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Abstract
Amyotrophic lateral sclerosis (ALS) is a late-onset neurodegenerative condition, most widely characterized by the selective vulnerability of motor neurons and the poor life expectancy of afflicted patients. Limited disease-modifying therapies currently exist, which only further attests to the substantial heterogeneity associated with this disease. In addition to established prognostic factors like genetic background, site of onset, and age at onset, wide consensus on the role of neuroinflammation as a disease exacerbator and driver has been established. In lieu of this, the emerging literature on chitinases in ALS is particularly intriguing. Individual groups have reported substantially elevated chitotriosidase (CHIT1), chitinase-3-like-1 (CHI3L1), and chitinase-3-like-2 (CHI3L2) levels in the cerebrospinal, motor cortex, and spinal cord of ALS patients with multiple—and often conflicting—lines of evidence hinting at possible links to disease severity and progression. This mini-review, while not exhaustive, will aim to discuss current evidence on the involvement of key chitinases in ALS within the wider framework of other neurodegenerative conditions. Implications for understanding disease etiology, developing immunomodulatory therapies and biomarkers, and other translational opportunities will be considered.
Highlights
ALS and NeuroinflammationAmyotrophic lateral sclerosis (ALS) is the most prevalent form of adult-onset motor neuron disease and clinically presents with the relentless destruction of primarily upper and lower motor neurons (UMN, Lower Motor Neuron (LMN))
Varghese et al [26] were the first to report chitinases in the context of ALS; using quantitative mass spectrometry (MS) and ELISA-based validation in an independent cohort, they showed that cerebrospinal fluid (CSF) levels of CHIT1, CHI3L1, and CHI3L2 were significantly elevated in ALS patients relative to healthy controls (HCs)
What can be concluded of the chitinases holds true for all biomarkers; no single molecule can capture all the pathogenic processes at play in a disease as heterogeneous as ALS
Summary
Amyotrophic lateral sclerosis (ALS) is the most prevalent form of adult-onset motor neuron disease and clinically presents with the relentless destruction of primarily (but not exclusively) upper and lower motor neurons (UMN, LMN). Varghese et al [26] were the first to report chitinases in the context of ALS; using quantitative mass spectrometry (MS) and ELISA-based validation in an independent cohort, they showed that CSF levels of CHIT1, CHI3L1, and CHI3L2 were significantly elevated in ALS patients relative to healthy controls (HCs) This elevation has since been confirmed by several studies using a range of proteomic and transcriptomic methods [27,28,29,30,31,32,33]. Presence of the CHIT1 polymorphism has no influence on neurofilament levels or age of onset in patients, making a causative role in ALS pathogenesis unlikely Both CHIT1 expression and activity are significantly elevated in ALS patients (relative to HCs) independent of genotype and other factors like gender and age, indicating that disease status—rather than the presence of the polymorphism—determines the extent of dysregulation [12, 27, 30]. The majority of the results discussed here focus on CSF, as almost no robust and consistent links between blood chitinase levels and prognostic factors have been
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