A lysosomal enigma CLN5 and its significance in understanding neuronal ceroid lipofuscinosis.

Neuronal Ceroid Lipofuscinosis (NCL), also known as Batten disease, is an incurable childhood brain disease. The thirteen forms of NCL are caused by mutations in thirteen CLN genes. Mutations in one CLN gene, CLN5, cause variant late-infantile NCL, with an age of onset between 4 and 7 years. The CLN5 protein is ubiquitously expressed in the majority of tissues studied and in the brain, CLN5 shows both neuronal and glial cell expression. Mutations in CLN5 are associated with the accumulation of autofluorescent storage material in lysosomes, the recycling units of the cell, in the brain and peripheral tissues. CLN5 resides in the lysosome and its function is still elusive. Initial studies suggested CLN5 was a transmembrane protein, which was later revealed to be processed into a soluble form. Multiple glycosylation sites have been reported, which may dictate its localisation and function. CLN5 interacts with several CLN proteins, and other lysosomal proteins, making it an important candidate to understand lysosomal biology. The existing knowledge on CLN5 biology stems from studies using several model organisms, including mice, sheep, cattle, dogs, social amoeba and cell cultures. Each model organism has its advantages and limitations, making it crucial to adopt a combinatorial approach, using both human cells and model organisms, to understand CLN5 pathologies and design drug therapies. In this comprehensive review, we have summarised and critiqued existing literature on CLN5 and have discussed the missing pieces of the puzzle that need to be addressed to develop an efficient therapy for CLN5 Batten disease.

Effects of phosphodiesterase V inhibition on nitric oxide-mediated relaxation responses in guinea pig trachea.

In the present study, we aimed to evaluate the effects of PDE V inhibition on NO-mediated relaxation responses in isolated guinea pig trachea. Under the NANC conditions, tracheal preparations were contracted with histamine (100 microm/l). When contraction had reached a plateau, relaxation responses to electrical field stimulation (EFS, 60 V, 0.5 ms, 5-10 Hz) were determined before and after incubation of the tracheal ring with L-NAME (1 mmol/l), a NO synthase inhibitor. L-NAME significantly inhibited the relaxation responses and this inhibitory effect was reversed by L-arginine (1 mmol/l), a precursor of NO, but was not affected by D-arginine. In addition, cumulative application of the NO donors, 3-morpholino-sydnonimine (SIN-1) and sodium nitroprusside (SNP), caused concentration-dependent relaxation of tissues precontracted with histamine. The selective PDE type V inhibitor zaprinast at EC50 concentration (30 micromol/l) significantly potentiated EFS-induced NANC relaxations and relaxant responses to SIN-1 and SNP. In conclusion, these data support the hypothesis that NO is a mediator of NANC relaxations of guinea pig tracheal rings and PDE V inhibition potentiates NO-mediated relaxation.