Arguing for Lipid Accumulation in Neurons to Contribute to Parkinson’s Disease

Parkinson’s disease is driven by the spread of misfolded α-synuclein and the death of dopaminergic neurons that are vulnerable to the consequences of α-synuclein proteopathy. A fair amount of effort has gone into trying to understand why these neurons become dysfunctional and die, in search of ways to protect them from disease processes. The research noted here is an example of the type, in which scientists point to the evidence for lipid accumulation to take place in these neurons, driving them into a state of cellular senescence. The senescent state is inflammatory and disruptive to surrounding tissue; a growing presence of lingering senescent cells has been demonstrated to contribute to many age-related conditions.

Parkinson’s disease (PD) is an age-related movement disorder caused by the loss of dopaminergic (DA) neurons of the substantia nigra pars compacta (SNpc) of the midbrain, however, the underlying causes of this DA neuron loss in PD is unknown and there are currently no effective treatment options to prevent or slow neuronal loss or the progression of related symptoms. It has been shown that both environmental factors as well as genetic predispositions underpin PD development and recent research has revealed that lysosomal dysfunction and lipid accumulation are contributors to disease progression, where an age-related aggregation of alpha-synuclein as well as lipids have been found in PD patients.

We have recently discovered that artificial induction of lipid accumulation leads to cellular senescence of DA neurons, suggesting that lipid aggregation plays a crucial role in the pathology of PD by driving senescence in these vulnerable DA neurons. We propose that the expression of a cellular senescence phenotype in the most vulnerable neurons in PD can be triggered by lysosomal impairment and lipid aggregation. Importantly, we highlight additional data that perilipin (PLIN2) is significantly upregulated in senescent DA neurons, suggesting an overall enrichment of lipid droplets (LDs) in these cells.

These findings align with our previous results in dopaminergic neurons in highlighting a central role for lipid accumulation in the senescence of DA neurons. Importantly, general lipid droplet aggregation and global lysosomal impairment have been implicated in many neurodegenerative diseases including PD. Taken together, our data suggest a connection between age-related lysosomal impairment, lipid accumulation, and cellular senescence in DA neurons that in turn drives inflammaging in the midbrain and ultimately leads to neurodegeneration and PD.