Retromer dysfunction at the nexus of tauopathies

Abstract

Tauopathies define a broad range of neurodegenerative diseases that encompass pathological aggregation of the microtubuleassociated protein tau. Although tau aggregation is a central feature of these diseases, their underlying pathobiology is remarkably heterogeneous at the molecular level. In this review, we summarize critical differences that account for this heterogeneity and contrast the physiological and pathological functions of tau. We focus on the recent understanding of its prion-like behavior that accounts for its spread in the brain. Moreover, we acknowledge the limited appreciation about how upstream cellular changes influence tauopathy. Dysfunction of the highly conserved endosomal trafficking complex retromer is found in numerous tauopathies such as Alzheimer's disease, Pick's disease, and progressive supranuclear palsy, and we discuss how this has emerged as a major contributor to various aspects of neurodegenerative diseases. In particular, we highlight recent investigations that have elucidated the contribution of retromer dysfunction to distinct measures of tauopathy such as tau hyperphosphorylation, aggregation, and impaired cognition and behavior. Finally, we discuss the potential benefit of targeting retromer for modifying disease burden and identify important considerations with such an approach moving toward clinical translation.

The neuronal retromer can regulate both neuronal and microglial phenotypes of Alzheimer's disease

“…A loss of glutamate receptors is what typifies this early synaptic stage of neurodegeneration ( Yasuda et al, 1995 ; Wakabayashi et al, 1999 ; Qu et al, 2021 ), and we extend previous work in the hippocampal slice ( Temkin et al, 2017 ) to show that this phenotype is regulated by retromer in the intact hippocampus. With respect to tau pathology, retromer has been linked to intraneuronal tauopathy in mouse models ( Carosi et al, 2021 ; Vagnozzi et al, 2019 ) or in IPS neurons derived from patients with AD ( Young et al, 2018 ), but only on the background of preexisting intraneuronal pathology. It is now understood that accelerated tau secretion represents an early and specific manifestation of tau pathology in AD that is distinct from other tauopathies ( Zetterberg, 2017 ), which occurs via active unconventional secretion ( Merezhko et al, 2018 ).…”

Autophagy in major human diseases

“…In recent years, dysfunction of the endosomal‐sorting complex, the retromer, has been linked to a number of neurodegenerative diseases, including AD. Reduced expression of the retromer proteins and variants of the core retromer component VPS35 (vacuolar protein sorting 35) are associated with neurodegenerative diseases, often overlapping with MAPT/tau aggregation in the brain (Carosi et al , 2021 ; Seaman, 2021 ). Recent data demonstrate that the autophagy–lysosomal axis is central for the clearance of aggregated MAPT/tau and depletion of VPS35 blocks autophagy, whereas VPS35 overexpression has the opposite effect (Carosi et al , 2020 ; Carosi et al , 2021 ).…”

“…Reduced expression of the retromer proteins and variants of the core retromer component VPS35 (vacuolar protein sorting 35) are associated with neurodegenerative diseases, often overlapping with MAPT/tau aggregation in the brain (Carosi et al , 2021 ; Seaman, 2021 ). Recent data demonstrate that the autophagy–lysosomal axis is central for the clearance of aggregated MAPT/tau and depletion of VPS35 blocks autophagy, whereas VPS35 overexpression has the opposite effect (Carosi et al , 2020 ; Carosi et al , 2021 ). Thus, the retromer–autophagy axis may play a relevant function in preventing multiple neurodegenerative diseases by ensuring that pathogenic protein aggregates are cleared as they arise.…”

Epidermal Stratification Requires Retromer-Mediated Desmoglein-1 Recycling

“…Lastly, this work identified the retromer as a target for therapeutic intervention in skin disease. Previous work established that the retromer is necessary for HPV infection and identified a HPV specific peptide that inhibits the association of the retromer with the cellular cargo, DMT1-II (Carosi et al, 2021;Lipovsky et al, 2013;Zhang et al, 2020). However, most investigation into the retromer's role in human health has been focused on neurological diseases and tauopathies such as Parkinson's disease, Alzheimer's disease, and ALS (Carosi et al, 2021).…”

“…It is composed of a trimer consisting of VPS35-VPS26-VPS29 with a role in cargo selection, and a Snx component, which plays a role in promoting the formation of dynamic tubulovesicular structures for protein transport (Burd and Cullen, 2014). While a role for retromer dysfunction in neuronal diseases such as Parkinson's, Alzheimer's and amyotrophic lateral sclerosis (ALS) disease is emerging (Carosi et al, 2021), information about retromer in the epidermis is limited to a role in Human Papilloma Virus (HPV) trafficking (Lipovsky et al, 2013). Here we demonstrate that the retromer promotes Dsg1 recycling and accumulation on the plasma membrane to promote epidermal stratification, which is enhanced by a small molecule retromer chaperone called R55.…”