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Batten disease, one of the most devastating types of neurodegenerative lysosomal storage disorders, is caused by mutations in CLN3 . Here, we show that CLN3 is a vesicular trafficking hub connecting the Golgi and lysosome compartments. Proteomic analysis reveals that CLN3 interacts with several endo-lysosomal trafficking proteins, including the cation-independent mannose 6 phosphate receptor (CI-M6PR), which coordinates the targeting of lysosomal enzymes to lysosomes. CLN3 depletion results in mis-trafficking of CI-M6PR, mis-sorting of lysosomal enzymes, and defective autophagic lysosomal reformation. Conversely, CLN3 overexpression promotes the formation of multiple lysosomal tubules, which are autophagy and CI-M6PR-dependent, generating newly formed proto-lysosomes. Together, our findings reveal that CLN3 functions as a link between the M6P-dependent trafficking of lysosomal enzymes and lysosomal reformation pathway, explaining the global impairment of lysosomal function in Batten disease. CLN3 mutations cause Batten disease, a devastating neurodegenerative lysosomal storage disease. Here, the authors discovered that CLN3 plays a crucial role in both trafficking of lysosomal proteins and autophagic lysosomal reformation.

The accumulation of senescent cells is a key mediator of tissue and organismal ageing. Persistent activation of the growth regulator, mTORC1, even in the absence of growth factors and amino acids, supports senescence phenotypes, such as increased cell size and secretion of inflammatory factors. Here we extend this finding to show that senescence is associated with lysosomal accumulation of the low-density lipoprotein receptor (LDLR) and a failure of mTORC1 signalling to respond to changes in cholesterol. These observations are reflective of a broader dysfunction through the endo-lysosomal pathway, with Rab GTPases and phosphoinositides localised to atypical hybrid organelles. We propose that endosomal mistrafficking, in concert with increased autophagy and elevated lysosomal pH are contributing to an accumulation of undegraded material and lysosomal membrane damage. Our data indicate that in response to lysosomal dysfunction, senescent cells not only upregulate TFEB/TFE3-dependent lysosomal quality control but also upregulate lysosomal repair via PI4K2A-dependent PITT pathway. Perturbation of the lipid transport machinery required for lysosomal repair caused senescent cell death, revealing that targeting mechanisms of lysosomal repair has senolytic potential.

The mammalian cell surface is decorated with a plethora of integral membrane proteins including those required for the transport of micronutrients, such as copper, which are essential to cellular health. The concentration of micronutrients within the cell is tightly regulated to avoid their adverse deficiency and toxicity effects. The sorting and recycling of nutrients transporters within the endo-lysosomal network is recognised as an essential process in regulating nutrient balance. The evolutionarily conserved endosomal sorting complex, retromer, coordinates integral membrane protein recognition and retrieval. Cellular copper homeostasis is regulated primarily by two transporters: the major copper influx transporter copper transporter 1 (CTR1/SLC31A1), which controls the uptake of copper from the extracellular environment and is essential for early embryonic development, and the established retromer cargo, the copper-transporting ATPase, ATP7A. Here, we show that in response to fluctuating extracellular copper the retromer complex controls the delivery of CTR1 to the cell surface. Following copper exposure, CTR1 is endocytosed to prevent excessive copper uptake. We reveal that internalised CTR1 localises on retromer-positive endosomes and in response to decreased extracellular copper retromer controls the recycling of CTR1 back to the cell surface to maintain copper homeostasis. In addition to copper, CTR1 plays a central role in platinum uptake. Significantly, the efficacy of platinum-based cancer drugs has been correlated with CTR1 expression. Consistent with this, we demonstrate that retromer-deficient cells show reduced sensitivity to the platinum-based drug, cisplatin.

Maraviroc may reduce hepatic inflammation in people with HIV and non-alcoholic fatty liver disease (HIV-NAFLD) through CCR5-receptor antagonism, which warrants further exploration. We performed an open-label 96-week randomised-controlled feasibility trial of maraviroc plus optimised background therapy (OBT) versus OBT alone, in a 1:1 ratio, for people with virologically-suppressed HIV-1 and NAFLD without cirrhosis. Dosing followed recommendations for HIV therapy in the Summary of Product Characteristics for maraviroc. The primary outcomes were safety, recruitment and retention rates, adherence and data completeness. Secondary outcomes included the change in Fibroscan-assessed liver stiffness measurements (LSM), controlled attenuation parameter (CAP) and Enhanced Liver Fibrosis (ELF) scores. Fifty-three participants (53/60, 88% of target) were recruited; 23 received maraviroc plus OBT; 89% were male; 19% had type 2 diabetes mellitus. The median baseline LSM, CAP & ELF scores were 6.2 (IQR 4.6-7.8) kPa, 325 (IQR 279-351) dB/m and 9.1 (IQR 8.6-9.6) respectively. Primary outcomes: all individuals eligible after screening were randomised; there was 92% (SD 6.6%) adherence to maraviroc [target >90%]; 83% (95%CI 70%-92%) participant retention [target >65%]; 5.5% of data were missing [target <20%]. There were noo Serious Adverse Reactions; mild-moderate intensity Adverse Reactions were reported by five participants (5/23, 22% (95%CI 5%-49%)) [target <10%]. All Adverse Reactions resolved. Secondary outcomes: no important differences were seen by treatment group for the change from baseline in LSM, CAP or ELF scores. This feasibility study provides preliminary evidence of maraviroc safety amongst people with HIV-NAFLD, and acceptable recruitment, retention, and adherence rates. These data support a definitive randomised-controlled trial assessing maraviroc impact on hepatic steatosis and fibrosis. Clinical trial registry: ISCRTN, registration number 31461655.