Our cells depend on specific systems to stay healthy. One important part of these systems is lysosomes, which are organelles that contain digestive enzymes. Essentially, lysosomes act as the cell’s “garbage disposal” by breaking down and recycling waste material in cells. In people affected by lysosomal disorders, also known as lysosomal storage disorders, there is a dysfunction or defect in lysosome function that impacts the breakdown or recycling of waste materials inside cells. As a result, waste builds up inside these cells, which impacts their normal function. Lysosomal disorders can affect many organs, including the brain, and many individuals affected by lysosomal disorders present with neurological symptoms and clinical manifestations of neurodegeneration. 

Continue reading to learn about what lysosomal storage disorders are, how they impact the brain, and why nervous system degeneration occurs so frequently in lysosomal disorders. 

What are lysosomal storage disorders?

Lysosomal storage disorders (LSDs) are a group of inherited conditions caused by genetic mutations in lysosome-related genes. Most LSDs occur due to enzyme deficiencies as a result of these genetic mutations.¹ In a normal lysosome, enzymes will break down different substances such as proteins, lipids, nucleic acids, and carbohydrates.² However, when there is an enzyme deficiency, this ‘waste system’ of the lysosome is impacted and there is an accumulation of these undegraded substances. As a result, normal cellular function will be affected. 

There are over 70 identified LSDs.³ Some of the more common examples include: 

• Tay-Sachs
• Gaucher disease
• Fabry disease 
• Hunter syndrome

Whilst LSDs can present differently and affect multiple organs, such as the heart, liver, and digestive system, their effect on the central nervous system and the brain is one of the most notable. Many LSDs can cause progressive degeneration in the brain, and many individuals affected by LSDs present with neurological symptoms, such as seizures and developmental delays.⁴ 

Mechanisms of nervous system degeneration: what goes wrong in the brain?

The nervous system is particularly vulnerable when there is dysfunction in lysosomes, possibly due to its reliance on lysosomes as the primary form of waste clearance.⁵ Whilst lysosomal storage disorders can impact the nervous system and cause degeneration through multiple underlying mechanisms, the root problem and defining feature of all LSDs is the buildup of undegraded substances inside cells. This accumulation of undegraded substances in cells can trigger a variety of secondary processes, including neuroinflammation, oxidative stress, and impaired autophagy, which can contribute to nervous system degeneration. 

Waste accumulation in neurons

In lysosomal storage disorders, defective lysosomal enzymes or missing lysosomal enzymes will prevent or limit the breakdown of substances in cells, such as lipids and carbohydrates. These undegraded substrates will accumulate in neurons and glial cells, and the accumulation of these substrates will interfere with normal cellular function. When waste builds up in cells, lysosomes can become enlarged and dysfunctional, which leads to several consequences, including cellular stress, inflammation, and possibly cell death. For example, Niemann-Pick disease type C, a type of LSD, typically involves progressive neurodegenerative symptoms. These neurological manifestations are a result of accumulated cholesterol and sphingolipids.⁶ Moreover, when neurons are overloaded with substrates that they can’t break down, it can impact their normal cellular function and ultimately lead to progressive degeneration and brain damage. 

Impaired autophagy 

Autophagy is a natural process carried out by cells to deliver cellular components to lysosomes for the purpose of degrading and recycling them.⁷ Because functioning lysosomes are essential for the process of autophagy, when there is dysfunction in lysosomes, it disrupts this process of breaking down and degrading cellular components. In LSDs, impaired autophagy can contribute to the accumulation of toxic proteins or cellular components, which triggers degenerative processes in neuronal cells and contributes to neurodegeneration.⁸ 

Neuroinflammation

The central nervous system has its own immune-like system, which consists of cells such as microglia and astrocytes. In LSDs, the accumulation of waste, or undegraded cell components, can trigger microglia and astrocytes in the central nervous system. This can stimulate a proinflammatory response and create a neurotoxic environment, which contributes to the damage of neurons and the progressive neurodegeneration observed in some LSDs. Additionally, neuroinflammation is often associated with the activation of reactive oxygen species.⁹ The buildup of reactive oxygen species, which are molecules that play a significant role in inflammation, contributes to oxidative stress. Moreover, when this inflammatory response becomes persistent, it can often worsen neurological symptoms and cause further damage to the nervous system and ultimately heighten disease progression.¹⁰ 

Additional mechanisms

Other mechanisms that may be involved in neurological lysosomal storage disorders include mitochondrial dysfunction, demyelination, and impaired synapse function.⁴ 

Examples of lysosomal disorders

Listed below are some examples of lysosomal disorders that have been associated with neurodegeneration and a clinical presentation of neurological symptoms. 

Tay-sachs disease

Tay-Sachs is a neurodegenerative disease that causes progressive neurological decline. Tay-Sachs can begin presenting in infancy, early childhood, or even adulthood, with symptoms and prognosis varying depending on the age of presentation. Tay-Sachs that begins in infancy, known as infantile Tay-Sachs, is usually diagnosed a few months after birth and is often the most severe type of Tay-Sachs. Typical symptoms include developmental delay, cognitive decline, seizures, incoordination, and weakness in muscles.¹¹ It is caused by an enzyme deficiency, which causes a build-up of certain lipids known as gangliosides. The buildup of these undegraded lipids contributes to neurodegeneration and damage to the central nervous system.

Gaucher disease types 2 & 3

Gaucher disease is another type of lysosomal storage disorder and is classified based on its involvement with the nervous system.¹² Gaucher type 1 is the most common type of Gaucher and typically has little or no neurological manifestation, whilst types 2 and 3 are associated with the involvement of the central nervous system and progressive neurodegeneration. Symptoms include cognitive decline, seizures, intellectual disability, apnea, and dementia.¹³ Gaucher disease is caused by a genetic mutation in the GBA1 gene, which causes an enzyme deficiency. The enzyme deficiency results in the accumulation of a glycolipid, known as glucocerebroside, in lysosomes. This contributes to the neurological effects of Gaucher disease and the subsequent neurodegeneration.¹²   

Krabbe disease 

Krabbe disease is an LSD that presents with significant neurological damage. It is caused by a mutation in the GALC gene, which results in a deficiency of an enzyme involved in the production of myelin. This enzyme deficiency causes a buildup of psychosine, a toxic lipid that triggers the death of cells that help form myelin.¹⁴ This damage to myelin is known as demyelination. A defining characteristic of Krabbe disease is the degeneration of white matter, which is a result of the demyelination that occurs.¹⁵ Symptoms of Krabbe disease, as well as their severity, will vary depending on the age of presentation. Krabbe’s disease presents in early infancy; common symptoms include difficulty feeding, developmental delays, irritability, restlessness, and possibly seizures. Infantile Krabbe disease can further progress and cause deafness and blindness. 

Niemann-pick type C

Another lysosomal storage disorder with neurological manifestations is Niemann-Pick Type C. It is caused by a genetic mutation in the NPC1 and NPC2 genes, which causes a buildup of cholesterol and lipids, specifically sphingolipids, in lysosomes. This accumulation leads to the manifestation of several neurological symptoms and results in progressive neurological decline. Symptoms include developmental delays, walking problems, falls, motor delays, language delays, and clumsiness.¹⁶

Summary 

• Lysosomal storage disorders are genetic conditions that impair the function of lysosomes, most often due to enzyme deficiencies caused by these genetic mutations
• Impaired lysosomal function will cause waste, or undegraded substances, in cells to build up and accumulate, which interferes with normal cell function
• Examples of LSDs that have neurological manifestations include Tay-Sachs, Krabbe disease, Gaucher disease types 2 & 3, and Niemann-Pick type C
• A majority of LSDs will cause neurological symptoms and can lead to neurodegeneration and damage to the central nervous system
• This neurodegeneration occurs as a result of various underlying mechanisms, which include:
  • Impaired autophagy: The process that involves delivering cells to lysosomes to be degraded and recycled can be impaired, which allows for the accumulation of toxic proteins or substrates in neurons
  • Neuroinflammation: Accumulated waste in cells can lead to the triggering of inflammatory responses in the nervous system, which creates a neurotoxic environment that exacerbates neurological symptoms
  • Demyelination: Accumulated waste in neuronal cells can lead to the degeneration of myelin, which causes damage to the white matter of the brain
• These underlying mechanisms can all play a role in neurodegeneration and damage to the nervous system