The Chitinases as Biomarkers for Amyotrophic Lateral Sclerosis: Signals From the CNS and Beyond

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.

Discovery of Biomarkers for Amyotrophic Lateral Sclerosis and Frontotemporal Lobar Degeneration From Human Cerebrospinal Fluid Using Mass Spectrometry-Based Proteomics

“…Neurofilament proteins are intermediate filament proteins that are elevated in response to neuronal damage [22,34], while CHIT1, CHI3L1 and CHI3L2 are members of the human chitinase family that are implicated in inflammation [21]. UCHL1 is a ubiquitin-protein hydrolase important for protein homeostasis that is expressed in neurons and neuroendocrine cells, whereas APOB is associated with metabolic changes in ALS [30,35].…”

“…These include the neurofilament proteins (NEFL, NEFM and NEFH) [22], which were robustly elevated in ALS, and CHIT1 [22,23,29], which showed a >16-fold increase in the ALS samples compared to HC samples. CHI3L2 and UCHL1 [20,21], which showed increases of ~6 fold and ~2 fold respectively and APOB [30], which was elevated by ~4 fold, were also identified in CSF from ALS patients. In addition, we identified several proteins that were downregulated in ALS, the most prominent of which included L1CAM1 and NPTX2, which was previously identified as downregulated in FTLD [31].…”

“…Mass spectrometry (MS)-based proteomics have been considered the gold standard for protein discovery and there have been multiple attempts to develop protein biomarkers for ALS using proteomics technology [5,6,[15][16][17][18][19]. So far, multiple proteins, including CHIT1, CHI3L1, CHI3L2, UCHL1, MAP2, GPNMB and neurofilament proteins, have been reported as candidate ALS biomarkers [20][21][22][23]. Many of these proteins await rigorous validation, but a few such as neurofilament are also altered in FTLD and have extremely promising clinical applications [24].…”

Monocyte-Derived Macrophages Contribute to Chitinase Dysregulation in Amyotrophic Lateral Sclerosis: A Pilot Study

“…The data reported here are also interesting given that the chitinases themselves are active immune-modulators; for instance, stimulating monocytes with either CHI3L1 or CHIT1 resulted in the release of IL-8, MCP-1, and RANTES (20). Indeed, a "feed-forward" loop wherein the chitinases sustain neuroinflammation in ALS via their autoand paracrine effects has already been postulated (12). For instance, Varghese et al demonstrated that microglia appear to be the primary cellular source for CHIT1 in the CNS using murine cultures and that microglia themselves were susceptible to the effects of accumulated CHIT1, as they were chronically activated as a result of exposure (11).…”

“…In ALS, these moieties exacerbate neuroinflammation and directly affect neuronal viability (11)(12)(13). While studies using post-mortem motor cortex and spinal cord tissue from ALS patients have reported micro-and astroglial expression of CHIT1 and CHI3L1, respectively, the cellular origins of these targets remain to be fully understood.…”