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Lysosomal storage diseases (LSDs) are a group of over 70 diseases that are characterized by lysosomal dysfunction, most of which are inherited as autosomal recessive traits. These disorders are individually rare but collectively affect 1 in 5,000 live births. LSDs typically present in infancy and childhood, although adult-onset forms also occur. Most LSDs have a progressive neurodegenerative clinical course, although symptoms in other organ systems are frequent. LSD-associated genes encode different lysosomal proteins, including lysosomal enzymes and lysosomal membrane proteins. The lysosome is the key cellular hub for macromolecule catabolism, recycling and signalling, and defects that impair any of these functions cause the accumulation of undigested or partially digested macromolecules in lysosomes (that is, ‘storage’) or impair the transport of molecules, which can result in cellular damage. Consequently, the cellular pathogenesis of these diseases is complex and is currently incompletely understood. Several LSDs can be treated with approved, disease-specific therapies that are mostly based on enzyme replacement. However, small-molecule therapies, including substrate reduction and chaperone therapies, have also been developed and are approved for some LSDs, whereas gene therapy and genome editing are at advanced preclinical stages and, for a few disorders, have already progressed to the clinic. Lysosomal storage diseases (LSDs) are a diverse group of disorders that can manifest at any stage of life. This Primer by Platt and colleagues provides an overview of the LSDs, including how lysosomal dysfunction gives rise to disease and how these disorders are diagnosed and treated. An overview of future therapeutic targets for LSDs is also provided.

BackgroundObesity has been linked with subtle differences in brain structure. These differences tend to be especially relevant in prefrontal cortex regions, areas which play an important role in executive control. However, results in this field are often contradictory: although studies tend to report lower gray matter volume in relation to obesity, some have also observed null or positive associations. To overcome this issue, we conducted a meta-analysis on voxel-based morphometry (VBM) differences associated with obesity-related variables and validated the findings with an independent dataset.MethodsThe literature search included combinations of the following key words: (i) neuroimaging terms: MRI, gray matter, brain, magnetic resonance; (ii) obesity-related terms: obesity, obese, body mass, waist circumference, adiposity. We conducted the meta-analysis using Anisotropic Effect-Size Seed-Based d Mapping (AES-SDM) software. Twenty-one studies on obesity and VBM fulfilled our inclusion criteria, representing 5882 participants (54% females) aged 18–92 years. To examine the validity of our meta-analytic results, we additionally tested on an independent dataset (Human Connectome Project, n = 378 participants) whether mean VBM values obtained for each cluster showed correlations with body mass index (BMI).ResultsWe found that obesity-related variables were consistently associated with lower gray matter volume in areas including the medial prefrontal cortex, bilateral cerebellum, and left temporal pole. The clusters showed negative associations between gray matter volume and BMI in the independent dataset, with the exception of one cluster in the cerebellum.ConclusionsOur findings provide robust evidence that obesity and body mass are related to significantly lower gray matter volume in brain areas with a key role in executive control. These findings might suggest a neurobiological link between obesity and self-regulatory deficits.

Defects in endolysosomal and autophagic functions are increasingly viewed as key pathological features of neurodegenerative disorders. A master regulator of these functions is phosphatidylinositol-3-phosphate (PI3P), a phospholipid synthesized primarily by class III PI 3-kinase Vps34. Here we report that disruption of neuronal Vps34 function in vitro and in vivo impairs autophagy, lysosomal degradation as well as lipid metabolism, causing endolysosomal membrane damage. PI3P deficiency also promotes secretion of unique exosomes enriched for undigested lysosomal substrates, including amyloid precursor protein C-terminal fragments (APP-CTFs), specific sphingolipids, and the phospholipid bis(monoacylglycero)phosphate (BMP), which normally resides in the internal vesicles of endolysosomes. Secretion of these exosomes requires neutral sphingomyelinase 2 and sphingolipid synthesis. Our results reveal a homeostatic response counteracting lysosomal dysfunction via secretion of atypical exosomes eliminating lysosomal waste and define exosomal APP-CTFs and BMP as candidate biomarkers for endolysosomal dysfunction associated with neurodegenerative disorders. Neurodegeneration is increasingly associated with endolysosomal and autophagy dysfunction. Here, Miranda and colleagues show that disruption of neuronal PI3P/Vps34 signaling leads to endolysosomal membrane damage and aberrant release of undigested material in APP-CTF- and BMP-positive exosomes.

ObjectiveAlzheimer’s disease (AD) is a global health problem without effective methods to alleviate the disease progression. Amyloid β-protein (Aβ) is widely accepted as a key biomarker for AD. Metabolic syndromes, including obesity and insulin resistance, are key high risk factors for AD. Akkermansia muciniphila (Akk), the only representative human gut microbe in the genus Verrucomicrobia, can prevent the weight gain caused by a high-fat diet, repair the damaged integrity of the intestinal epithelium barrier, reduce endotoxin levels in blood and improve insulin resistance. The aim of this study is to explore the impact of Akk administration in AD model mice in different diets.MethodsAPP/PS1 mice were fed either a normal chow diet or a high-fat diet and were treated with Akk by gavage each day for 6 months. The impacts of Akk on glucose metabolism, intestinal barrier and lipid metabolism in the mouse model of AD were determined. Changes in brain pathology and neuroethology were also analyzed.ResultsAkk effectively reduced the fasting blood glucose and serum diamine oxidase levels, and alleviated the reduction of colonic mucus cells in APP/PS1 mice. After treatment with Akk, the APP/PS1 mice showed obviously reduced blood lipid levels, improved hepatic steatosis and scapular brown fat whitening. Moreover, Akk promoted the reduction of Aβ 40–42 levels in the cerebral cortex of APP/PS1 mice, shortened the study time and improved the completion rate in Y-maze tests.ConclusionAkk effectively improved glucose tolerance, intestine barrier dysfunction and dyslipidemia in AD model mice. Our study results suggested that Akk could delay the pathological changes in the brain and relieve impairment of spatial learning and memory in AD model mice, which provides a new strategy for prevention and treatment of AD.APP/PS1 mice display alterations in physiological processes after treated with Akk. It is showed that the damaged integrity of the intestinal epithelium barrier is repaired, leading to obviously reduced blood glucose and lipid levels, improved hepatic steatosis, insulin resistance and scapular brown fat whitening, which are beneficial to reduce Aβ 40–42 levels in the brain of APP/PS1 mice.

Niemann–Pick type C disease is a fatal, progressive neurodegenerative disorder caused by loss-of-function mutations in NPC1, a multipass transmembrane glycoprotein essential for intracellular lipid trafficking. We sought to define the cellular machinery controlling degradation of the most common disease-causing mutant, I1061T NPC1. We show that this mutant is degraded, in part, by the proteasome following MARCH6-dependent ERAD. Unexpectedly, we demonstrate that I1061T NPC1 is also degraded by a recently described autophagic pathway called selective ER autophagy (ER-phagy). We establish the importance of ER-phagy both in vitro and in vivo, and identify I1061T as a misfolded endogenous substrate for this FAM134B-dependent process. Subcellular fractionation of I1061T Npc1 mouse tissues and analysis of human samples show alterations of key components of ER-phagy, including FAM134B. Our data establish that I1061T NPC1 is recognized in the ER and degraded by two different pathways that function in a complementary fashion to regulate protein turnover. Niemann-Pick type C1 disease is most commonly caused by the allele NPC1 I1061T, which is misfolded in the ER and rapidly degraded by the ubiquitin proteasome system. Here the authors show that the I1061T mutant is also degraded by ER-phagy.

Cholesterol is a structural component of cellular membranes particularly enriched in synapses but its role in synaptic transmission remains poorly understood. We used rat hippocampal cultures and their acute cholesterol depletion by methyl-β-cyclodextrin as a tool to describe the physiological role of cholesterol in glutamatergic synaptic transmission. Cholesterol proved to be a key molecule for the function of synapses as its depletion resulted in a significant reduction of both NMDA receptor (NMDAR) and AMPA/kainate receptor-mediated evoked excitatory postsynaptic currents (eEPSCs), by 94% and 72%, respectively. We identified two presynaptic and two postsynaptic steps of synaptic transmission which are modulated by cholesterol and explain together the above-mentioned reduction of eEPSCs. In the postsynapse, we show that physiological levels of cholesterol are important for maintaining the normal probability of opening of NMDARs and for keeping NMDARs localized in synapses. In the presynapse, our results favour the hypothesis of a role of cholesterol in the propagation of axonal action potentials. Finally, cholesterol is a negative modulator of spontaneous presynaptic glutamate release. Our study identifies cholesterol as an important endogenous regulator of synaptic transmission and provides insight into molecular mechanisms underlying the neurological manifestation of diseases associated with impaired cholesterol synthesis or decomposition.

Disclaimer: This diagnostic guideline is intended as an educational resource and represents the opinions of the authors, and is not representative of recommendations or policy of the American College of Medical Genetics and Genomics (ACMG). The information should be considered a consensus based on expert opinion, as more comprehensive levels of evidence were not available in the literature in all cases. Background: Acid sphingomyelinase deficiency (ASMD) is a rare, progressive, and often fatal lysosomal storage disease. The underlying metabolic defect is deficiency of the enzyme acid sphingomyelinase that results in progressive accumulation of sphingomyelin in target tissues. ASMD manifests as a spectrum of severity ranging from rapidly progressive severe neurovisceral disease that is uniformly fatal to more slowly progressive chronic neurovisceral and chronic visceral forms. Disease management is aimed at symptom control and regular assessments for multisystem involvement. Purpose and methods: An international panel of experts in the clinical and laboratory evaluation, diagnosis, treatment/management, and genetic aspects of ASMD convened to review the evidence base and share personal experience in order to develop a guideline for diagnosis of the various ASMD phenotypes. Conclusions: Although care of ASMD patients is typically provided by metabolic disease specialists, the guideline is directed at a wide range of providers because it is important for primary care providers (e.g., pediatricians and internists) and specialists (e.g., pulmonologists, hepatologists, and hematologists) to be able to identify ASMD. Genet Med advance online publication 13 April 2017

Lysosomal storage disorders (LSDs) are a large disease class involving lysosomal dysfunction, often resulting in neurodegeneration. Sandhoff disease (SD) is an LSD caused by a deficiency in the β subunit of the β-hexosaminidase enzyme ( Hexb ). Although Hexb expression in the brain is specific to microglia, SD primarily affects neurons. To investigate how a microglial gene is involved in neuronal homeostasis, here we show that β-hexosaminidase is secreted by microglia and integrated into the lysosomal compartment of neurons. To assess therapeutic relevance, we treat the Hexb -/- SD mouse model with bone marrow transplant and colony stimulating factor 1 receptor inhibition, which broadly replaces Hexb -/- microglia with Hexb -sufficient cells. Microglial replacement reverses apoptotic gene signatures, improves behavior, restores β-hexosaminidase enzymatic activity and Hexb expression, prevents substrate buildup, and normalizes neuronal lysosomal phenotypes, underscoring the critical role of myeloid-derived β-hexosaminidase in maintaining neuronal health and establishing microglial replacement as a potential LSD therapy. Sandhoff disease (SD) is a lysosomal storage disorder caused by deficiency in the β subunit of the β-hexosaminidase enzyme. Here, the authors show via bone marrow-based microglial replacement in a SD mouse model that myeloid-derived β-hexosaminidase is necessary for maintaining neuronal health.

Niemann-Pick disease Type C (NPC) is caused by mutations in the cholesterol transport protein NPC1 leading to the endolysosomal accumulation of the lipid and to psychiatric alterations. Using an NPC mouse model (Npc1 nmf164 ) we show aberrant mGluR 5 lysosomal accumulation and reduction at plasma membrane in NPC1 deficient neurons. This phenotype was induced in wild-type (wt) neurons by genetic and pharmacological NPC1 silencing. Extraction of cholesterol normalized mGluR 5 distribution in NPC1-deficient neurons. Intracellular accumulation of mGluR 5 was functionally active leading to enhanced mGluR-dependent long-term depression (mGluR-LTD) in Npc1 nmf164 hippocampal slices. mGluR-LTD was lower or higher in Npc1 nmf164 slices compared with wt when stimulated with non-membrane-permeable or membrane-permeable mGluR 5 agonists, respectively. Oral treatment with the mGluR 5 antagonist 2-chloro-4-((2,5-dimethyl-1-(4-(trifluoromethoxy)phenyl)-1 H -imidazol-4-yl)ethynyl)pyridine (CTEP) reduced mGluR-LTD and ameliorated psychiatric anomalies in the Npc1 nmf164 mice. Increased neuronal mGluR 5 levels were found in an NPC patient. These results implicate mGluR 5 alterations in NPC psychiatric condition and provide a new therapeutic strategy that might help patients suffering from this devastating disease.