Neuroinflammation in Gaucher disease, neuronal ceroid lipofuscinosis, and commonalities with Parkinson’s disease

• Published in: Brain research Vol. 1780; p. 147798
• Main Authors: Francelle, Laetitia, Mazzulli, Joseph R.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01-04-2022
• Subjects: Animals; Batten’s disease; Gaucher disease; Gaucher Disease - metabolism; Gaucher Disease - pathology; Humans; Lysosomal storage disorders; Lysosomes - metabolism; Lysosomes - pathology; Neuroinflammation; Neuroinflammatory Diseases - metabolism; Neuroinflammatory Diseases - pathology; Neuronal Ceroid-Lipofuscinoses - metabolism; Neuronal Ceroid-Lipofuscinoses - pathology; Parkinson Disease - metabolism; Parkinson Disease - pathology; Parkinson’s disease; Neuroinflammation; Gaucher disease; Lysosomal storage disorders; Batten’s disease; Parkinson’s disease
• ISSN: 0006-8993; 1872-6240
• DOI: 10.1016/j.brainres.2022.147798

•Distinct molecular subtypes of microglia and astrocytes exist in the brain that have deleterious or beneficial effects on neurons.•Neuroinflammatory processes play an important role in neurodegenerative process of lysosomal diseases.•Common genetic, pathological, and molecular features exist that link rare lysosomal diseases to common age-related neurodegeneration.
Lysosomal storage diseases (LSDs) are rare genetic disorders caused by a disruption in cellular clearance, resulting in pathological storage of undegraded lysosomal substrates. Recent clinical and genetic studies have uncovered links between multiple LSDs and common neurodegenerative diseases such as Parkinson’s disease (PD). Here, we review recent literature describing the role of glia cells and neuroinflammation in PD and LSDs, including Gaucher disease (GD) and neuronal ceroid lipofuscinosis (NCL), and highlight converging inflammation pathways that lead to neuron loss. Recent data indicates that lysosomal dysfunction and accumulation of storage materials can initiate the activation of glial cells, through interaction with cell surface or cytosolic pattern recognition receptors that detect pathogenic aggregates of cellular debris. Activated glia cells could act to protect neurons through the elimination of toxic protein or lipid aggregates early in the disease process. However prolonged glial activation that occurs over several decades in chronic-age related neurodegeneration could induce the inappropriate elimination of synapses, leading to neuron loss. These studies provide mechanistic insight into the relationship between lysosomal dysfunction and glial activation, and offer novel therapeutic pathways for the treatment of PD and LSDs focused on reducing neuroinflammation and mitigating cell loss.