potential biomarkers in cerebrospinal fluid.

1. Lysosomal Biomarkers in Neuronal Ceroid Lipofuscinosis
David Sleat and Peter Lobel, CABM and Rutgers University, Piscataway, NJ, 08854, sleat@cabm.rutgers.edu
KEY PROJECTS
WHAT THIS MEANS FOR THERAPY
1. Given that these are relatively slowly progressing diseases, the efficacy of
treatment can be difficult to evaluate using standard clinical methods.
Lysosomal changes that respond to disease at the cellular level can provide a
rapid method to tell whether treatment may be effective.
2. Lysosomal changes may provide important clues towards the functions of
the NCL proteins and shed light on why their deficiency results in disease.
This is especially important for JNCL where the function of the CLN3 protein
remains unclear.
Acknowledgements:
We gratefully acknowledge the support of the Batten Disease Support and Research Association, Beyond Batten Disease Foundation and Hope 4 Bridget.
This work has provided a platform for the recent NIH award to DES:
R21 NS088786-01A1 Biomarker discovery for juvenile neuronal ceroid lipofuscinosis
INTRODUCTION
A number of clinical trials have been initiated
for the neuronal ceroid lipofuscinoses (NCLs)
and we anticipate more in the near future as
methods for enzyme replacement therapy to
the central nervous system are developed.
Key to the success of these trials will be the
ability to monitor the short-term progression
of disease. This will allow for titration of
treatment regimens for optimal response and
will provide clinical surrogates to accelerate
approval of effective therapies and facilitate
the timely termination of failed trials. The
overall goal of this proposal is to identify
sensitive and responsive biomarkers for
disease progression in infantile (CLN1, Ppt1),
late-infantile (CLN2, Tpp1) and juvenile NCL
(CLN3, Cln3).
1
CLN1 mouse, late stage
C
athepsin
D
H
exosam
inidase
B
PPT1
A
cid
lipase
C
athepsin
C
TPP1
10
100
1000
10000
CLN1 knockout
wild-type
log10Proteinamount
2
CLN2 mouse, late stage
TPP1Cathepsin
S
Hexosam
inidase
BCathepsin
H
Serine
carboxypeptidase
1
Phospholipase
D3
10
100
1000
CLN2 knockout
wild-type
log10Proteinamount
8
3
CLN3 mouse, late stage
A
lpha
fucosidase
A
cid
sphingom
yelinase
1A
cid
lipase
TPP1
C
LN
5
N
-acetylgalactosam
ine
6-sulfatase
10
100
1000
CLN3 knockout
wild-type
log10Proteinamount
Our approach is to use mass spectrometric and
biochemical methods to identify secondary
alterations in lysosomal proteins in the brains
of mouse models for these diseases and to
validate their expression in cerebrospinal fluid.
We have now completed mass spectrometry
studies on CLN1, CLN2, and CLN3 mice at both
early and late-stage disease.
Figs. 1-3. Lysosomal proteins were purified from the brains of late-stage disease CLN1, CLN2
and CLN3 mice. The 6 lysosomal proteins that exhibit the greatest alteration in expression are
shown.