TY - JOUR
T1 - A mouse mutant deficient in both neuronal ceroid lipofuscinosis-associated proteins CLN3 and TPP1
AU - Sleat, David E.
AU - Banach-Petrosky, Whitney
AU - Larrimore, Katherine E.
AU - Nemtsova, Yuliya
AU - Wiseman, Jennifer A.
AU - Najafi, Allison
AU - Johnson, Dymonn
AU - Poole, Timothy A.
AU - Takahashi, Keigo
AU - Cooper, Jonathan D.
AU - Lobel, Peter
N1 - Publisher Copyright:
© 2023 The Authors. Journal of Inherited Metabolic Disease published by John Wiley & Sons Ltd on behalf of SSIEM.
PY - 2023/7
Y1 - 2023/7
N2 - Late-infantile neuronal ceroid lipofuscinosis (LINCL) and juvenile neuronal ceroid lipofuscinosis (JNCL) are inherited neurodegenerative diseases caused by mutations in the genes encoding lysosomal proteins tripeptidyl peptidase 1 (TPP1) and CLN3 protein, respectively. TPP1 is well-understood and, aided by animal models that accurately recapitulate the human disease, enzyme replacement therapy has been approved and other promising therapies are emerging. In contrast, there are no effective treatments for JNCL, partly because the function of the CLN3 protein remains unknown but also because animal models have attenuated disease and lack robust survival phenotypes. Mouse models for LINCL and JNCL, with mutations in Tpp1 and Cln3, respectively, have been thoroughly characterized but the phenotype of a double Cln3/Tpp1 mutant remains unknown. We created this double mutant and find that its phenotype is essentially indistinguishable from the single Tpp1−/− mutant in terms of survival and brain pathology. Analysis of brain proteomic changes in the single Tpp1−/− and double Cln3−/−;Tpp1−/− mutants indicates largely overlapping sets of altered proteins and reinforces earlier studies that highlight GPNMB, LYZ2, and SERPINA3 as promising biomarker candidates in LINCL while several lysosomal proteins including SMPD1 and NPC1 appear to be altered in the Cln3−/− animals. An unexpected finding was that Tpp1 heterozygosity significantly decreased lifespan of the Cln3−/− mouse. The truncated survival of this mouse model makes it potentially useful in developing therapies for JNCL using survival as an endpoint. In addition, this model may also provide insights into CLN3 protein function and its potential functional interactions with TPP1.
AB - Late-infantile neuronal ceroid lipofuscinosis (LINCL) and juvenile neuronal ceroid lipofuscinosis (JNCL) are inherited neurodegenerative diseases caused by mutations in the genes encoding lysosomal proteins tripeptidyl peptidase 1 (TPP1) and CLN3 protein, respectively. TPP1 is well-understood and, aided by animal models that accurately recapitulate the human disease, enzyme replacement therapy has been approved and other promising therapies are emerging. In contrast, there are no effective treatments for JNCL, partly because the function of the CLN3 protein remains unknown but also because animal models have attenuated disease and lack robust survival phenotypes. Mouse models for LINCL and JNCL, with mutations in Tpp1 and Cln3, respectively, have been thoroughly characterized but the phenotype of a double Cln3/Tpp1 mutant remains unknown. We created this double mutant and find that its phenotype is essentially indistinguishable from the single Tpp1−/− mutant in terms of survival and brain pathology. Analysis of brain proteomic changes in the single Tpp1−/− and double Cln3−/−;Tpp1−/− mutants indicates largely overlapping sets of altered proteins and reinforces earlier studies that highlight GPNMB, LYZ2, and SERPINA3 as promising biomarker candidates in LINCL while several lysosomal proteins including SMPD1 and NPC1 appear to be altered in the Cln3−/− animals. An unexpected finding was that Tpp1 heterozygosity significantly decreased lifespan of the Cln3−/− mouse. The truncated survival of this mouse model makes it potentially useful in developing therapies for JNCL using survival as an endpoint. In addition, this model may also provide insights into CLN3 protein function and its potential functional interactions with TPP1.
KW - CLN3 protein
KW - mouse
KW - neuronal ceroid lipofuscinosis
KW - tripeptidyl peptidase 1
UR - http://www.scopus.com/inward/record.url?scp=85156173684&partnerID=8YFLogxK
U2 - 10.1002/jimd.12619
DO - 10.1002/jimd.12619
M3 - Article
C2 - 37078466
AN - SCOPUS:85156173684
SN - 0141-8955
VL - 46
SP - 720
EP - 734
JO - Journal of Inherited Metabolic Disease
JF - Journal of Inherited Metabolic Disease
IS - 4
ER -