The lysosome plays a pivotal role between catabolic and anabolic processes as the nexus for signalling pathways responsive to a variety of factors, such as growth, nutrient availability, energetic status and cellular stressors. Lysosomes are also the terminal degradative organelles for autophagy through which macromolecules and damaged cellular components and organelles are degraded. Autophagy acts as a cellular homeostatic pathway that is essential for organismal physiology. Decline in autophagy during ageing or in many diseases, including late-onset forms of neurodegeneration is considered a major contributing factor to the pathology. Multiple lines of evidence indicate that impairment in autophagy is also a central mechanism underlying several lysosomal storage disorders (LSDs). LSDs are a class of rare, inherited disorders whose histopathological hallmark is the accumulation of undegraded materials in the lysosomes due to abnormal lysosomal function. Inefficient degradative capability of the lysosomes has negative impact on the flux through the autophagic pathway, and therefore dysregulated autophagy in LSDs is emerging as a relevant disease mechanism. Pathology in the LSDs is generally early-onset, severe and life-limiting but current therapies are limited or absent; recognizing common autophagy defects in the LSDs raises new possibilities for therapy. In this review, we describe the mechanisms by which LSDs occur, focusing on perturbations in the autophagy pathway and present the latest data supporting the development of novel therapeutic approaches related to the modulation of autophagy.

The neuronal ceroid lipofuscinoses (NCLs) are a group of fatal, monogenic neurodegenerative disorders with an early onset in infancy or childhood. Despite identification of the genes disrupted in each form of the disease, their normal cellular role and how their deficits lead to disease pathology is not fully understood. Cln7, a major facilitator superfamily domain-containing protein, is affected in a late infantile-onset form of NCL. Cln7 is conserved across species suggesting a common function. Here we demonstrate that Cln7 is required for the normal growth of synapses at the Drosophila larval neuromuscular junction. In a Cln7 mutant, synapses fail to develop fully leading to reduced function and behavioral changes with dysregulation of TOR activity. Cln7 expression is restricted to the post-synaptic cell and the protein localizes to vesicles immediately adjacent to the post-synaptic membrane. Our data suggest an involvement for Cln7 in regulating trans-synaptic communication necessary for normal synapse development.

Background: Increased lipid storage is observed within the brains of patients with Alzheimer's disease (AD). Genetic risk factors for AD involved in lipid processing include APOE, ABCA7 and TREM2. Lipid transport between neurons and glia is induced by mitochondrial stress and NMDA-induced excitotoxicity in vitro and is dependent on glial apolipoprotein E (ApoE) expression. Therefore, this suggests that lipid transport between neurons and glia of the brain by ApoE and intracellular lipid processing are critical cellular adaptations to stress. This in turn suggests that insufficient ApoE activity may underpin the elevated lipid storage associated with neurodegenerative diseases. Method: To determine whether ApoE function is required for cellular adaptation to increased lipid load relevant to dementia, 3-month-old WT and ApoE-KO mice received daily intraperitoneal injections of the glucocerebrosidase inhibitor, CBE, for 18 d. Animals were sacrificed 1 d after the final dose and perfused with paraformaldehyde for immunohistochemistry, or were perfused with saline and dissected to isolate the cortex, hippocampus and substantia nigra for biochemical analysis by Western blot. Microglial and astrocyte reactivity to CBE were assessed by Iba1 and GFAP immunohistochemistry respectively. Result: Microglial reactivity was greater in the dentate gyrus, substantia nigra and cortical layer V in ApoE-KO mice after 18 d CBE, relative to WT. Loss of ApoE also elevated astrocyte reactivity in the dentate gyrus, substantia nigra and cortical layer V after 18 d CBE. Ongoing analyses into the molecular and cellular consequences of prolonged CBE include changes in lipid transport, tau phosphorylation, lysosome biogenesis, autophagy and proteostasis, to determine how loss of ApoE function may impact cellular adaptation to intracellular lipid formation resulting from sustained glucocerebrosidase inhibition. Conclusion:The exacerbated glial activation in ApoE-KO animals receiving CBE suggests that ApoE expression and function may, in part, determine the capacity of neuron-glia networks to overcome damaging stimuli. When ApoE function is insufficient, failed resolution of lipids may then lead to persistent damage and degeneration.Therefore, characterizing the consequences of limited lipid clearance on the adapta-

Equal contribution # co-senior and co-corresponding authors: R.I.Tuxworth@bham.ac.uk +44 (0)121 414 7046 Guy.Tear@kcl.ac.uk +44 (0)20 7848 6539 AbstractThe neuronal ceroid lipofuscinoses (NCLs) are a group of fatal, monogenic neurodegenerative disorders with an early onset in infancy or childhood. Despite identification of the genes disrupted in each form of the disease, their normal cellular role and how their deficits lead to disease pathology is not fully understood. Cln7, a major facilitator superfamily domain-containing protein, is affected in a late infantile-onset form of NCL. Using the Drosophila larval neuromuscular junction as a model to study neural development, we demonstrate that Cln7 is required for the normal growth of synapses. In a Cln7 mutant, synapses fail to develop fully leading to reduced function and behavioral changes with dysregulation of TOR activity. Cln7 expression is restricted to the postsynaptic cell and the protein localizes to vesicles immediately adjacent to the post-synaptic membrane. Our data suggest an involvement for Cln7 in regulating trans-synaptic communication.