Introduction

Lysosomal storage diseases (LSDs) are a collection of inherited metabolic disorders caused by lysosomal dysfunction. Lysosomes are structures inside cells containing digestive enzymes that cause chemical reactions to break down or metabolise nutrients and cellular debris. LSDs lead to the accumulation of undigested substances in the body’s cells and organs.¹ 

Most people with LSD develop their condition through autosomal recessive inheritance. They lack certain enzymes or proteins that assist with enzyme function, leading to the inability to digest carbohydrates (sugars), lipids (fats), proteins, and other substances, leading to a subsequent toxic accumulation of those substances.^1,2

LSDs also disrupt cellular processes such as autophagy and cause inflammation.¹ Understanding the interplay between lysosomal dysfunction caused by LSDs, autophagy, and inflammation can provide insights on how to improve the health outcomes of people affected. 

In this article, we will explore the role of autophagy and inflammation in lysosomal storage diseases. 

Overview of autophagy

Autophagy is a process that degrades and recycles old and damaged cell parts, maintains homeostasis within the cell, and clears cell debris from the cytoplasm. Autophagy is a normal and ongoing process in the cell. It is important for survival and maintaining normal cell functions.

Autophagy occurs when the cell senses a lack of nutrients or oxygen or damage to the cell. When parts of the cell stop functioning properly, they must be recycled so the cell can make new proteins or other cell structures.³

During autophagy, structures called autophagosomes form using autophagy-related proteins (ATGs). Autophagosomes contain cellular waste, organelles, and proteins that will be transported to lysosomes for degradation. The fusion of an autophagosome with a lysosome results in the formation of an autolysosome.⁴

There are three main types of autophagy:

• Macroautophagy – The main pathway of autophagy. Autophagosomes engulf material from the cytoplasm and fuse with lysosomes to degrade and recycle the contents
• Microautophagy – Lysosomes directly take in small volumes of cytoplasm and digest its contents 
• Chaperone-mediated autophagy – This process does not involve autophagosomes. Proteins directly cross into the lysosomes with the aid of special proteins called chaperones

Selective autophagy is autophagy that targets specific cellular components or damaged organelles. For example, selective autophagy of mitochondria is called mitophagy.⁵

Disruption of autophagy in LSDs

The functions of autophagosomes and lysosomes are highly interconnected. LSDs have been reported to impair autophagy.^6-9 Impaired fusion of autophagosomes to lysosomes occurs in Pompe disease, Danon disease, and Mucopolysaccharidoses.⁷ Blocked autophagosome-lysosome fusion leads to the accumulation of cellular components that would be degraded and recycled under normal circumstances. 

Examples of these undegraded components that can build up due to impairment of autophagy are specially-tagged proteins and damaged organelles. Blocking autophagy can result in the cell compensating for this impairment by increasing the formation of autophagosomes.⁷

Examples of LSDs where there is impaired autophagy are:

• Gaucher disease^6,7
• Batten disease^6,7
• Niemann-Pick disease¹⁰
• Tay-Sachs disease¹¹

Disruption of autophagy negatively affects cellular health and can lead to mitochondrial dysfunction, oxidative stress, and even cell death. Defective or unhealthy mitochondria are cleared through autophagy (mitophagy), and it can be impaired in LSDs. Defective mitophagy results in a buildup of damaged mitochondria and can cause neurodegenerative disorders.¹² 

While LSDs are rare, they share common signalling pathways that cause neurodegeneration with more common and well-studied neurodegenerative disorders. The connections between lysosomes, mitochondria, and autophagy contribute to LSD pathology, as well as to neurodegenerative disorders.¹²

Inflammation in LSDs

Lysosomes are important players in regulating inflammation. An early cell response to LSD is to produce more lysosomes. However, these new lysosomes are abnormal and become dysfunctional, leading to downstream cellular abnormalities, including increased autophagy, inflammation, endocytosis, and cell death.¹³

Gaucher disease is a sphingolipidosis, a type of LSD where there is a deficiency of an enzyme that breaks down lipids called sphingolipids.¹ Gaucher disease is a prime example showing the links between LSDs and inflammation. In Gaucher disease, there is a deficiency in the enzyme glucocerebrosidase, which leads to a buildup of glucosylceramide and macrophage activation. The activation of macrophages, immune cells that clear dead cells and kill microorganisms, leads to the release of cytokines. Cytokines are signalling proteins that communicate to other immune cells to migrate to a site of infection. Migration of these immune cells to where sphingolipids accumulate can contribute to inflammatory pathways.¹³

Immune cell activation

Astrocytes, a type of non-neuronal cell that supports neuronal health in the brain, and microglia, resident immune cells in the central nervous system (CNS), have roles in neuroinflammation. Both of these cell types release proinflammatory and anti-inflammatory cytokines. Accumulation of materials due to LSDs can cause an imbalance in astrocyte and microglia functions, leading to neuroinflammation and neuropathology.¹⁴

Lysosomal dysfunction and (neuro)inflammation

Neuroinflammation is known to occur in many LSDs. Buildup of lysosomal storage can activate or sustain neuroinflammation and lead to the death of brain cells.14 Imbalanced production and degradation of sphingolipids, as observed in Gaucher disease and other sphingolipidoses, influence neuroinflammation. High concentrations of ceramides trigger inflammation cascades and induce apoptosis.^13,14

Accumulated lysosomal storage material in LSDs can cause endoplasmic reticulum (ER) dysfunction and ER stress due to the presence of misfolded proteins. This leads to activation of the unfolded protein response (UPR) in cells, a physiological reaction that stops protein synthesis to fix misfolded proteins.¹⁴ ER stress can contribute to neurodegeneration.¹⁵ 

Chronic inflammation

Chronic inflammation is a feature of many LSDs. It can contribute to neurodegeneration by raising the levels of cytokines, chemokines and pro-apoptotic (programmed cell death) factors. Chronic neuroinflammation can impair astrocyte activity, reducing the support they provide for neuronal health, function and protection.¹⁴

Interplay between autophagy and inflammation

Autophagy has roles in maintaining immune responses and regulating inflammation in healthy cells. Autophagy itself can be anti-inflammatory in healthy cells. Altered or defective autophagy can trigger inflammation.¹³ Debris or bacteria and other pathogens trigger the release of pro-inflammatory cytokines, which signal for autophagy induction to clear the infection. The immune system’s host cell defence mechanisms against viruses also activate autophagy.¹³

Defective autophagy leads to the accumulation of mitochondria, increased release of inflammasome activators, and increased production of reactive oxygen species (ROS). The role of normal autophagy would be to clear inflammasome structures, remove damaged organelles, reduce inflammatory responses and prevent the release of ROS, which are harmful to DNA.¹³

Inflammation, in turn, disrupts autophagy. In infections, pathogens such as viruses can manipulate pro-inflammatory factors such as cytokines and inflammasome components to impair or hijack autophagy, leading to even more inflammation. The connection between autophagy and inflammation is highly important in maintaining homeostasis, or balance, within the cell. In disease contexts, the imbalance in these processes feeds back on each other.¹⁶

Therapeutic implications

Therapeutic strategies stimulating autophagy may prevent or delay the aggregation of proteins. Pharmacological activation of autophagy has protected against neurodegeneration in Huntington's disease models. Enhancing autophagy has the potential to be a therapeutic strategy to combat the buildup of substances in the lysosome.^7,17

Anti-inflammatory therapies can be used to reduce the effects of inflammatory cytokines and reduce organ damage. Examples of such therapies include IL-1 inhibitors, corticosteroids, and immune modulators.^1,2

Combined strategies to address changes in autophagy and inflammation in lysosomal storage diseases are a potential approach to develop more effective therapeutics. 

Summary

Lysosomal storage diseases are inherited metabolic disorders that affect the proper function of lysosomes, structures in the cell that contain digestive enzymes. Alterations in autophagy and inflammation are linked to lysosomal storage diseases. Autophagy is impaired in lysosomal storage diseases. This can lead to mitochondrial dysfunction, oxidative stress, and even cell death, including neurodegeneration. Defects in lysosomal storage contribute to pro-inflammatory cell responses, including innate immune responses and neuroinflammation. 

In healthy cells, autophagy regulates immunity and inflammation; in lysosomal storage diseases, dysregulation of autophagy contributes to inflammation, which in turn further impairs autophagy. 

To improve treatments for lysosomal storage disorders, addressing dysfunction in autophagy and inflammation mechanisms is important due to their roles in maintaining homeostasis.