ABSTRACT
Hereditary retinal degeneration (RD) relates to a heterogeneous group of blinding human diseases in which the light sensitive neurons of the retina, the photoreceptors, die. RD is currently untreatable and the underlying cellular mechanisms remain poorly understood. However, the activity of the enzyme poly-ADP-ribose polymerase-1 (PARP1) and excessive generation of poly-ADP-ribose (PAR) polymers in photoreceptor nuclei have been shown to be causally involved in RD. The activity of PARP1 is to a large extent governed by its functional antagonist, poly-ADP-glycohydrolase (PARG), which thus also may have a role in RD. To investigate this, we analyzed PARG expression in the retina of wild-type (wt) mice and in the rd1 mouse model for human RD, and detected increased PARG protein in a subset of degenerating rd1 photoreceptors. Knockout (KO) animals lacking the 110 kDa nuclear PARG isoform were furthermore analyzed, and their retinal morphology and function were indistinguishable from wild-type animals. Organotypic wt retinal explants can be experimentally treated to induce rd1-like photoreceptor death, but PARG110 KO retinal explants were unexpectedly highly resistant to such treatment. The resistance was associated with decreased PAR accumulation and low PARP activity, indicating that PARG110 may positively regulate PARP1, an event that therefore is absent in PARG110 KO tissue. Our study demonstrates a causal involvement of PARG110 in the process of photoreceptor degeneration. Contrasting its anticipated role as a functional antagonist, absence of PARG110 correlated with low PARP activity, suggesting that PARG110 and PARP1 act in a positive feedback loop, which is especially active under pathologic conditions. This in turn highlights both PARG110 and PARP1 as potential targets for neuroprotective treatments for RD.
Subject(s)
Cyclic AMP/metabolism , Glycoside Hydrolases/deficiency , Nerve Degeneration , Photoreceptor Cells, Vertebrate/enzymology , Retinal Degeneration/enzymology , Animals , Cell Death , Cyclic Nucleotide Phosphodiesterases, Type 6/antagonists & inhibitors , Cyclic Nucleotide Phosphodiesterases, Type 6/genetics , Disease Models, Animal , Enzyme Activation , Genetic Predisposition to Disease , Glycoside Hydrolases/genetics , Mice , Mice, Knockout , Mice, Mutant Strains , Mutation , Phenotype , Phosphodiesterase Inhibitors/pharmacology , Photoreceptor Cells, Vertebrate/drug effects , Photoreceptor Cells, Vertebrate/pathology , Poly (ADP-Ribose) Polymerase-1 , Poly Adenosine Diphosphate Ribose/metabolism , Poly(ADP-ribose) Polymerases/deficiency , Poly(ADP-ribose) Polymerases/genetics , Protein Isoforms , Retinal Degeneration/genetics , Retinal Degeneration/pathology , Time Factors , Tissue Culture TechniquesABSTRACT
Presentamos cinco pacientes HIV positivos que desarrollaron inflamación periungueal dolorosa en uñas de pies durante el tratamiento con antirretrovirales inhibidores de proteasas (indinavir). La paroniquia asociada a indinavir y lamivudina en pacientes HIV fue recientemente reportada. Su patogenia no es bien conocida
Subject(s)
Humans , Male , Adult , Granuloma, Pyogenic/etiology , HIV Protease Inhibitors/adverse effects , Paronychia/etiology , Anti-HIV Agents/adverse effects , Granuloma, Pyogenic/complications , Granuloma, Pyogenic/diagnosis , Indinavir/adverse effects , Paronychia/complications , Paronychia/diagnosis , Acquired Immunodeficiency Syndrome/complicationsABSTRACT
Presentamos cinco pacientes HIV positivos que desarrollaron inflamación periungueal dolorosa en uñas de pies durante el tratamiento con antirretrovirales inhibidores de proteasas (indinavir). La paroniquia asociada a indinavir y lamivudina en pacientes HIV fue recientemente reportada. Su patogenia no es bien conocida (AU)
Subject(s)
Humans , Male , Adult , Paronychia/etiology , HIV Protease Inhibitors/adverse effects , Granuloma, Pyogenic/etiology , Paronychia/complications , Paronychia/diagnosis , Indinavir/adverse effects , Anti-HIV Agents/adverse effects , Acquired Immunodeficiency Syndrome/complications , Granuloma, Pyogenic/complications , Granuloma, Pyogenic/diagnosisABSTRACT
El uso de inhibidores de proteasas en el tratamiento de la infección por HIV-1, ha revolucionado la sobrevida de éstos enfermos. Pero también se lo ha asociado a diabetes mellitus de nuevo comienzo, hiperlipidemia y lipodistrofia. Presentamos tres pacientes con lipodistrofia secundaria y comentamos la fisiopatogenia y tratamiento
Subject(s)
Humans , Male , Female , Adult , Middle Aged , Indinavir/adverse effects , Lipodystrophy/etiology , Protease Inhibitors/adverse effects , Anti-HIV Agents/adverse effects , Lipodystrophy/complications , Lipodystrophy/drug therapy , Acquired Immunodeficiency Syndrome/complicationsABSTRACT
El uso de inhibidores de proteasas en el tratamiento de la infección por HIV-1, ha revolucionado la sobrevida de éstos enfermos. Pero también se lo ha asociado a diabetes mellitus de nuevo comienzo, hiperlipidemia y lipodistrofia. Presentamos tres pacientes con lipodistrofia secundaria y comentamos la fisiopatogenia y tratamiento (AU)
