Central aspects of the cellular lipid trafficking mechanisms that occur during keratinocyte differentiation are still not well understood. In the past years, evidence has accumulated to suggest that members of the superfamily of adenosine triphosphate binding cassette (ABC) transporters are critically involved in the transmembrane transport of cellular lipids. To test the hypothesis that ABC molecules are potentially involved in the epidermal transport of sphingolipids, glycerophospholipids, cholesterol, and fatty acids, we performed mRNA expression profiling of all currently known ABC molecules during in vitro differentiation of human keratinocytes and HaCaT cells. We identified six ABC molecules that displayed significant regulation during differentiation of these cells. The recently cloned transporter ABCA7 was highly expressed in keratinocytes and HaCaT cells and upregulated during differentiation. Overexpression of ABCA7 in HeLa cells resulted in increased expression of intracellular and cell surface ceramide and elevated intracellular phosphatidylserine levels. Given the observation that during terminal keratinocyte differentiation intracellular and surface ceramide levels are increased, our results render ABCA7 a candidate regulator of ceramide transport in this process. In addition to ABCA7, the cholesterol transporters ABCB1 and ABCG1 and the glutathione/glucuronide sulfate transporters ABCC1, ABCC3, and ABCC4, were strongly upregulated during keratinocyte and HaCaT cell differentiation. These findings support the notion that ABCB1 and ABCG1 are potentially implicated in cholesterol transport, whereas ABCC1, ABCC3, and ABCC4 are candidate regulators of the translocation of sulfated lipids during stratum corneum keratinization. Our results suggest specific biologic functions for members of the ABC transporter family in epidermal lipid reorganization during terminal keratinocyte differentiation.

Juvenile neuronal ceroid lipofuscinosis (jNCL) is a rare but fatal inherited lysosomal storage disorder mainly affecting children. The disease is caused by mutations in the CLN3 gene that lead to the accumulation of storage material in many tissues, prominent immune responses and neuronal degeneration. One of the first symptoms is vision loss followed by motor dysfunction and mental decline. The established Cln3Δex7/8 mouse model mimics many pathological features of the human disease except the retinal phenotype, which is very mild and occurs only very late in these mice. Here, we first carefully analyzed the retinal structure and microglia responses in these animals. While prominent autofluorescent spots were present in the fundus, only a moderate reduction of retinal thickness and no prominent microgliosis was seen in young CLN3-deficient mice. We next genetically introduced a light-sensitive RPE65 variant and established a light-damage paradigm that showed a high susceptibility of young Cln3Δex7/8 mice after exposure to 10,000 lux bright light for 30 min. Under these ‘low light’ conditions, CLN3-deficient mice showed a strong retinal degeneration, microglial activation, deposition of autofluorescent material and transcriptomic changes compared to wild-type animals. Finally, we treated the light-exposed Cln3Δex7/8 animals with the immunomodulatory compound minocycline, and thereby rescued the retinal phenotype and diminished microgliosis. Our findings indicate that exposure to specific light conditions accelerates CLN3-dependent retinal degeneration, and that immunomodulation by minocycline could be a possible treatment option to delay vision loss in jNCL patients..

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