Characterization of Endopeptidase Activity of Tripeptidyl Peptidase-I/CLN2 Protein Which Is Deficient in Classical Late Infantile Neuronal Ceroid Lipofuscinosis

2000 ◽  
Vol 268 (3) ◽  
pp. 904-908 ◽  
Author(s):  
Junji Ezaki ◽  
Mitsue Takeda-Ezaki ◽  
Kohei Oda ◽  
Eiki Kominami
Keyword(s):  
Neuronal Ceroid Lipofuscinosis ◽  
Infantile Neuronal Ceroid Lipofuscinosis ◽  
Ceroid Lipofuscinosis ◽  
Tripeptidyl Peptidase ◽  
Endopeptidase Activity

scholarly journals Dipeptidyl-peptidase I does not functionally compensate for the loss of tripeptidyl-peptidase I in the neurodegenerative disease late-infantile neuronal ceroid lipofuscinosis

2008 ◽  
Vol 415 (2) ◽  
pp. 225-232 ◽  
Author(s):  
Kwi-Hye Kim ◽  
Christine T. Pham ◽  
David E. Sleat ◽  
Peter Lobel
Keyword(s):  
Neurodegenerative Disease ◽  
Neuronal Ceroid Lipofuscinosis ◽  
Dipeptidyl Peptidase ◽  
The Body ◽  
Peripheral Tissues ◽  
Infantile Neuronal Ceroid Lipofuscinosis ◽  
Lysosomal Protease ◽  
Ceroid Lipofuscinosis ◽  
Tripeptidyl Peptidase ◽  
The Brain

LINCL (late-infantile neuronal ceroid lipofuscinosis) is a fatal neurodegenerative disease resulting from mutations in the gene encoding the lysosomal protease TPPI (tripeptidyl-peptidase I). TPPI is expressed ubiquitously throughout the body but disease appears restricted to the brain. One explanation for the absence of peripheral pathology is that in tissues other than brain, other proteases may compensate for the loss of TPPI. One such candidate is another lysosomal aminopeptidase, DPPI (dipeptidyl-peptidase I), which appears to have overlapping substrate specificity with TPPI and is expressed at relatively low levels in brain. Compensation for the loss of TPPI by DPPI may have therapeutic implications for LINCL and, in the present study, we have investigated this possibility using mouse genetic models. Our rationale was that if DPPI could compensate for the loss of TPPI in peripheral tissues, then its absence should exacerbate disease in an LINCL mouse model but, conversely, increased CNS (central nervous system) expression of DPPI should ameliorate disease. By comparing TPPI and DPPI single mutants with a double mutant lacking both proteases, we found that the loss of DPPI had no effect on accumulation of storage material, disease severity or lifespan of the LINCL mouse. Transgenic expression of DPPI resulted in a ∼2-fold increase in DPPI activity in the brain, but this had no significant effect on survival of the LINCL mouse. These results together indicate that DPPI cannot functionally compensate for the loss of TPPI. Therapeutic approaches to increase neuronal expression of DPPI are therefore unlikely to be effective for treatment of LINCL.

Sign in / Sign up

Export Citation Format

Share Document