Chitinases as a Novel Therapeutic Target in Parkinson’s Disease

Parkinson's disease (PD) is a progressive neurodegenerative disorder primarily characterized by motor symptoms, including tremors, impaired balance, and bradykinesia. In addition to these motor symptoms, many individuals with PD also experience a range of non-motor symptoms such as dementia, depression, and sleep disturbances, which significantly affect their quality of life. Two key pathological features of PD are the degeneration of dopaminergic neurons in the nigrostriatal pathway and the accumulation of Lewy bodies—aggregates primarily composed of α-synuclein (α-syn) protein. Neuroinflammation is also recognized as a critical hallmark of PD, and neurodegeneration in general, likely contributing to neuronal damage and disease progression. Interestingly, members of the chitinase protein family, particularly chitinase-3-like protein-1 (CHI3L1), exhibit elevated levels in a number of neurodegenerative conditions and have been implicated in various inflammatory pathways. To explore the role of CHI3L1 in PD, CHI3L1’s expression was examined in both postmortem brain tissue from PD patients and in the recombinant adeno-associated virus (rAAV)-mediated α-syn overexpression rat model of PD. Additionally, characterization of different AAVs was undertaken in efforts to manipulate CHI3L1 expression specifically in astrocytes for future studies, as CHI3L1 is an astrocytic protein. In human post-mortem samples, protein levels of intracellular, extracellular, and total CHI3L1 were significantly higher in the substantia nigra pars compacta (SNpc) samples from PD patients compared to non-diseased controls. Additionally, qualitative histological analyses reveal elevated CHI3L1 expression in the α-syn rat model within the substantia nigra. The presence of elevated CHI3L1 in PD raises the question: Is this increase causal or merely a consequence of the disease? Ongoing research seeks to address this by identifying an astrocyte-specific viral capsid allowing for altering astrocytic CHI3L1 expression in the α-syn model. These efforts aim to distinguish cause from consequence, and uncover the underlying mechanisms driving the association between CHI3L1 levels and neurodegeneration.