Neuropathology in mouse models of mucopolysaccharidosis type I, IIIA and IIIB

Mucopolysaccharide diseases (MPS) are caused by deficiency of glycosaminoglycan (GAG) degrading enzymes, leading to GAG accumulation. Neurodegenerative MPS diseases exhibit cognitive decline, behavioural problems and shortened lifespan. We have characterised neuropathological changes in mouse models of MPSI, IIIA and IIIB to provide a better understanding of these events.Wild-type (WT), MPSI, IIIA and IIIB mouse brains were analysed at 4 and 9 months of age. Quantitative immunohistochemistry showed significantly increased lysosomal compartment, GM2 ganglioside storage, neuroinflammation, decreased and mislocalised synaptic vesicle associated membrane protein, (VAMP2), and decreased post-synaptic protein, Homer-1, in layers II/III-VI of the primary motor, somatosensory and parietal cortex. Total heparan sulphate (HS), was significantly elevated, and abnormally N-, 6-O and 2-O sulphated compared to WT, potentially altering HS-dependent cellular functions. Neuroinflammation was confirmed by significantly increased MCP-1, MIP-1α, IL-1α, using cytometric bead arrays. An overall genotype effect was seen in all parameters tested except for synaptophysin staining, neuronal cell number and cortical thickness which were not significantly different from WT. MPSIIIA and IIIB showed significantly more pronounced pathology than MPSI in lysosomal storage, astrocytosis, microgliosis and the percentage of 2-O sulphation of HS. We also observed significant time progression of all genotypes from 4-9 months in lysosomal storage, astrocytosis, microgliosis and synaptic disorganisation but not GM2 gangliosidosis. Individual genotype*time differences were disparate, with significant progression from 4 to 9 months only seen for MPSIIIB with lysosomal storage, MPSI with astrocytocis and MPSIIIA with microgliosis as well as neuronal loss. Transmission electron microscopy of MPS brains revealed dystrophic axons, axonal storage, and extensive lipid and lysosomal storage. These data lend novel insight to MPS neuropathology, suggesting that MPSIIIA and IIIB have more pronounced neuropathology than MPSI, yet all are still progressive, at least in some aspects of neuropathology, from 4-9 months.     

Metabolic Adaptations to Interrupted Glycosaminoglycan Recycling

Lysosomal storage diseases (LSD) are metabolic disorders characterized by accumulation of undegraded material. The mucopolysaccharidoses (MPS) are LSDs defined by the storage of glycosaminoglycans. Previously, we hypothesized that cells affected with LSD have increased energy expenditure for biosynthesis because of deficiencies of raw materials sequestered within the lysosome. Thus, LSDs can be characterized as diseases of deficiency as well as overabundance (lysosomal storage). In this study, metabolite analysis identified deficiencies in simple sugars, nucleotides, and lipids in the livers of MPSI mice. In contrast, most amino acids, amino acid derivatives, dipeptides, and urea were elevated. These data suggest that protein catabolism, perhaps because of increased autophagy, is at least partially fulfilling intermediary metabolism. Thus, maintaining glycosaminoglycan synthesis in the absence of recycled precursors results in major shifts in the energy utilization of the cells. A high fat diet increased simple sugars and some fats and lowered the apparent protein catabolism. Interestingly, autophagy, which is increased in several LSDs, is responsive to dietary intervention and is reduced in MPSVII and MPSI mice fed a high fat diet. Although long term dietary treatment improved body weight in MPSVII mice, it failed to improve life span or retinal function. In addition, the ventricular hypertrophy and proximal aorta dilation observed in MPSVII mice were unchanged by a high fat, simple sugar diet. As the mechanism of this energy imbalance is better understood, a more targeted nutrient approach may yet prove beneficial as an adjunct therapy to traditional approaches.Lysosomal storage disease (LSD)² typically results from a genetic deficiency of an acid hydrolase (1). The material usually degraded by the enzyme now accumulates in the lysosomes of cells throughout the body. In normal cells, some proportion of the degraded material is exported to the cytosol for reuse, thereby reducing the energy burden on the cell (2, 3). In the case of LSDs, more energy must be diverted to the synthesis of raw material because of the impaired recycling. Thus, this class of disorders presents with an energy imbalance caused by a simultaneous excess of stored material and a deficiency of raw material (4).Deficiencies in lysosomal enzymes involved in glycosaminoglycan (GAG) catabolism result in the mucopolysaccharidoses (MPS) (5). The biochemical, histological, and clinical phenotypes of MPS are likely due to a combination of the adaptations to both lysosomal storage and a deficiency of recycled monosaccharides. Maintaining a normal rate of GAG biosynthesis would require newly imported or synthesized monosaccharides, irrespective of the adaptations to stored material. The increased demand for GAG precursors is likely to be considerable. It has been shown previously in cultured cells that reutilization of catabolites from lysosomal GAG degradation is substantial (2). Therefore, the increased energy burden required for de novo synthesis of GAG precursors might be expected to reduce the levels of stored energy throughout the body. Consistent with this hypothesis, we and others have shown that a number of lysosomal storage diseases have significantly reduced adiposity (4, 6–8). We showed that the reduced adiposity was not the result of reduced food intake, higher metabolic rate, or lipid malabsorption (4). Furthermore, the missing lipid energy was not found in other tissues (4). However, the total caloric content in the liver was normal and in the form of carbohydrates other than glycogen (4). Enzyme replacement therapy reduced the levels of carbohydrates suggesting that their identity was glycosaminoglycans (4). These data strongly argued that energy was being diverted from potential storage as fat in adipocytes to storage in lysosomes as undegraded glycosaminoglycans. It is unclear how diseased cells are adapting to the energy diversion resulting from the block in recycling and what effect this has on the whole organism.In this study, we identified a number of biochemical and metabolic abnormalities associated with two MPS disorders. The data are consistent with the idea that physiologic malnutrition (9) and altered energy flow (4) are common adaptations in many, if not most LSDs. We also determined the effects of nutritional supplementation on these changes. Many of the metabolic abnormalities approached normal when the animals were placed on a high fat, simple sugar diet. Of particular interest is the fact that autophagy was responsive to dietary intervention and approached normal levels when the animals were fed a high fat diet. This identifies at least one mechanism that contributes to the increased autophagy observed in a number of diverse LSDs (10–19). Although long term dietary intervention in MPSVII mice resulted in only minor clinical improvements, a more thorough understanding of this defect may ultimately lead to more targeted metabolic interventions that provide clinical benefit as an adjunct therapy.     

Secondary biochemical and morphological consequences in lysosomal storage diseases

More than 50 hereditary lysosomal storage disorders (LSDs) are currently described. Most of these disorders are due to a deficiency of certain hydrolases/glycosidases and subsequent accumulation of nonhydrolyzable carbohydrate-containing compounds in lysosomes. Such accumulation causing hypertrophy of the lysosomal compartment is a characteristic feature of affected cells in LSDs. The investigation of biochemical and cellular parameters is of particular interest for understanding “life” of lysosomes in the normal state and in LSDs. This review highlights the wide spectrum of biochemical and morphological changes during developing LSDs that are extremely critical for many metabolic processes inside the various cells and tissues of affected persons. The data presented will help establish new complex strategies for metabolic correction of LSDs.     

Role of fatty acid transport protein 4 in metabolic tissues: insights into obesity and fatty liver disease

Fatty acid (FA) metabolism is a series of processes that provide structural substances, signalling molecules and energy. Ample evidence has shown that FA uptake is mediated by plasma membrane transporters including FA transport proteins (FATPs), caveolin-1, fatty-acid translocase (FAT)/CD36, and fatty-acid binding proteins. Unlike other FA transporters, the functions of FATPs have been controversial because they contain both motifs of FA transport and fatty acyl-CoA synthetase (ACS). The widely distributed FATP4 is not a direct FA transporter but plays a predominant function as an ACS. FATP4 deficiency causes ichthyosis premature syndrome in mice and humans associated with suppression of polar lipids but an increase in neutral lipids including triglycerides (TGs). Such a shift has been extensively characterized in enterocyte-, hepatocyte-, and adipocyte-specific Fatp4-deficient mice. The mutants under obese and non-obese fatty livers induced by different diets persistently show an increase in blood non-esterified free fatty acids and glycerol indicating the lipolysis of TGs. This review also focuses on FATP4 role on regulatory networks and factors that modulate FATP4 expression in metabolic tissues including intestine, liver, muscle, and adipose tissues. Metabolic disorders especially regarding blood lipids by FATP4 deficiency in different cell types are herein discussed. Our results may be applicable to not only patients with FATP4 mutations but also represent a model of dysregulated lipid homeostasis, thus providing mechanistic insights into obesity and development of fatty liver disease.     

Molecular mechanisms of pathogenesis in a glycosphingolipid and a glycoprotein storage disease

The lysosomal system comprises a specialized network of organelles crucial for the sorting, digestion, recycling and secretion of cellular components. With their content of hydrolytic enzymes, lysosomes regulate the degradation of a multitude of substrates that reach these organelles via the biosynthetic or the endocytic route. Gene defects that affect one or more of these hydrolases lead to LSDs (lysosomal storage diseases). This underscores the apparent lack of redundancy of these enzymes and the importance of the lysosomal system in cell and tissue homoeostasis. Some of the lysosomal enzymes may form multiprotein complexes, which usually work synergistically on substrates and, in this configuration, may respond more efficiently to changes in substrate load and composition. A well-characterized lysosomal multienzyme complex is the one comprising the glycosidases β-gal (β-galactosidase) and NEU1 (neuramidase-1), and of the serine carboxypeptidase PPCA (protective protein/cathepsin A). Three neurodegenerative LSDs are caused by either single or combined deficiency of these lysosomal enzymes. Sialidosis (NEU1 deficiency) and galactosialidosis (combined NEU1 and β-gal deficiency, secondary to a primary defect of PPCA) belong to the glycoprotein storage diseases, whereas GM1-gangliosidosis (β-gal deficiency) is a glycosphingolipid storage disease. Identification of novel molecular pathways that are deregulated because of loss of enzyme activity and/or accumulation of specific metabolites in various cell types has shed light on mechanisms of disease pathogenesis and may pave the way for future development of new therapies for these LSDs.     

Genistein improves neuropathology and corrects behaviour in a mouse model of neurodegenerative metabolic disease

Background

Neurodegenerative metabolic disorders such as mucopolysaccharidosis IIIB (MPSIIIB or Sanfilippo disease) accumulate undegraded substrates in the brain and are often unresponsive to enzyme replacement treatments due to the impermeability of the blood brain barrier to enzyme. MPSIIIB is characterised by behavioural difficulties, cognitive and later motor decline, with death in the second decade of life. Most of these neurodegenerative lysosomal storage diseases lack effective treatments. We recently described significant reductions of accumulated heparan sulphate substrate in liver of a mouse model of MPSIIIB using the tyrosine kinase inhibitor genistein.

Methodology/Principal Findings

We report here that high doses of genistein aglycone, given continuously over a 9 month period to MPSIIIB mice, significantly reduce lysosomal storage, heparan sulphate substrate and neuroinflammation in the cerebral cortex and hippocampus, resulting in correction of the behavioural defects observed. Improvements in synaptic vesicle protein expression and secondary storage in the cerebral cortex were also observed.

Conclusions/Significance

Genistein may prove useful as a substrate reduction agent to delay clinical onset of MPSIIIB and, due to its multimodal action, may provide a treatment adjunct for several other neurodegenerative metabolic diseases.     

Improved glucose control and reduced body fat mass in free fatty acid receptor 2-deficient mice fed a high-fat diet

Free fatty acid receptor 2 (Ffar2), also known as GPR43, is activated by short-chain fatty acids (SCFA) and expressed in intestine, adipocytes, and immune cells, suggesting involvement in lipid and immune regulation. In the present study, Ffar2-deficient mice (Ffar2-KO) were given a high-fat diet (HFD) or chow diet and studied with respect to lipid and energy metabolism. On a HFD, Ffar2-KO mice had lower body fat mass and increased lean body mass. The changed body composition was accompanied by improved glucose control and lower HOMA index, indicating improved insulin sensitivity in Ffar2-KO mice. Moreover, the Ffar2-KO mice had higher energy expenditure accompanied by higher core body temperature and increased food intake. The liver weight and content of triglycerides as well as plasma levels of cholesterol were lower in the Ffar2-KO mice fed a HFD. A histological examination unveiled decreased lipid interspersed in brown adipose tissue of the Ffar2-KO mice. Interestingly, no significant differences in white adipose tissue (WAT) cell size were observed, but significantly lower macrophage content was detected in WAT from HFD-fed Ffar2-KO compared with wild-type mice. In conclusion, Ffar2 deficiency protects from HFD-induced obesity and dyslipidemia at least partly via increased energy expenditure.     

Autophagy in astrocytes: A novel culprit in lysosomal storage disorders

Neurodegeneration is a prominent feature of lysosomal storage disorders (LSDs). Emerging data identify autophagy dysfunction in neurons as a major component of the phenotype. However, the autophagy pathway in the CNS has been studied predominantly in neurons, whereas in other cell types it has been largely unexplored. We studied the lysosome-autophagic pathway in astrocytes from a murine model of multiple sulfatase deficiency (MSD), a severe form of LSD. Similar to what was observed in neurons, we found that lysosomal storage in astrocytes impairs autophagosome maturation and this, in turn, has an impact upon the survival of cortical neurons and accounts for some of the neurological features found in MSD. Thus, our data indicate that lysosomal/autophagic dysfunction in astrocytes is an important component of neurodegeneration in LSDs.     

Letting lipids go: hormone-sensitive lipase

PURPOSE OF REVIEW: Despite their pathophysiological importance, the molecular mechanisms and enzymatic components of lipid mobilization from intracellular storage compartments are insufficiently understood. The aim of this review is to evaluate the role of hormone-sensitive lipase in this process. RECENT FINDINGS: Hormone-sensitive lipase exhibits a broad specificity for lipid substrates such as triglycerides, diglycerides, cholesteryl esters, and retinyl esters and the enzyme is in a wide variety of tissues. The high enzyme activity in adipose tissue was considered rate-limiting in the degradation of stored triglycerides. This view of a single enzyme controlling the catabolism of stored fat was challenged by recent findings that in hormone-sensitive lipase deficient mice adipose tissue triglycerides were still hydrolyzed and that these animals were leaner than normal mice. These results indicated that in adipose tissue hormone-sensitive lipase cooperates with other yet unidentified lipases to control the mobilization of fatty acids from cellular depots and that this process is coordinately regulated with lipid synthesis. Induced mutant mouse lines that overexpress or lack hormone-sensitive lipase also provided evidence that hormone-sensitive lipase-mediated cholesteryl ester hydrolysis is involved in steroid-hormone production in adrenals and affects testis function. Finally, hormone-sensitive lipase deficiency in mice results in a lipoprotein profile characterized by low triglyceride and VLDL levels and increased HDL cholesterol concentrations. SUMMARY: The 'anti-atherosclerotic' plasma lipoprotein profile and the fact that hormone-sensitive lipase deficient animals become lean identifies the inhibition of hormone-sensitive lipase as a potential target for the treatment of lipid disorders and obesity.     

Mitochondrial Ca2+ homeostasis in lysosomal storage diseases

Lysosomal storage diseases (LSDs) are a class of genetic disorders in which proteins responsible for digestion or absorption of endocytosed material do not function or do not localize properly. The resulting cellular "indigestion" causes buildup of intracellular storage inclusions that contain unprocessed lipids and proteins that form macromolecular complexes. The buildup of storage material is associated with degenerative processes that are observed in all LSDs, albeit the correlation between the amount of storage inclusions and the severity of the degenerative processes is not always evident. The latter suggests that a specific mechanism set in motion by aberrant lysosomal function drives the degenerative processes in LSDs. It is becoming increasingly clear that in addition to their function in degrading endocytosed material, lysosomes are essential housekeeping organelles responsible for maintaining healthy population of intracellular organelles, in particular mitochondria. The present review surveys the current knowledge on the lysosomal-mitochondrial axis and its possible role as a contributing factor to mitochondrial Ca(2+) homeostasis and to cell death in LSDs.     

Autophagy in astrocytes

Neurodegeneration is a prominent feature of lysosomal storage disorders (LSDs). Emerging data identify autophagy dysfunction in neurons as a major component of the phenotype. However, the autophagy pathway in the CNS has been studied predominantly in neurons, whereas in other cell types it has been largely unexplored. We studied the lysosome-autophagic pathway in astrocytes from a murine model of multiple sulfatase deficiency (MSD), a severe form of LSD. Similar to what was observed in neurons, we found that lysosomal storage in astrocytes impairs autophagosome maturation and this, in turn, has an impact upon the survival of cortical neurons and accounts for some of the neurological features found in MSD. Thus, our data indicate that lysosomal/autophagic dysfunction in astrocytes is an important component of neurodegeneration in LSDs.     

Finding pathogenic commonalities between Niemann-Pick type C and other lysosomal storage disorders: Opportunities for shared therapeutic interventions

Lysosomal storage disorders (LSDs) are diseases characterized by the accumulation of macromolecules in the late endocytic system and are caused by inherited defects in genes that encode mainly lysosomal enzymes or transmembrane lysosomal proteins. Niemann-Pick type C disease (NPCD), a LSD characterized by liver damage and progressive neurodegeneration that leads to early death, is caused by mutations in the genes encoding the NPC1 or NPC2 proteins. Both proteins are involved in the transport of cholesterol from the late endosomal compartment to the rest of the cell. Loss of function of these proteins causes primary cholesterol accumulation, and secondary accumulation of other lipids, such as sphingolipids, in lysosomes. Despite years of studying the genetic and molecular bases of NPCD and related-lysosomal disorders, the pathogenic mechanisms involved in these diseases are not fully understood. In this review we will summarize the pathogenic mechanisms described for NPCD and we will discuss their relevance for other LSDs with neurological components such as Niemann- Pick type A and Gaucher diseases. We will particularly focus on the activation of signaling pathways that may be common to these three pathologies with emphasis on how the intra-lysosomal accumulation of lipids leads to pathology, specifically to neurological impairments. We will show that although the primary lipid storage defect is different in these three LSDs, there is a similar secondary accumulation of metabolites and activation of signaling pathways that can lead to common pathogenic mechanisms. This analysis might help to delineate common pathological mechanisms and therapeutic targets for lysosomal storage diseases.     

Early neurodegeneration progresses independently of microglial activation by heparan sulfate in the brain of mucopolysaccharidosis IIIB mice

Background

In mucopolysaccharidosis type IIIB, a lysosomal storage disease causing early onset mental retardation in children, the production of abnormal oligosaccharidic fragments of heparan sulfate is associated with severe neuropathology and chronic brain inflammation. We addressed causative links between the biochemical, pathological and inflammatory disorders in a mouse model of this disease.

Methodology/Principal Findings

In cell culture, heparan sulfate oligosaccharides activated microglial cells by signaling through the Toll-like receptor 4 and the adaptor protein MyD88. CD11b positive microglial cells and three-fold increased expression of mRNAs coding for the chemokine MIP1α were observed at 10 days in the brain cortex of MPSIIIB mice, but not in MPSIIIB mice deleted for the expression of Toll-like receptor 4 or the adaptor protein MyD88, indicating early priming of microglial cells by heparan sulfate oligosaccharides in the MPSIIIB mouse brain. Whereas the onset of brain inflammation was delayed for several months in doubly mutant versus MPSIIIB mice, the onset of disease markers expression was unchanged, indicating similar progression of the neurodegenerative process in the absence of microglial cell priming by heparan sulfate oligosaccharides. In contrast to younger mice, inflammation in aged MPSIIIB mice was not affected by TLR4/MyD88 deficiency.

Conclusions/Significance

These results indicate priming of microglia by HS oligosaccharides through the TLR4/MyD88 pathway. Although intrinsic to the disease, this phenomenon is not a major determinant of the neurodegenerative process. Inflammation may still contribute to neurodegeneration in late stages of the disease, albeit independent of TLR4/MyD88. The results support the view that neurodegeneration is primarily cell autonomous in this pediatric disease.     

Bis(monoacylglycero)phosphate: a secondary storage lipid in the gangliosidoses

Bis(monoacylglycero)phosphate (BMP) is a negatively charged glycerophospholipid with an unusual sn-1;sn-1′ structural configuration. BMP is primarily enriched in endosomal/lysosomal membranes. BMP is thought to play a role in glycosphingolipid degradation and cholesterol transport. Elevated BMP levels have been found in many lysosomal storage diseases (LSDs), suggesting an association with lysosomal storage material. The gangliosidoses are a group of neurodegenerative LSDs involving the accumulation of either GM1 or GM2 gangliosides resulting from inherited deficiencies in β-galactosidase or β-hexosaminidase, respectively. Little information is available on BMP levels in gangliosidosis brain tissue. Our results showed that the content of BMP in brain was significantly greater in humans and in animals (mice, cats, American black bears) with either GM1 or GM2 ganglioside storage diseases, than in brains of normal subjects. The storage of BMP and ganglioside GM2 in brain were reduced similarly following adeno-associated viral-mediated gene therapy in Sandhoff disease mice. We also found that C22:6, C18:0, and C18:1 were the predominant BMP fatty acid species in gangliosidosis brains. The results show that BMP accumulates as a secondary storage material in the brain of a broad range of mammals with gangliosidoses.     

Adipose deficiency and aberrant autophagy in a Drosophila model of MPS VII is corrected by pharmacological stimulators of mTOR

Mucopolysaccharidosis type VII (MPS VII) is a recessively inherited lysosomal storage disorder caused due to β-glucuronidase (β-GUS) enzyme deficiency. Prominent clinical symptoms include hydrops fetalis, musculoskeletal deformities, neurodegeneration and hepatosplenomegaly leading to premature death in most cases. Apart from these, MPS VII is also characterized as adipose storage deficiency disorder although the underlying mechanism of this lean phenotype in the patients or β-GUS-deficient mice still remains a mystery. We addressed this issue using our recently developed Drosophila model of MPS VII (the CG2135^-/- fly), which also exhibited a significant loss of body fat. We report here that the lean phenotype of the CG2135^?/? larvae is due to fewer number of adipocytes, smaller lipid droplets and reduced adipogenesis. Our data further revealed that there is an abnormal accumulation of autophagosomes in the CG2135^?/? larvae due to autophagosome-lysosome fusion defect. Decreased lysosome-mediated turnover also led to attenuated mTOR activity in the CG2135^?/? larvae. Interestingly, treatment of the CG2135^?/? larvae with mTOR stimulators, 3BDO or glucose, led to the restoration of mTOR activity with simultaneous correction of the autophagy defect and adipose storage deficiency. Our finding thus established a hitherto unknown mechanistic link between autophagy dysfunction, mTOR downregulation and reduced adiposity in MPS VII.     

Hepatocyte-specific lysosomal acid lipase deficiency protects mice from diet-induced obesity but promotes hepatic inflammation

Lysosomal acid lipase (LAL) hydrolyzes cholesteryl esters (CE) and triglycerides (TG) to generate fatty acids (FA) and cholesterol. LAL deficiency (LAL-D) in both humans and mice leads to hepatomegaly, hypercholesterolemia, and shortened life span. Despite its essential role in lysosomal neutral lipid catabolism, the cell type-specific contribution of LAL to disease progression is still elusive. To investigate the role of LAL in the liver in more detail and to exclude the contribution of LAL in macrophages, we generated hepatocyte-specific LAL-deficient mice (Liv-Lipa^−/−) and fed them either chow or high fat/high cholesterol diets (HF/HCD). Comparable to systemic LAL-D, Liv-Lipa^−/− mice were resistant to diet-induced obesity independent of food intake, movement, and energy expenditure. Reduced body weight gain was mainly due to reduced white adipose tissue depots. Furthermore, Liv-Lipa^−/− mice exhibited improved glucose clearance during glucose and insulin tolerance tests compared to control mice. Analysis of hepatic lipid content revealed a massive reduction of TG, whereas CE concentrations were markedly increased, leading to CE crystal formation in the livers of Liv-Lipa^−/− mice. Elevated plasma transaminase activities, increased pro-inflammatory cytokines and chemokines as well as hepatic macrophage infiltration indicated liver inflammation. Our data provide evidence that hepatocyte-specific LAL deficiency is sufficient to alter whole-body lipid and energy homeostasis in mice. We conclude that hepatic LAL plays a pivotal role by preventing liver damage and maintaining lipid and energy homeostasis, especially during high lipid availability.     

From Lysosomal Storage Disorders to Parkinson’s Disease – Challenges and Opportunities

Lysosomes are specialized organelles with an acidic pH that act as recycling hubs for intracellular and extracellular components. They harbour numerous different hydrolytic enzymes to degrade substrates like proteins, peptides, and glycolipids. Reduced catalytic activity of lysosomal enzymes can cause the accumulation of these substrates and loss of lysosomal integrity, resulting in lysosomal dysfunction and lysosomal storage disorders (LSDs). Post-mitotic cells, such as neurons, seem to be highly sensitive to damages induced by lysosomal dysfunction, thus LSDs often manifest with neurological symptoms. Interestingly, some LSDs and Parkinson’s disease (PD) share common cellular pathomechanisms, suggesting convergence of aetiology of the two disease types. This is further underlined by genetic associations of several lysosomal genes involved in LSDs with PD. The increasing number of lysosome-associated genetic risk factors for PD makes it necessary to understand functions and interactions of lysosomal proteins/enzymes both in health and disease, thereby holding the potential to identify new therapeutic targets. In this review, we highlight genetic and mechanistic interactions between the complex lysosomal network, LSDs and PD, and elaborate on methodical challenges in lysosomal research.