Pathophysiology of neuropathic lysosomal storage disorders

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.

Gemfibrozil and Fenofibrate, Food and Drug Administration-approved Lipid-lowering Drugs, Up-regulate Tripeptidyl-peptidase 1 in Brain Cells via Peroxisome Proliferator-activated Receptor α

“…Mutations in the Cln2 gene result in deficiency or loss of function of the TPP1 enzyme (9,30,35). There have been reports of over 68 missense mutations in the Cln2 gene, including 35 single amino acid substitutions.…”

Development of targeted therapies for Parkinson's disease and related synucleinopathies

“…In these diseases, a defi ciency of hexosaminidase A and/or B leads to a buildup of GM2 that leads to neurodegeneration. Both diseases are associated with development of Lewy bodies and synuclein aggregates ( 7,8 ). As in the case of GlcCer, GM2 also has been shown to interact with synuclein and may contribute to neurodegeneration via a similar feedback loop, as proposed for glucocerebrosidase and synuclein ( 49,50 ).…”

“…More than 50 LSDs are known and are usually classifi ed according to the nature of the accumulating substrate. Pathology in the CNS is a common feature of most LSDs ( 7,8 ). While the best example of this is the link between Gaucher's disease (GD) and parkinsonism, the link between other LSDs and PD is suggested, but less well documented due to the small number of patients ( 8 ).…”

Non Viral Gene Transfer Approaches for Lysosomal Storage Disorders

“…Lysosomal enzymes are ubiquitously distributed, but substrate storage is usually restricted to cells, tissues and organs with higher substrate turnover. Recently, it has been suggested that the primary gene defect and substrate storage are triggers of a complex cascade of events that lead to many of the disease manifestations (Bellettato & Scarpa, 2010). In this context, secondary substrate storage, perturbations of Calcium homeostasis and lipid trafficking would contribute to disease pathogenesis.…”