Disease relevance of TPP1

• Three typical forms, the infantile (INCL), late-infantile (LINCL), and juvenile (JNCL), are among the most common childhood-onset neurodegenerative disorders [1].
• Late-infantile neuronal ceroid lipofuscinosis (CLN2), previously known as the late-infantile form of Batten disease, is a lysosomal storage disease which results from mutations in the gene that codes for tripeptidyl peptidase-I (TPP-I) [2].
• To understand the enzymological properties of the protein, we purified and characterized C-terminal hexahistidine-tagged human CLN2p/tripeptidyl-peptidase I produced from insect cells transfected with a baculovirus vector [3].
• The CLN2 gene mutated in the fatal hereditary neurodegenerative disease late infantile neuronal ceroid lipofuscinosis encodes a lysosomal protease with tripeptidyl-peptidase I activity [3].
• Except for 1 case, clinical findings were homogeneous in LINCL, characterized by refractive epilepsy, mental regression and progressive deterioration, ataxia, myoclonia, and visual loss [4].
• The inhibitory properties of TPP I prosegment with the introduced classic late infantile neuronal ceroid lipofuscinosis disease-associated mutation, G77R, significantly differed from those revealed by wild-type prosegment in both the mechanism of interaction and the inhibitory rate [5].
• 28 disease-causing missense mutations are analyzed in the light of the TPP1 structure providing insight into the molecular basis of late infantile neuronal ceroid lipofuscinosis [6].
• These data provide new insights into TPP1 function and represent a valuable resource for constructing improved TPP1 variants for treatment of late infantile neuronal ceroid lipofuscinosis [7].

Psychiatry related information on TPP1

• With research progress, four additional forms have been recognized: 5) Finnish, 6) Gypsy/Indian, and 7) Turkish variants of LINCL and 8) northern epilepsy, also known as progressive epilepsy with mental retardation [8].
• This study describes the phenotype/genotype analysis of 159 probands with neuronal ceroid lipofuscinosis (37 CLN1, 72 classic CLN2, 10 variant LINCL, and 40 CLN3) collected at the New York State Institute for Basic Research in Developmental Disabilities (IBR) [9].
• Comparison of aminopeptidase, dipeptidyl aminopeptidase and tripeptidyl aminopeptidase activities in brain tissue from normal and Alzheimer's disease cases [10].

High impact information on TPP1

• They are interconnected by three additional shelterin proteins, TIN2, TPP1, and Rap1, forming a complex that allows cells to distinguish telomeres from sites of DNA damage [11].
• Conversely, knocking down TPP1 reduced the ability of endogenous TRF1 to associate with the TRF2 complex [12].
• In 14 patients, CLN2 protease activities were normal and no mutations were identified, suggesting other forms of NCL [13].
• The late-infantile form of neuronal ceroid lipofuscinosis (LINCL) is a progressive and ultimately fatal neurodegenerative disease of childhood [13].
• The defective gene in this hereditary disorder, CLN2, encodes a recently identified lysosomal pepstatin-insensitive acid protease [13].

Chemical compound and disease context of TPP1

• Classical late-infantile neuronal ceroid lipofuscinosis (LINCL), a progressive and fatal neurodegenerative disease of childhood, results from mutations in a gene (CLN2) that encodes a protein with significant sequence similarity to prokaryotic pepstatin-insensitive acid proteases [14].
• In the current study, using subtraction cloning for genes that are differentially expressed in metastasis, the authors isolated a clone encoding ceroid lipofuscinosis, neuronal 2 (CLN2), which is a lysosomal serine protease defective in neuronal ceroid lipofuscinosis (NCL) [15].
• Tripeptidyl peptidase I (TTP-I), also known as CLN2, a member of the family of serine-carboxyl proteinases (S53), plays a crucial role in lysosomal protein degradation and a deficiency in this enzyme leads to fatal neurodegenerative disease [16].

Biological context of TPP1

• A frame shift mutation in canine TPP1 (the ortholog of human CLN2) in a juvenile Dachshund with neuronal ceroid lipofuscinosis [17].
• A common region of homozygosity was also observed on chromosome 15q21-23 in the two variant LINCL families [18].
• A genome search was initiated using a homozygosity mapping strategy in five classical LINCL and two variant LINCL consanguineous families [18].
• Two first trimester pregnancies at risk for LINCL were analysed and a clear TPP-I deficiency was detected in both cases (TPP-I activity 3-4%) [19].
• Conversely, blocking CLN3 or CLN2 expression in hNT neurons with adenoviral antisense-CLN3 or antisense-CLN2-AAV2 constructs causes apoptosis [20].

Anatomical context of TPP1

• To date, three of the four proteins whose subcellular localization has been confirmed, namely PPT1, TPP1, and CLN3, reside in the lysosome [21].
• In fibroblasts from LINCL patients we found a similar deficiency of tripeptidyl-peptidase I activity (TPP-I), with < 2% activity in 16 patients [19].
• Palmitoyl-protein thioesterase or TPP-I activities were measured in chorionic villi and cultured chorionic villi cells in three pregnancies [22].
• The importance of electron microscopic (EM) examination of blood lymphocytes in these forms is outlined, particularly when combined with molecular analysis of the CLN2 or CLN3 genes, respectively [23].
• We also show that TPP-I immunoreactivity is increased in the brain tissue of CLN1 and CLN3 subjects, stronger in glial cells and macrophages than neurons [24].

Associations of TPP1 with chemical compounds

• CLN1 and CLN2 are caused by mutations in genes that encodes lysosomal enzymes,palmitoyl protein thioesterase and pepstatin-insensitive proteinase, respectively [25].
• The genes CLN1 and CLN2 encode lysosomal palmitoyl protein thioesterase and tripeptidyl peptidase 1 [8].
• Flupirtine also prevents the death of CLN3- and CLN2-deficient postmitotic hNT neurons at the mitochondrial level [20].
• A specific inhibitor of TPP-I is able to abolish neuromedin B degradation in a variety of cell types [2].
• These data indicate that the CLN2 gene product is synthesized as an inactive proenzyme that is autocatalytically converted to an active serine protease [3].

Physical interactions of TPP1

• The major storage component in CLN2 is the subunit c of mitochondrial ATP synthase complex and its accumulation is the direct result of lack of CLN2p in this disease [25].
• TPP1 is a previously identified binding partner of POT1 that has been proposed to form part of a six-protein shelterin complex at telomeres [26].
• The POT1-TPP1 telomere complex is a telomerase processivity factor [26].

Other interactions of TPP1

• Only products of two of these genes, CLN 1 and CLN2, have structural and functional properties of lysosomal enzymes [27].
• Previously, diagnosis of NCL was based on age at onset and clinicopathologic (C-P) findings, classified as 1) infantile (INCL), 2) late infantile (LINCL), 3) juvenile (JNCL), and 4) adult (ANCL) [8].
• Analysis of a further 33 classical LINCL families supported linkage in this region (Zmax = 3.07 at theta = 0.06 at D11S1338) [18].
• Accumulation of subunit c of mitochondrial ATP synthase, to curvilinear profiles, is found in LINCL cases [28].
• Extensive neuronal death is seen in CLN2- and CLN3-deficient human brain as well as in CLN6-deficient sheep brain and retina [20].
• Noteworthy, correction of the lysosomal enzyme defect of LINCL fibroblasts using a medium enriched in CLN2 protein enabled restoration of TNF-induced Bid and caspase-3 processing and toxicity [29].

Analytical, diagnostic and therapeutic context of TPP1

• Identification of genes for INCL and JNCL, together with electron microscopy in LINCL, allows safe prenatal diagnosis which is still impossible by biochemical techniques, unlike other lysosomal disorders [30].
• In the present study, we analysed the molecular basis of 15 different mutations of TPP-I by using immunocytochemistry, immunofluorescence, Western blotting, enzymatic assay and subcellular fractionation [24].
• This study demonstrates that AAV-mediated TPP1 enzyme replacement corrects the hallmark cellular pathologies of cLINCL in the mouse model and raises the possibility of using AAV gene therapy to treat cLINCL patients [31].
• Lysosome-associated membrane protein 1 immunostaining and confocal microscopy showed intracellular targeting of TPP1 to the lysosomal compartment [31].
• The authors examined the possibility of diagnosis of LINCL with immunostaining and immunoblotting using specific antibodies made of the recently identified defective gene in LINCL [32].

References