β-Arrestin2 arrests the clearance of tau in FTLD

Abstract

Frontotemporal dementia (FTD) comprises a spectrum of clinical syndromes associated with several underlying neurodegenerative diseases. The primary brain areas affected in patients with FTD are the frontal and temporal lobes. As such, FTD is also referred to as frontotemporal lobar degeneration (FTLD) (1). In patients younger than 65 y, FTLD is the second most common cause of neurodegenerative dementia after Alzheimer’s disease (AD), accounting for ∼10% of cases. Clinically, FTD is characterized by progressive deterioration in behavior, personality, and/or language. FTLD neuropathology is characterized by the pathological aggregation of misfolded proteins in neurons and/or glia. Approximately 45% of FTLD cases are characterized by inclusions of the microtubule-binding protein tau (FTLD-tau) and encompass Pick’s disease (PiD), cortical basal degeneration (CBD), progressive supranuclear palsy (PSP), argyrophilic grain disease (AGD), multiple system tauopathy with dementia, neurofibrillary tangle predominant dementia (NFT-dementia), and white matter tauopathy with globular glial inclusions (1, 2). Despite enormous advances in FTLD research over the past 20 y, lack of understanding of the connection between the genetic, phenotypic, and pathological features and the underlying disease mechanisms remains a major gap in the dissection of FTLD pathogenesis. Tau is encoded by the microtubule-associated protein tau ( MAPT ) gene, which consists of 16 exons on chromosome 17q21 (3). The adult human brain contains six main tau isoforms, which are generated by alternative splicing of exons 2, 3, and 10. Tau isoforms differ in the number of amino (N)-terminal inserts (0N, 1N, 2N) and contain either three or four highly conserved microtubule-binding repeat domains (3R and 4R tau, respectively). The alternative splicing of exon 10 generates 3R and 4R tau and is associated with distinct tauopathies, which can be classified into three groups based on the tau isoforms found in the aggregates: 4R tauopathies (e.g., … [↵][1]1Email: amantha{at}pitt.edu. [1]: #xref-corresp-1-1