The Batten disease gene CLN3 is required for the response to oxidative stress

Abstract

Mutations in the CLN3 gene cause juvenile neuronal ceroid lipofuscinosis (JNCL or Batten disease), an early onset neurodegenerative disorder. JNCL is the most common of the NCLs, a group of disorders with infant or childhood onset that are caused by single gene mutations. The NCLs, although relatively rare, share many pathological and clinical similarities with the more common late-onset neurodegenerative disorders, while their simple genetic basis makes them an excellent paradigm. The early onset and rapid disease progression in the NCLs suggests that one or more key cellular processes are severely compromised. To identify the functional pathways compromised in JNCL, we have performed a gain-of-function modifier screen in Drosophila. We find that CLN3 interacts genetically with the core stress signalling pathways and components of stress granules, suggesting a function in stress responses. In support of this, we find that Drosophila lacking CLN3 function are hypersensitive to oxidative stress yet they respond normally to other physiological stresses. Overexpression of CLN3 is sufficient to confer increased resistance to oxidative stress. We find that CLN3 mutant flies perceive conditions of increased oxidative stress correctly but are unable to detoxify reactive oxygen species, suggesting that their ability to respond is compromised. Together, our data suggest that the lack of CLN3 function leads to a failure to manage the response to oxidative stress and this may be the key deficit in JNCL that leads to neuronal degeneration.

Fruit Flies in Biomedical Research

“…For example, null alleles of homologs of genes that cause familial forms of Alzheimer's disease (Appl; Luo et al 1992 Instead, these mutants exhibit behavior defects, subtle morphological phenotypes, shortened lifespan, and/or reduction in fertility. In some cases the phenotypes are very subtle or can only be seen when the animals are under stress, as seen in mutants in genes whose human homologs are mutated in Batten's disease (cln3, cathD, and Ppt1; Myllykangas et al 2005;Hickey et al 2006;Tuxworth et al 2011). However, it is currently difficult to estimate the proportion of genes in the Drosophila genome that are nonessential but are related to Mendelian disorders (Flybase 2014;St Pierre et al 2014).…”

Mutations in palmitoyl-protein thioesterase 1 alter exocytosis and endocytosis at synapses inDrosophilalarvae

“…This has also been the case for lysosomal storage disorders where both gain-of-function and loss-of-function genetic models have been produced for Congenital NCL (Ctsd), 15,16 INCL 17,18 and Juvenile NCL (Cln3). 19,20 Mutations in Drosophila that mimic the Ppt1 loss-of-function seen in human INCL produce cytoplasmic inclusions and autoflourescent storage material. 17 Embryological characterization of these mutations in the fly demonstrates a role for Ppt1 in early neuronal specification and axon guidance.…”

Neuronal ceroid lipofuscinosis protein CLN3 interacts with motor proteins and modifies location of late endosomal compartments

“…Based on the phenotypes of CLN3-deficient mammalian cells, alongside yeast and animal models, CLN3 has been proposed to function in multiple cellular processes including autophagy, apoptosis, lipid metabolism, intracellular signalling, RNA metabolism and maintenance of lysosomal/vacuolar size, pH and amino acid homeostasis [8][9][10][11][12][13][14][15][16][17][18][19][20].…”