Histochemical localization of palmitoyl protein thioesterase-1 activity

Dearborn, Joshua T.; Ramachandran, S.; Shyng, Charles; Lu, Jui Yun; Thornton, Jonah; Hofmann, Sandra L.; Sands, Mark S.

doi:10.1016/j.ymgme.2015.11.004

Cited by 8 publications

(6 citation statements)

References 17 publications

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“…A histochemical stain for PPT1 activity was performed on sagittal forebrain sections and transverse sections of spinal cord, as previously described (35). See SI Materials and Methods for further details.…”

Section: Methodsmentioning

confidence: 99%

Synergistic effects of treating the spinal cord and brain in CLN1 disease

Shyng

Nelvagal

Dearborn

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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101

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Infantile neuronal ceroid lipofuscinosis (INCL, or CLN1 disease) is an inherited neurodegenerative storage disorder caused by a deficiency of the lysosomal enzyme palmitoyl protein thioesterase 1 (PPT1). It was widely believed that the pathology associated with INCL was limited to the brain, but we have now found unexpectedly profound pathology in the human INCL spinal cord. Similar pathological changes also occur at every level of the spinal cord of PPT1-deficient (Ppt1 −/− ) mice before the onset of neuropathology in the brain. Various forebrain-directed gene therapy approaches have only had limited success in Ppt1 −/− mice. Targeting the spinal cord via intrathecal administration of an adeno-associated virus (AAV) gene transfer vector significantly prevented pathology and produced significant improvements in life span and motor function in Ppt1 −/− mice. Surprisingly, forebrain-directed gene therapy resulted in essentially no PPT1 activity in the spinal cord, and vice versa. This leads to a reciprocal pattern of histological correction in the respective tissues when comparing intracranial with intrathecal injections. However, the characteristic pathological features of INCL were almost completely absent in both the brain and spinal cord when intracranial and intrathecal injections of the same AAV vector were combined. Targeting both the brain and spinal cord also produced dramatic and synergistic improvements in motor function with an unprecedented increase in life span. These data show that spinal cord pathology significantly contributes to the clinical progression of INCL and can be effectively targeted therapeutically. This has important implications for the delivery of therapies in INCL, and potentially in other similar disorders.infantile Batten disease | adeno-associated virus | spinal cord | brain | combination therapy

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Section: Methodsmentioning

confidence: 99%

Synergistic effects of treating the spinal cord and brain in CLN1 disease

Shyng

Nelvagal

Dearborn

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

101

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“…Treatment of the entire parenchyma of brain is possible with transvascular delivery of PPT1 across the BBB. The normal brain PPT1 enzyme activity is 70 nmol/hour/mgp using the Mu-6S-Palm-betaGlc substrate 34 , which is equal to 116 mU/gram, where 1 mU = 1 nmol/min, and 1 gram brain is equal to 100 mgp. The PPT1 enzyme activity administered with an ID of 3 mg/kg of the HIRMAb-HC-LL-PPT1 fusion protein, in a 50 kg human, is equivalent to an ID of 260,000 milliunits, given the specific activity of 1742 mU/mg for this fusion protein (Table 3).…”

Section: Discussionmentioning

confidence: 99%

Bi-functional IgG-lysosomal enzyme fusion proteins for brain drug delivery

Boado

Hui

et al. 2019

Sci Rep

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Most lysosomal storage disorders affect the central nervous system. However, lysosomal enzymes do not cross the blood-brain barrier (BBB), and intravenous enzyme infusion is not effective for the brain. Lysosomal enzymes can be re-engineered for BBB transport as IgG-enzyme fusion proteins, where the IgG domain is a monoclonal antibody (MAb) against an endogenous BBB receptor/transporter, and which acts as a molecular Trojan horse to deliver the enzyme to brain. However, the problem is retention of high enzyme activity following enzyme fusion to the IgG. The present investigation shows this is possible with a versatile approach that employs fusion of the enzyme to either the IgG heavy chain or light chain using a long flexible linker. The model IgG is a chimeric monoclonal antibody (MAb) against the human insulin receptor (HIR). The enzyme activity of the HIRMAb-enzyme fusion protein is preserved for hexosaminidase A, which is mutated in Tay Sachs disease, for protein palmitoylthioesterase-1, which is mutated in Batten disease type 1, acid sphingomyelinase, which is mutated in Niemann Pick disease type A, and beta galactosidase-1, which is mutated in GM1 gangliosidosis.

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“…Palmitoyl-protein thioesterase 1 (PPT1) is an enzyme involved in the catabolism of lipid-modified proteins during lysosomal degradation by removing thioester-linked fatty acyl groups from cysteine residues . Mutations in the PPT1 gene cause a deficiency or complete lack of PPT1 activity, consequently resulting in infantile neuronal ceroid lipofuscinosis . Tubulin is the major constituent of microtubules.…”

Section: Discussionmentioning

confidence: 99%

“…57 Mutations in the PPT1 gene cause a deficiency or complete lack of PPT1 activity, consequently resulting in infantile neuronal ceroid lipofuscinosis. 58 Tubulin is the major constituent of microtubules. Interestingly, the α-tubulin proteins are related to heavy metal tolerance.…”

Section: Environmental Science and Technologymentioning

confidence: 99%

Global Proteome Profiling of a Marine Copepod and the Mitigating Effect of Ocean Acidification on Mercury Toxicity after Multigenerational Exposure

Wang¹,

Lee

Li³

2017

Environ. Sci. Technol.

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Previously, we found that ocean acidification (OA) mitigates mercury (Hg) toxicity to marine copepod Tigriopus japonicus under multigenerational exposure (four generations, F0-F3). To determine the response mechanisms of T. japonicus against long-term exposure to OA and Hg pollution, we investigated the proteome of F3 copepods after multigenerational exposure to four conditions: pCO 400 μatm + control; pCO 1000 μatm + control; pCO 400 μatm +1.0 μg/L Hg; and pCO 1000 μatm +1.0 μg/L Hg. Functional enrichment analysis indicated that OA enhanced the copepod's energy production mainly by increasing protein assimilation and proteolysis as a compensatory strategy, which explained its physiological resilience to reduced pH. Conversely, Hg treatment decreased many critical processes, including ferric iron binding, antioxidant activity, cellular homeostasis, and glutathione metabolism, and these toxic events could translate into higher-level responses, i.e., restrained reproduction in copepods. Importantly, the mediation of Hg toxicity in T. japonicus by OA could be explained by the enhanced lysosome-autophagy pathway proteomes that are responsible for repairing and removing damaged proteins and enzymes under stress. Overall, this study provided molecular insights into the response of T. japonicus to long-term exposure of OA and Hg, with a particular emphasis on the mitigating impact of the CO-driven acidification on Hg toxicity.

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Histochemical localization of palmitoyl protein thioesterase-1 activity

Cited by 8 publications

References 17 publications

Synergistic effects of treating the spinal cord and brain in CLN1 disease

Synergistic effects of treating the spinal cord and brain in CLN1 disease

Bi-functional IgG-lysosomal enzyme fusion proteins for brain drug delivery

Global Proteome Profiling of a Marine Copepod and the Mitigating Effect of Ocean Acidification on Mercury Toxicity after Multigenerational Exposure

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