Interpreting Continuous Glucose Monitoring Through Metabolic Physiology: A Framework for Precision Nutrition in Type 2 Diabetes.

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by motor symptoms such as rigidity, tremor, bradykinesia, and postural instability, as well as nonmotor symptoms such as cognitive impairments, anxiety, depression, and dementia []. With disease progression, there is a progressive loss of dopaminergic neurons in the substantia nigra pars compacta, accompanied by the accumulation of α-synuclein (α-syn) in Lewy bodies and Lewy neurites across various brain regions []. Lysosomes, which are membrane-bound organelles with an acidic lumen containing hydrolytic enzymes, are primarily responsible for degrading macromolecules and clearing damaged organelles. Dysfunction of lysosomal proteolytic systems is believed to contribute to the accumulation of pathological α-syn aggregation in PD [–]. Genetic insights from genome-wide association studies (GWASs) have strengthened the connection between lysosomal abnormalities and PD susceptibility, identifying multiple risk loci encoding lysosomal components [–]. Among the identified risk loci, genes such as and , which are essential for maintaining lysosomal pH homeostasis, are significantly associated with PD pathogenesis [, ]. The lysosomal enzymes (cathepsin B) and (cathepsin D) are important for lysosomal proteolysis, which are tightly associated with α-syn pathology [, , , ]. A study utilizing correlative light and electron microscopy (CLEM) for the morphological analysis of Lewy bodies in PD patients provided more direct evidence linking lysosomal dysfunction with α-syn pathology, showing that Lewy bodies are composed of large amounts of α-synuclein, lipids, and lysosomal structures []. In addition, in lysosomal storage disorders (LSDs), in which the deficiencies of lysosomal enzymes lead to lysosomal dysfunction, α-syn pathology is present in the brains of patients with various LSDs, further suggesting that there is a close link between lysosomal dysfunction and PD pathology [–]. Among genetic risk factors, mutations in the gene, which are linked to the lysosomal storage disorder Gaucher’s disease, are recognized as the most common genetic risk factor for PD [, ]. The gene encodes glucocerebrosidase (GCase), a lysosomal enzyme responsible for degrading glucosylceramide and glucosylsphingosine []. Deficiency of GCase leads to the accumulation of the lipid substrates glucosylceramide and glucosylsphingosine, which are associated with the aggregation of α-syn [–]. Furthermore, α-syn accumulation may disturb the trafficking of newly synthesized GCase from the endoplasmic reticulum into lysosomes, contributing to a positive pathogenic feedback loop, which further induces α-syn accumulation []. Despite conclusive evidence positioning lysosomal failure as a central driver of PD pathophysiology [, ] and preclinical validation of GCase activation strategies for α-syn clearance [, ], the precise cascade through which GCase insufficiency compromises lysosomal fidelity remains enigmatic.