Precision Medicine in Parkinson's Disease: From Genetic Risk Signals to Personalized Therapy

Abstract

Understanding the pathophysiology and genetic background of Parkinson's disease (PD) increases the likelihood of developing effective disease-modifying therapeutic strategies. In particular, the discovery of genetic variants causing or increasing the risk for PD has contributed to refining the clinical, biological, and molecular classification of the disease and has offered new insights into sporadic forms. It is even more evident that specific genetic mutations can show different responses to pharmacological and device-aided therapies. To date, several agents acting on multiple PD-causing pathogenic pathways have been tested as disease-modifying strategies, with disappointing results. This may be caused by the recruitment of PD populations whose underlying molecular pathophysiology is heterogeneous. We believe that an effective model of personalized medicine must be prioritized in the near future. Here, we review the current therapeutic options under clinical and preclinical development for PD and discuss the key pending questions and challenges to face for successful clinical trials. Furthermore, we provide some insights into the role of genetics in guiding the decision-making process on symptomatic and device-aided therapies for PD in daily clinical practice.

Keywords: GBA; Parkinson’s disease; disease-modifying therapy; genetics; precision medicine.

Figure 1

Implicated pathways for α-syn toxicity. (A). Cellular pathways in healthy subjects and PD patients are shown. In PD, there is a disfunction of clearance mechanisms based on autophagia and lysosomal activity leading to an accumulation of aggregated protein, which impair these homeostatic mechanisms promoting protein aggregation. In PD, endoplasmic reticulum and mitochondrial functions are impaired. In turn, pathological α-syn aggregates interact with several cellular proteins and functions, causing synaptic dysfunction and neurodegeneration. (B). Cellular pathways potential targets of disease-modifying therapeutic strategies. [35].

Figure 2

Summarized LRRK2 targeting strategies. LRRK2 dysfunction induces an increase in kinase activity, influencing PD development. Inhibition of LRRK2 kinase activity could prevente or restore several impaired cellular processes (see the text for details). Cross: blocked pathwas; full arrow: promoting activities; dashed arrow: final effect of the strategies. From [145].