Author: Asher Agarwal, Class of 2027

Figure 1. A man assisting an old patient with taking their medication.

Parkinson’s Disease (PD) is a neurodegenerative disorder associated with neuronal death, specifically of the dopaminergic (DA) neurons in the region of the brain responsible for motor coordination and control. The death of these neurons, most commonly due to aging, causes a classic triad of symptoms: bradykinesia (slow movement), tremor, and rigidity. The hallmark of PD is the accumulation of a misfolded protein called alpha-synuclein, visible in intracellular inclusions when viewed under a microscope. The potential mechanisms of the pathology behind PD are vast and not completely understood, with no known treatments that can slow disease progression. Recent research has shown that lipid accumulation is a contributor to PD disease progression and that the most common genetic risk factor for PD is the absence of Glucosylceramidase Beta 1 (GBA), which includes lysosomal glucocerebrosidase (GCase), an enzyme that cleaves lipids. The Riessland Lab at Stony Brook University set out to understand the importance of age-related lipid accumulation and its link to inflammation, cellular senescence, and death of DA neurons. They hypothesized lysosomal impairment was causing the expression of a cellular senescence phenotype.

Results from Riessland’s research have found the molecular pathway from lipid buildup to DA neuron impairment and death. They found that the risk factor for PD, genetic regulator SATB1, controls microRNA expression, which in turn regulates GBA expression. Decreased SATB1, therefore, results in glucocerebrosides (GluCer) lipid accumulation, which triggers cellular aging via mitochondrial dysfunction and lysosome overload. The buildup of lipid droplets (LDs) has also been implicated in PD disease progression. The Riessland lab found that, in SATB1 knockouts, LDs were visible under a transmission electron microscope. They also found that PLIN2 was upregulated in these cells, and proposed that LDs form from this upregulation of PLIN2, which is triggered by lysosomal impairment. This LD buildup caused by disease symptoms can further amplify alpha-synuclein aggregation, which reinforces disease progression by worsening neuroinflammation and DA neuron death. 

The Riessland lab had detailed a new mechanistic pathway for PD pathology caused by the absence of the SATB1 genetic risk factor, a known risk factor for PD. This study highlights lipid accumulation, specifically by PLIN2-driven LD formation, as a critical factor underlying DA neuron vulnerability in PD. With further investigation, targeted therapies can be developed to finally slow or stop neuronal loss in PD and other neurodegenerative diseases, rather than just treat the symptoms as the disease inevitably progresses.

Works Cited:

[1] T. Russo and M. Riessland M., Lipid accumulation drives cellular senescence in dopaminergic neurons. Aging 16 (2024). doi: 10.18632/aging.206030 

[2] Image retrieved from: https://www.pexels.com/photo/a-man-in-blue-sweater-sitting-beside-man-in-white-long-sleeves-7551646/.