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Pathophysiology of neuropathic lysosomal storage disorders

  • LSDs with Neurologic Involvement
  • Published:
Journal of Inherited Metabolic Disease

Abstract

Although neurodegenerative diseases are most prevalent in the elderly, in rare cases, they can also affect children. Lysosomal storage diseases (LSDs) are a group of inherited metabolic neurodegenerative disorders due to deficiency of a specific protein integral to lysosomal function, such as enzymes or lysosomal components, or to errors in enzyme trafficking/targeting and defective function of nonenzymatic lysosomal proteins, all preventing the complete degradation and recycling of macromolecules. This primary metabolic event determines a cascade of secondary events, inducing LSD’s pathology. The accumulation of intermediate degradation affects the function of lysosomes and other cellular organelles. Accumulation begins in infancy and progressively worsens, often affecting several organs, including the central nervous system (CNS). Affected neurons may die through apoptosis or necrosis, although neuronal loss usually does not occur before advanced stages of the disease. CNS pathology causes mental retardation, progressive neurodegeneration, and premature death. Many of these features are also found in adult neurodegenerative disorders, such as Alzheimer’s, Parkinson’s, and Huntington’s diseases. However, the nature of the secondary events and their exact contribution to mental retardation and dementia remains largely unknown. Recently, lysosomal involvement in the pathogenesis of these disorders has been described. Improved knowledge of secondary events may have impact on diagnosis, staging, and follow-up of affected children. Importantly, new insights may provide indications about possible disease reversal upon treatment. A discussion about the CNS pathophysiology involvement in LSDs is the aim of this review. The lysosomal involvement in adult neurodegenerative diseases will also be briefly described.

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Abbreviations

AD:

Alzheimer’s disease

ATP:

Adenosine-5'-triphosphate

Aβ:

β-amyloid peptide

CNS:

Central nervous system

E/L:

Endosomal/lysosomal

ER:

Endoplasmic reticulum

GSL:

Glycosphingolipid

HD:

Huntington’s disease

LSDs:

Lysosomal storage diseases

MAL:

Myelin and lymphocyte protein

ML:

Mucolipidosis

MLD:

Metachromatic leukodystrophy

MPS:

Mucopolysaccharidosis

MSD:

Multiple sulfatase deficiency

NCLs:

Neuronal ceroid lipofuscinoses

NFTs:

Neurofibrillary tangles

NPC:

Niemann-Pick type C

PD:

Parkinson’s disease

PHFs:

Paired helical filaments

SERCA:

Sarco/endoplasmic reticulum Ca2+−ATPase

TGN:

Trans-Golgi network

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Acknowledgement

Authors thank Prof. Ed Wraith, Manchester Children’s Hospital, Manchester, UK, for critical reading of the manuscript. Maurizio Scarpa and David Begley, Kings College London, London UK, have recently co-founded the Pan-European Consortium, Brains For Brain, designed to foster and improve research on, and treatment of, lysosomal storage disorders throughout Europe. (www.brains4brain.eu).

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  1. Department of Paediatrics, Centre for Rare Diseases, University of Padova, Via Giustiniani 3, 35128, Padova, Italy

    Cinzia Maria Bellettato & Maurizio Scarpa

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  1. Cinzia Maria Bellettato
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  2. Maurizio Scarpa
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Correspondence to Maurizio Scarpa.

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Communicated by: Gregory Pastores

Competing interest: None declared.

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Bellettato, C.M., Scarpa, M. Pathophysiology of neuropathic lysosomal storage disorders. J Inherit Metab Dis 33, 347–362 (2010). https://doi.org/10.1007/s10545-010-9075-9

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