The Lonafarnib target, Rhes, is uniquely dysregulated in tauopathies: A human postmortem study

Abstract

AbstractBackgroundThe farnesyltransferase inhibitor, Lonafarnib, is capable of reducing tau lesions and associated atrophy in tauopathy models through activity on the Ras GTPase, Rhes (Hernandez I et al., 2019). While hinting at a role of Rhes in tau proteinopathic etiology, it is unclear how Rhes activity changes in human tauopathies or other neurodegenerative diseases. As these models reflect rare, familial forms of tauopathy, we sought to detect evidence of Rhes changes in human sporadic tauopathy versus FTLD‐TDP and synucleinopathies.MethodAllocortical and neocortical sections from postmortem cases (Table 1) representing five different tauopathies, FTLD‐TDP, Lewy body disease, and healthy controls (HC) were immunohistochemically stained for Rhes, proteinopathic lesions (i.e. PHF‐1 positive tau inclusions, phospho‐TDP‐43, or α‐synuclein), and NeuN. Single‐nucleus RNA‐sequencing (snRNA‐seq) was also performed in a separate cohort representing HC and early AD.Result40 cases were examined in this study (Table 1). Rhes is widespread in cortical neurons, as detected by immunohistochemical staining and snRNA‐seq (Figure 1). In tauopathies, neurons either present Rhes as diffuse or punctiform, or feature an absence of Rhes (Figure 2). Accordingly, we classified neurons as Rhes type Diffuse, Punctiform, or Absent. The proportion of neurons with PHF‐1 positive tau inclusions significantly differ between the three neuronal Rhes phenotypes (p < 0.0001) with the majority of Absent type neurons harboring PHF‐1 positive tau inclusions and Diffuse type neurons mostly devoid of PHF‐1 positive tau inclusions (Figure 3, Table 2). Punctiform and Absent type neurons were not detected in neurons with phospho‐TDP‐43 inclusions or α‐synuclein inclusions (Figure 4).ConclusionGiven the distribution of PHF‐1 positive tau inclusions across different Rhes‐deliniated neuronal phenotypes, we propose a model by which Rhes takes on a punctiform phenotype then is ultimately cleared from neurons with tau lesions. This postmortem study in humans, together with in vivo and in vitro work done in familial tauopathy models, suggests the presence of a causal relationship between Rhes clearance and tau proteinopathic lesions, but not phospho‐TDP‐43 or α‐synuclein inclusions. As such, Rhes cellular phenotype represents a novel postmortem hallmark of tauopathy and supports to application of Lonafarnib to the treatment of tauopathies.