Emerging strategies for progressive supranuclear palsy (PSP) combination therapies

Progressive supranuclear palsy (PSP) is a neurodegenerative disorder characterised by a combination of motor, ocular, cognitive, and behavioural impairment, but has a heterogeneous clinical presentation. It is a devastating and rapidly progressive atypical parkinsonian disorder with no current disease-modifying treatments. PSP is classified as a primary tauopathy characterised by abnormal accumulation of tau within neurons and glial cells, primarily in the brain stem, culminating in cell death. While genome wide association studies have been instrumental in identifying multiple risk loci, recent multi-omics studies combining brain gene expression and other omics measures have revealed a plethora of perturbed transcripts and molecular pathways that may play pivotal roles in PSP. This includes genes such as MAPT, STOM, KANK2, DDR2, LRRK2, and STX6, but their precise roles remain elusive. These genes are differentially expressed and may regulate processes including neuroinflammation, glymphatic clearance of tau, cytoskeletal maintenance, and synaptic function. In this review, we summarise current treatment strategies attempted in PSP, compile disease-modifying therapies in development, and explore potential disease mechanisms suggested by multi-omics studies. By targeting several underlying disease processes at once, combination strategies have the potential to improve both motor and cognitive function, slow neurodegeneration, and ultimately alter disease progression.