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

Abstract

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.

Deficiency of the Lysosomal Protein CLN5 Alters Lysosomal Function and Movement

“…Batten disease or neuronal ceroid lipofuscinosis (NCL) is a group of rare, fatal inherited neurological diseases predominantly affecting children and is characterised by symptoms including motor deficits, mental retardation, cognitive impairment, visual impairment, and epileptic seizures (reviewed in [1]). There are thirteen forms of Batten disease caused by mutations in thirteen CLN genes (CLN1-8 and 10-14) [2,3].…”

“…Mutations in one of the CLN genes, CLN5, cause a variant late-infantile NCL [4][5][6]. Life expectancy for children with CLN5 mutations is between ten and thirty years, and there is currently no cure or approved treatment for CLN5 Batten disease [1,4,6,7].…”

“…However, a functional assay with purified human CLN5 has never been performed; hence, the protein function is still unknown. CLN5 interacts with other CLN proteins associated with Batten disease to maintain lysosomal homeostasis (reviewed in [1]).…”

Deficiency of the lysosomal protein CLN5 alters lysosomal function and movement

“…Batten disease or neuronal ceroid lipofuscinosis (NCL) is a group of rare, fatal inherited neurological diseases predominantly affecting children and is characterized by symptoms including motor deficits, mental retardation, cognitive impairment, visual impairment, and epileptic seizures (reviewed in [1]). There are thirteen forms of Batten disease caused by mutations in thirteen CLN genes ( CLN1-8 and 10-14 )[2, 3].…”

“…CLN5 is a lysosomal protein with ambiguous protein function (reviewed in [1]). A cellular hallmark of Batten disease is defective lysosomes, the cellular waste recycling machinery [3].…”